PMC:1942070 / 237-13197 JSON TXT

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2_test

Id	Subject	Object	Predicate	Lexical cue
17349631-10859332-30580518	1111-1112	10859332	denotes	3
17349631-12506120-30580518	1111-1112	12506120	denotes	3
17349631-12506120-30580519	1425-1426	12506120	denotes	6
17349631-9765302-30580519	1425-1426	9765302	denotes	6
17349631-11062248-30580519	1425-1426	11062248	denotes	6
17349631-11410586-30580519	1425-1426	11410586	denotes	6
17349631-15590638-30580520	1570-1571	15590638	denotes	7
17349631-10471840-30580521	1647-1649	10471840	denotes	12
17349631-10856238-30580521	1647-1649	10856238	denotes	12
17349631-11410587-30580521	1647-1649	11410587	denotes	12
17349631-12646243-30580521	1647-1649	12646243	denotes	12
17349631-12676944-30580521	1647-1649	12676944	denotes	12
17349631-11912133-30580522	1757-1759	11912133	denotes	16
17349631-11514571-30580522	1757-1759	11514571	denotes	16
17349631-16899224-30580522	1757-1759	16899224	denotes	16
17349631-12505989-30580523	1789-1791	12505989	denotes	18
17349631-14654790-30580523	1789-1791	14654790	denotes	18
17349631-14563314-30580524	1820-1822	14563314	denotes	19
17349631-16678913-30580525	1981-1983	16678913	denotes	20
17349631-12505989-30580526	2145-2147	12505989	denotes	23
17349631-15604256-30580526	2145-2147	15604256	denotes	23
17349631-15226414-30580526	2145-2147	15226414	denotes	23
17349631-15728188-30580527	2201-2203	15728188	denotes	24
17349631-16875491-30580528	2290-2292	16875491	denotes	25
17349631-16449666-30580529	2471-2473	16449666	denotes	28
17349631-15738054-30580529	2471-2473	15738054	denotes	28
17349631-15623513-30580529	2471-2473	15623513	denotes	28
17349631-15367659-30580529	2471-2473	15367659	denotes	28
17349631-16449666-30580530	2618-2619	16449666	denotes	1
17349631-16449666-30580531	2918-2919	16449666	denotes	1
17349631-16449666-30580532	3685-3686	16449666	denotes	1
17349631-16449666-30580533	3798-3799	16449666	denotes	1
17349631-7730364-30580534	3876-3878	7730364	denotes	29
17349631-16449666-30580535	4585-4586	16449666	denotes	1
17349631-16449666-30580536	5281-5282	16449666	denotes	1
17349631-15728188-30580537	5368-5370	15728188	denotes	24
17349631-16678913-30580538	6786-6788	16678913	denotes	20
17349631-12505989-30580539	8033-8035	12505989	denotes	32
17349631-16166634-30580539	8033-8035	16166634	denotes	32
17349631-16421204-30580539	8033-8035	16421204	denotes	32
17349631-15145937-30580539	8033-8035	15145937	denotes	32
17349631-16006559-30580540	10157-10159	16006559	denotes	35
17349631-14963034-30580540	10157-10159	14963034	denotes	35
17349631-8995387-30580541	10700-10702	8995387	denotes	36
17349631-12505989-30580542	12043-12045	12505989	denotes	37
17349631-15604256-30580542	12043-12045	15604256	denotes	37
17349631-16166634-30580542	12043-12045	16166634	denotes	37
17349631-15024053-30580542	12043-12045	15024053	denotes	37
17349631-15743830-30580543	12140-12142	15743830	denotes	38
17349631-16356855-30580544	12208-12210	16356855	denotes	40
17349631-16301747-30580544	12208-12210	16301747	denotes	40

MyTest

Id	Subject	Object	Predicate	Lexical cue
17349631-10859332-30580518	1111-1112	10859332	denotes	3
17349631-12506120-30580518	1111-1112	12506120	denotes	3
17349631-12506120-30580519	1425-1426	12506120	denotes	6
17349631-9765302-30580519	1425-1426	9765302	denotes	6
17349631-11062248-30580519	1425-1426	11062248	denotes	6
17349631-11410586-30580519	1425-1426	11410586	denotes	6
17349631-15590638-30580520	1570-1571	15590638	denotes	7
17349631-10471840-30580521	1647-1649	10471840	denotes	12
17349631-10856238-30580521	1647-1649	10856238	denotes	12
17349631-11410587-30580521	1647-1649	11410587	denotes	12
17349631-12646243-30580521	1647-1649	12646243	denotes	12
17349631-12676944-30580521	1647-1649	12676944	denotes	12
17349631-11912133-30580522	1757-1759	11912133	denotes	16
17349631-11514571-30580522	1757-1759	11514571	denotes	16
17349631-16899224-30580522	1757-1759	16899224	denotes	16
17349631-12505989-30580523	1789-1791	12505989	denotes	18
17349631-14654790-30580523	1789-1791	14654790	denotes	18
17349631-14563314-30580524	1820-1822	14563314	denotes	19
17349631-16678913-30580525	1981-1983	16678913	denotes	20
17349631-12505989-30580526	2145-2147	12505989	denotes	23
17349631-15604256-30580526	2145-2147	15604256	denotes	23
17349631-15226414-30580526	2145-2147	15226414	denotes	23
17349631-15728188-30580527	2201-2203	15728188	denotes	24
17349631-16875491-30580528	2290-2292	16875491	denotes	25
17349631-16449666-30580529	2471-2473	16449666	denotes	28
17349631-15738054-30580529	2471-2473	15738054	denotes	28
17349631-15623513-30580529	2471-2473	15623513	denotes	28
17349631-15367659-30580529	2471-2473	15367659	denotes	28
17349631-16449666-30580530	2618-2619	16449666	denotes	1
17349631-16449666-30580531	2918-2919	16449666	denotes	1
17349631-16449666-30580532	3685-3686	16449666	denotes	1
17349631-16449666-30580533	3798-3799	16449666	denotes	1
17349631-7730364-30580534	3876-3878	7730364	denotes	29
17349631-16449666-30580535	4585-4586	16449666	denotes	1
17349631-16449666-30580536	5281-5282	16449666	denotes	1
17349631-15728188-30580537	5368-5370	15728188	denotes	24
17349631-16678913-30580538	6786-6788	16678913	denotes	20
17349631-12505989-30580539	8033-8035	12505989	denotes	32
17349631-16166634-30580539	8033-8035	16166634	denotes	32
17349631-16421204-30580539	8033-8035	16421204	denotes	32
17349631-15145937-30580539	8033-8035	15145937	denotes	32
17349631-16006559-30580540	10157-10159	16006559	denotes	35
17349631-14963034-30580540	10157-10159	14963034	denotes	35
17349631-8995387-30580541	10700-10702	8995387	denotes	36
17349631-12505989-30580542	12043-12045	12505989	denotes	37
17349631-15604256-30580542	12043-12045	15604256	denotes	37
17349631-16166634-30580542	12043-12045	16166634	denotes	37
17349631-15024053-30580542	12043-12045	15024053	denotes	37
17349631-15743830-30580543	12140-12142	15743830	denotes	38
17349631-16356855-30580544	12208-12210	16356855	denotes	40
17349631-16301747-30580544	12208-12210	16301747	denotes	40

pmc-enju-pas

Id	Subject	Object	Predicate	Lexical cue
T61	3-15	NN	denotes	B-lymphocyte
T62	16-20	NN	denotes	cell
T63	21-25	NN	denotes	line
T64	27-37	RB	denotes	Previously
T65	38-40	PRP	denotes	we
T66	41-45	VB	denotes	have
T67	46-51	VB	denotes	shown
T68	52-56	IN	denotes	that
T69	57-61	NN	denotes	PKDs
T70	62-66	VB	denotes	have
T71	67-69	DT	denotes	an
T72	70-79	JJ	denotes	essential
T73	80-84	NN	denotes	role
T74	85-87	IN	denotes	in
T75	88-98	VB	denotes	regulating
T76	99-104	NN	denotes	class
T77	105-107	CD	denotes	II
T78	108-115	NN	denotes	histone
T79	116-128	NN	denotes	deacetylases
T80	129-131	IN	denotes	in
T81	132-136	NN	denotes	DT40
T82	137-144	NN	denotes	B-cells
T83	145-146	-LRB-	denotes	[
T84	146-154	NNP	denotes	Matthews
T85	154-155	-COMMA-	denotes	,
T86	156-160	NNP	denotes	S.A.
T87	160-161	-COMMA-	denotes	,
T88	162-165	NNP	denotes	Liu
T89	165-166	-COMMA-	denotes	,
T90	167-169	NNP	denotes	P.
T91	169-170	-COMMA-	denotes	,
T92	171-179	NNP	denotes	Spitaler
T93	179-180	-COMMA-	denotes	,
T94	181-183	NNP	denotes	M.
T95	183-184	-COMMA-	denotes	,
T96	185-190	NNP	denotes	Olson
T97	190-191	-COMMA-	denotes	,
T98	192-196	NNP	denotes	E.N.
T99	196-197	-COMMA-	denotes	,
T100	198-206	NNP	denotes	McKinsey
T101	206-207	-COMMA-	denotes	,
T102	208-212	NNP	denotes	T.A.
T103	212-213	-COMMA-	denotes	,
T104	214-222	NNP	denotes	Cantrell
T105	222-223	-COMMA-	denotes	,
T106	224-228	NNP	denotes	D.A.
T107	229-232	CC	denotes	and
T108	233-244	NNP	denotes	Scharenberg
T109	244-245	-COMMA-	denotes	,
T110	246-250	NNP	denotes	A.M.
T111	251-252	-LRB-	denotes	(
T112	252-256	CD	denotes	2006
T113	256-257	-RRB-	denotes	)
T114	258-267	JJ	denotes	Essential
T115	268-272	NN	denotes	role
T116	273-276	IN	denotes	for
T117	277-284	NN	denotes	protein
T118	285-291	NN	denotes	kinase
T119	292-293	NN	denotes	D
T120	294-300	NN	denotes	family
T121	301-308	NN	denotes	kinases
T122	309-311	IN	denotes	in
T123	312-315	DT	denotes	the
T124	316-326	NN	denotes	regulation
T125	327-329	IN	denotes	of
T126	330-335	NN	denotes	class
T127	336-338	CD	denotes	II
T128	339-346	NN	denotes	histone
T129	347-359	NN	denotes	deacetylases
T130	360-362	IN	denotes	in
T131	363-364	NN	denotes	B
T132	365-376	NN	denotes	lymphocytes
T133	378-382	NNP	denotes	Mol.
T134	383-387	NNP	denotes	Cell
T135	388-393	NNP	denotes	Biol.
T136	394-396	CD	denotes	26
T137	396-397	-COMMA-	denotes	,
T138	398-407	CD	denotes	1569–1577
T139	407-408	-RRB-	denotes	]
T140	410-412	PRP	denotes	We
T141	413-416	RB	denotes	now
T142	417-421	VB	denotes	show
T143	422-426	IN	denotes	that
T144	427-431	NN	denotes	PKDs
T145	432-435	VB	denotes	are
T146	436-440	RB	denotes	also
T147	441-449	VB	denotes	required
T148	450-452	TO	denotes	to
T149	453-461	VB	denotes	regulate
T150	462-467	NN	denotes	HSP27
T151	468-483	NN	denotes	phosphorylation
T152	484-486	IN	denotes	in
T153	487-491	NN	denotes	DT40
T154	492-499	NN	denotes	B-cells
T155	501-508	RB	denotes	However
T156	508-509	-COMMA-	denotes	,
T157	510-512	IN	denotes	in
T158	513-521	NN	denotes	contrast
T159	522-524	TO	denotes	to
T160	525-533	JJ	denotes	previous
T161	534-546	NN	denotes	observations
T162	547-549	IN	denotes	in
T163	550-555	JJ	denotes	other
T164	556-560	NN	denotes	cell
T165	561-566	NN	denotes	types
T166	566-567	-COMMA-	denotes	,
T167	568-571	NN	denotes	PKD
T168	572-579	NN	denotes	enzymes
T169	580-582	VB	denotes	do
T170	583-586	RB	denotes	not
T171	587-595	VB	denotes	regulate
T172	596-601	JJ	denotes	basic
T173	602-610	JJ	denotes	cellular
T174	611-620	NN	denotes	processes
T175	621-625	JJ	denotes	such
T176	626-628	IN	denotes	as
T177	629-642	NN	denotes	proliferation
T178	643-645	CC	denotes	or
T179	646-654	NN	denotes	survival
T180	655-664	NN	denotes	responses
T181	664-665	-COMMA-	denotes	,
T182	666-669	CC	denotes	nor
T183	670-674	NN	denotes	NFκB
T184	675-690	JJ	denotes	transcriptional
T185	691-699	NN	denotes	activity
T186	700-710	RB	denotes	downstream
T187	711-713	IN	denotes	of
T188	714-717	DT	denotes	the
T189	718-719	NN	denotes	B
T190	720-724	NN	denotes	cell
T191	725-732	NN	denotes	antigen
T192	733-741	NN	denotes	receptor
T193	743-747	RB	denotes	Thus
T194	747-748	-COMMA-	denotes	,
T195	749-753	NN	denotes	PKDs
T196	754-758	VB	denotes	have
T197	759-760	DT	denotes	a
T198	761-770	JJ	denotes	selective
T199	771-775	NN	denotes	role
T200	776-778	IN	denotes	in
T201	779-783	NN	denotes	DT40
T202	784-790	NN	denotes	B-cell
T203	791-798	NN	denotes	biology
T532	398-820	NN	denotes	1569–1577]. We now show that PKDs are also required to regulate HSP27 phosphorylation in DT40 B-cells. However, in contrast to previous observations in other cell types, PKD enzymes do not regulate basic cellular processes such as proliferation or survival responses, nor NFκB transcriptional activity downstream of the B cell antigen receptor. Thus, PKDs have a selective role in DT40 B-cell biology. 1 Introduction The
T533	821-828	NN	denotes	protein
T534	829-835	NN	denotes	kinase
T535	836-837	NN	denotes	D
T536	838-839	-LRB-	denotes	(
T537	839-842	NN	denotes	PKD
T538	842-843	-RRB-	denotes	)
T539	844-860	NN	denotes	serine/threonine
T540	861-867	NN	denotes	kinase
T541	868-874	NN	denotes	family
T542	875-878	VB	denotes	has
T543	879-884	CD	denotes	three
T544	885-892	NN	denotes	members
T545	892-893	-COLON-	denotes	:
T546	894-898	NN	denotes	PKD1
T547	898-899	-COMMA-	denotes	,
T548	900-904	NN	denotes	PKD2
T549	905-908	CC	denotes	and
T550	909-913	NN	denotes	PKD3
T551	915-919	JJ	denotes	Most
T552	920-924	NN	denotes	cell
T553	925-930	NN	denotes	types
T554	931-938	VB	denotes	express
T555	939-941	IN	denotes	at
T556	942-947	JJ	denotes	least
T557	948-951	CD	denotes	two
T558	952-955	NN	denotes	PKD
T559	956-964	NN	denotes	isoforms
T560	965-968	CC	denotes	but
T561	969-972	NN	denotes	PKD
T562	973-980	NN	denotes	enzymes
T563	981-984	VB	denotes	are
T564	985-995	RB	denotes	especially
T565	996-1002	RB	denotes	highly
T566	1003-1012	VB	denotes	expressed
T567	1013-1015	IN	denotes	in
T568	1016-1030	JJ	denotes	haematopoietic
T569	1031-1036	NN	denotes	cells
T570	1036-1037	-COMMA-	denotes	,
T571	1038-1043	WRB	denotes	where
T572	1044-1048	PRP	denotes	they
T573	1049-1052	VB	denotes	are
T574	1053-1062	VB	denotes	activated
T575	1063-1065	IN	denotes	in
T576	1066-1074	NN	denotes	response
T577	1075-1077	TO	denotes	to
T578	1078-1085	NN	denotes	antigen
T579	1086-1095	NN	denotes	receptors
T580	1096-1107	NN	denotes	stimulation
T581	1108-1109	-LRB-	denotes	[
T582	1109-1112	CD	denotes	2,3
T583	1112-1113	-RRB-	denotes	]
T584	1115-1116	DT	denotes	A
T585	1117-1126	VB	denotes	conserved
T586	1127-1137	NN	denotes	signalling
T587	1138-1145	NN	denotes	pathway
T588	1146-1153	VB	denotes	linking
T589	1154-1161	NN	denotes	antigen
T590	1162-1171	NN	denotes	receptors
T591	1172-1174	TO	denotes	to
T592	1175-1179	NN	denotes	PKDs
T593	1180-1188	VB	denotes	involves
T594	1189-1192	DT	denotes	the
T595	1193-1203	NN	denotes	activation
T596	1204-1206	IN	denotes	of
T597	1207-1211	NN	denotes	PLCγ
T598	1212-1215	CC	denotes	and
T599	1216-1219	DT	denotes	the
T600	1220-1230	JJ	denotes	subsequent
T601	1231-1241	NN	denotes	production
T602	1242-1244	IN	denotes	of
T603	1245-1259	NN	denotes	diacylglycerol
T604	1260-1261	-LRB-	denotes	(
T605	1261-1264	NN	denotes	DAG
T606	1264-1265	-RRB-	denotes	)
T607	1266-1271	WDT	denotes	which
T608	1272-1282	VB	denotes	stimulates
T609	1283-1292	JJ	denotes	classical
T610	1293-1299	CC	denotes	and/or
T611	1300-1305	JJ	denotes	novel
T612	1306-1313	NN	denotes	protein
T613	1314-1320	NN	denotes	kinase
T614	1321-1323	NN	denotes	Cs
T615	1324-1325	-LRB-	denotes	(
T616	1325-1328	NN	denotes	PKC
T617	1328-1329	-RRB-	denotes	)
T618	1330-1334	WDT	denotes	that
T619	1335-1348	VB	denotes	phosphorylate
T620	1349-1352	CD	denotes	two
T621	1353-1356	JJ	denotes	key
T622	1357-1367	JJ	denotes	regulatory
T623	1368-1374	NN	denotes	serine
T624	1375-1383	NN	denotes	residues
T625	1384-1386	IN	denotes	in
T626	1387-1390	DT	denotes	the
T627	1391-1401	NN	denotes	activation
T628	1402-1406	NN	denotes	loop
T629	1407-1409	IN	denotes	of
T630	1410-1413	NN	denotes	PKD
T631	1414-1421	NN	denotes	kinases
T632	1422-1423	-LRB-	denotes	[
T633	1423-1426	CD	denotes	3–6
T634	1426-1427	-RRB-	denotes	]
T635	1429-1432	DT	denotes	The
T636	1433-1443	JJ	denotes	N-terminal
T637	1444-1454	JJ	denotes	regulatory
T638	1455-1461	NN	denotes	region
T639	1462-1464	IN	denotes	of
T640	1465-1468	NN	denotes	PKD
T641	1469-1476	NN	denotes	enzymes
T642	1477-1485	VB	denotes	contains
T643	1486-1487	DT	denotes	a
T644	1488-1491	NN	denotes	DAG
T645	1492-1499	NN	denotes	binding
T646	1500-1506	NN	denotes	domain
T647	1507-1510	CC	denotes	and
T648	1511-1517	JJ	denotes	direct
T649	1518-1525	NN	denotes	binding
T650	1526-1528	IN	denotes	of
T651	1529-1532	NN	denotes	DAG
T652	1533-1537	RB	denotes	also
T653	1538-1549	VB	denotes	contributes
T654	1550-1552	TO	denotes	to
T655	1553-1557	NN	denotes	PKD1
T656	1558-1568	NN	denotes	activation
T657	1569-1570	-LRB-	denotes	[
T658	1570-1571	CD	denotes	7
T659	1571-1572	-RRB-	denotes	]
T660	1573-1575	RB	denotes	as
T661	1576-1580	RB	denotes	well
T662	1581-1583	IN	denotes	as
T663	1584-1594	VB	denotes	regulating
T664	1595-1598	DT	denotes	the
T665	1599-1606	JJ	denotes	spatial
T666	1607-1615	NN	denotes	location
T667	1616-1618	IN	denotes	of
T668	1619-1622	NN	denotes	PKD
T669	1623-1630	NN	denotes	enzymes
T670	1631-1637	IN	denotes	within
T671	1638-1643	NN	denotes	cells
T672	1644-1645	-LRB-	denotes	[
T673	1645-1649	CD	denotes	8–12
T674	1649-1650	-RRB-	denotes	]
T675	1652-1655	NN	denotes	PKD
T676	1656-1663	NN	denotes	enzymes
T677	1664-1668	VB	denotes	have
T678	1669-1673	VB	denotes	been
T679	1674-1682	VB	denotes	proposed
T680	1683-1685	TO	denotes	to
T681	1686-1694	VB	denotes	regulate
T682	1695-1703	JJ	denotes	numerous
T683	1704-1712	JJ	denotes	cellular
T684	1713-1722	NN	denotes	functions
T685	1722-1723	-COMMA-	denotes	,
T686	1724-1733	VB	denotes	including
T687	1734-1738	NN	denotes	cell
T688	1739-1752	NN	denotes	proliferation
T689	1753-1754	-LRB-	denotes	[
T690	1754-1759	CD	denotes	13–16
T691	1759-1760	-RRB-	denotes	]
T692	1760-1761	-COMMA-	denotes	,
T693	1762-1776	JJ	denotes	anti-apoptotic
T694	1777-1784	NN	denotes	signals
T695	1785-1786	-LRB-	denotes	[
T696	1786-1791	CD	denotes	17,18
T697	1791-1792	-RRB-	denotes	]
T698	1793-1796	CC	denotes	and
T699	1797-1806	NN	denotes	thymocyte
T700	1807-1818	NN	denotes	development
T701	1819-1820	-LRB-	denotes	[
T702	1820-1822	CD	denotes	19
T703	1822-1823	-RRB-	denotes	]
T704	1825-1835	NN	denotes	Expression
T705	1836-1838	IN	denotes	of
T706	1839-1845	JJ	denotes	mutant
T707	1846-1859	RB	denotes	catalytically
T708	1860-1868	JJ	denotes	inactive
T709	1869-1872	CC	denotes	and
T710	1873-1887	RB	denotes	constitutively
T711	1888-1897	VB	denotes	activated
T712	1898-1902	NN	denotes	PKDs
T713	1903-1906	MD	denotes	can
T714	1907-1911	RB	denotes	also
T715	1912-1918	VB	denotes	modify
T716	1919-1924	NNP	denotes	Golgi
T717	1925-1933	NN	denotes	function
T718	1933-1934	-COMMA-	denotes	,
T719	1935-1939	NN	denotes	cell
T720	1940-1948	NN	denotes	adhesion
T721	1949-1952	CC	denotes	and
T722	1953-1957	NN	denotes	cell
T723	1958-1966	NN	denotes	motility
T724	1967-1968	-LRB-	denotes	(
T725	1968-1976	VB	denotes	reviewed
T726	1977-1979	IN	denotes	in
T727	1980-1981	-LRB-	denotes	[
T728	1981-1983	CD	denotes	20
T729	1983-1984	-RRB-	denotes	]
T730	1984-1985	-RRB-	denotes	)
T731	1987-1989	IN	denotes	In
T732	1990-2000	JJ	denotes	particular
T733	2000-2001	-COMMA-	denotes	,
T734	2002-2006	NN	denotes	PKDs
T735	2007-2011	VB	denotes	have
T736	2012-2016	VB	denotes	been
T737	2017-2023	RB	denotes	widely
T738	2024-2030	VB	denotes	linked
T739	2031-2033	TO	denotes	to
T740	2034-2037	DT	denotes	the
T741	2038-2048	NN	denotes	activation
T742	2049-2051	IN	denotes	of
T743	2052-2055	DT	denotes	the
T744	2056-2060	NN	denotes	NFκB
T745	2061-2074	NN	denotes	transcription
T746	2075-2081	NN	denotes	factor
T747	2082-2085	CC	denotes	and
T748	2086-2088	IN	denotes	in
T749	2089-2099	VB	denotes	regulating
T750	2100-2104	NN	denotes	cell
T751	2105-2113	NN	denotes	survival
T752	2114-2120	IN	denotes	during
T753	2121-2130	JJ	denotes	oxidative
T754	2131-2137	NN	denotes	stress
T755	2138-2139	-LRB-	denotes	[
T756	2139-2147	CD	denotes	17,21–23
T757	2147-2148	-RRB-	denotes	]
T758	2150-2157	DT	denotes	Another
T759	2158-2166	RB	denotes	recently
T760	2167-2175	VB	denotes	proposed
T761	2176-2180	NN	denotes	PKD1
T762	2181-2190	NN	denotes	substrate
T763	2191-2193	VB	denotes	is
T764	2194-2199	NN	denotes	HSP27
T765	2200-2201	-LRB-	denotes	[
T766	2201-2203	CD	denotes	24
T767	2203-2204	-RRB-	denotes	]
T768	2204-2205	-COMMA-	denotes	,
T769	2206-2207	DT	denotes	a
T770	2208-2213	JJ	denotes	small
T771	2214-2218	NN	denotes	heat
T772	2219-2224	NN	denotes	shock
T773	2225-2232	NN	denotes	protein
T774	2233-2241	VB	denotes	involved
T775	2242-2244	IN	denotes	in
T776	2245-2255	VB	denotes	regulating
T777	2256-2260	NN	denotes	cell
T778	2261-2270	NN	denotes	migration
T779	2271-2274	CC	denotes	and
T780	2275-2279	NN	denotes	cell
T781	2280-2288	NN	denotes	survival
T782	2289-2290	-LRB-	denotes	[
T783	2290-2292	CD	denotes	25
T784	2292-2293	-RRB-	denotes	]
T785	2295-2297	DT	denotes	An
T786	2298-2307	JJ	denotes	essential
T787	2308-2312	NN	denotes	role
T788	2313-2316	IN	denotes	for
T789	2317-2320	NN	denotes	PKD
T790	2321-2328	NN	denotes	enzymes
T791	2329-2331	IN	denotes	in
T792	2332-2342	VB	denotes	regulating
T793	2343-2348	NN	denotes	class
T794	2349-2351	CD	denotes	II
T795	2352-2359	NN	denotes	histone
T796	2360-2372	NN	denotes	deacetylases
T797	2373-2374	-LRB-	denotes	(
T798	2374-2379	NN	denotes	HDACs
T799	2379-2380	-RRB-	denotes	)
T800	2380-2381	-COMMA-	denotes	,
T801	2382-2389	NN	denotes	enzymes
T802	2390-2394	WDT	denotes	that
T803	2395-2402	VB	denotes	repress
T804	2403-2417	JJ	denotes	MEF2-dependent
T805	2418-2422	NN	denotes	gene
T806	2423-2436	NN	denotes	transcription
T807	2436-2437	-COMMA-	denotes	,
T808	2438-2441	VB	denotes	has
T809	2442-2446	RB	denotes	also
T810	2447-2451	VB	denotes	been
T811	2452-2464	VB	denotes	demonstrated
T812	2465-2466	-LRB-	denotes	[
T813	2466-2473	CD	denotes	1,26–28
T814	2473-2474	-RRB-	denotes	]
T815	2476-2478	TO	denotes	To
T816	2479-2490	VB	denotes	investigate
T817	2491-2494	DT	denotes	the
T818	2495-2505	JJ	denotes	biological
T819	2506-2510	NN	denotes	role
T820	2511-2513	IN	denotes	of
T821	2514-2518	NN	denotes	PKDs
T822	2519-2521	PRP	denotes	we
T823	2522-2526	VB	denotes	have
T824	2527-2536	VB	denotes	generated
T825	2537-2541	NN	denotes	DT40
T826	2542-2543	NN	denotes	B
T827	2544-2548	NN	denotes	cell
T828	2549-2554	NN	denotes	lines
T829	2555-2559	WDT	denotes	that
T830	2560-2564	VB	denotes	lack
T831	2565-2575	NN	denotes	expression
T832	2576-2578	IN	denotes	of
T833	2579-2582	CD	denotes	one
T834	2583-2585	CC	denotes	or
T835	2586-2590	JJ	denotes	more
T836	2591-2598	NN	denotes	members
T837	2599-2601	IN	denotes	of
T838	2602-2605	DT	denotes	the
T839	2606-2609	NN	denotes	PKD
T840	2610-2616	NN	denotes	family
T841	2617-2618	-LRB-	denotes	[
T842	2618-2619	CD	denotes	1
T843	2619-2620	-RRB-	denotes	]
T844	2620-2621	-COMMA-	denotes	,
T845	2622-2630	VB	denotes	allowing
T846	2631-2633	PRP	denotes	us
T847	2634-2636	TO	denotes	to
T848	2637-2648	VB	denotes	investigate
T849	2649-2652	DT	denotes	the
T850	2653-2661	NN	denotes	function
T851	2661-2662	-LRB-	denotes	(
T852	2662-2663	NN	denotes	s
T853	2663-2664	-RRB-	denotes	)
T854	2665-2667	IN	denotes	of
T855	2668-2671	NN	denotes	PKD
T856	2672-2680	NN	denotes	isoforms
T857	2681-2690	VB	denotes	following
T858	2691-2692	NN	denotes	B
T859	2693-2697	NN	denotes	cell
T860	2698-2705	NN	denotes	antigen
T861	2706-2714	NN	denotes	receptor
T862	2715-2716	-LRB-	denotes	(
T863	2716-2719	NN	denotes	BCR
T864	2719-2720	-RRB-	denotes	)
T865	2721-2732	NN	denotes	stimulation
T866	2732-2733	-COMMA-	denotes	,
T867	2734-2736	RB	denotes	as
T868	2737-2741	RB	denotes	well
T869	2742-2752	VB	denotes	addressing
T870	2753-2756	DT	denotes	the
T871	2757-2762	NN	denotes	issue
T872	2763-2765	IN	denotes	of
T873	2766-2776	JJ	denotes	functional
T874	2777-2787	NN	denotes	redundancy
T875	2788-2795	IN	denotes	between
T876	2796-2799	DT	denotes	the
T877	2800-2809	JJ	denotes	different
T878	2810-2813	NN	denotes	PKD
T879	2814-2820	NN	denotes	family
T880	2821-2828	NN	denotes	members
T881	2830-2838	JJ	denotes	Previous
T882	2839-2846	NN	denotes	studies
T883	2847-2851	VB	denotes	have
T884	2852-2857	VB	denotes	shown
T885	2858-2862	IN	denotes	that
T886	2863-2867	NN	denotes	PKDs
T887	2868-2871	VB	denotes	are
T888	2872-2885	JJ	denotes	indispensable
T889	2886-2889	IN	denotes	for
T890	2890-2894	NN	denotes	HDAC
T891	2895-2905	NN	denotes	regulation
T892	2906-2908	IN	denotes	in
T893	2909-2910	NN	denotes	B
T894	2911-2916	NN	denotes	cells
T895	2917-2918	-LRB-	denotes	[
T896	2918-2919	CD	denotes	1
T897	2919-2920	-RRB-	denotes	]
T898	2922-2928	RB	denotes	Herein
T899	2929-2931	PRP	denotes	we
T900	2932-2936	VB	denotes	show
T901	2937-2941	IN	denotes	that
T902	2942-2946	NN	denotes	PKDs
T903	2947-2950	VB	denotes	are
T904	2951-2955	RB	denotes	also
T905	2956-2969	JJ	denotes	indispensable
T906	2970-2973	IN	denotes	for
T907	2974-2979	NN	denotes	HSP27
T908	2980-2995	NN	denotes	phosphorylation
T909	2996-2998	IN	denotes	in
T910	2999-3000	NN	denotes	B
T911	3001-3006	NN	denotes	cells
T912	3008-3015	RB	denotes	However
T913	3015-3016	-COMMA-	denotes	,
T914	3017-3025	JJ	denotes	PKD-null
T915	3026-3030	NN	denotes	DT40
T916	3031-3032	NN	denotes	B
T917	3033-3038	NN	denotes	cells
T918	3039-3042	VB	denotes	are
T919	3043-3049	JJ	denotes	viable
T920	3050-3053	CC	denotes	and
T921	3054-3065	VB	denotes	proliferate
T922	3066-3074	RB	denotes	normally
T923	3076-3084	RB	denotes	Moreover
T924	3084-3085	-COMMA-	denotes	,
T925	3086-3090	NN	denotes	loss
T926	3091-3093	IN	denotes	of
T927	3094-3097	DT	denotes	the
T928	3098-3104	JJ	denotes	entire
T929	3105-3113	JJ	denotes	cellular
T930	3114-3118	NN	denotes	pool
T931	3119-3121	IN	denotes	of
T932	3122-3125	NN	denotes	PKD
T933	3126-3130	VB	denotes	does
T934	3131-3134	RB	denotes	not
T935	3135-3145	RB	denotes	critically
T936	3146-3152	VB	denotes	affect
T937	3153-3162	JJ	denotes	oxidative
T938	3163-3169	NN	denotes	stress
T939	3170-3179	NN	denotes	responses
T940	3180-3182	IN	denotes	in
T941	3183-3184	NN	denotes	B
T942	3185-3190	NN	denotes	cells
T943	3191-3194	CC	denotes	nor
T944	3195-3197	VB	denotes	do
T945	3198-3201	NN	denotes	PKD
T946	3202-3209	NN	denotes	kinases
T947	3210-3214	VB	denotes	play
T948	3215-3217	DT	denotes	an
T949	3218-3227	JJ	denotes	essential
T950	3228-3232	NN	denotes	role
T951	3233-3235	IN	denotes	in
T952	3236-3246	VB	denotes	regulating
T953	3247-3251	NN	denotes	NFκB
T954	3252-3267	JJ	denotes	transcriptional
T955	3268-3276	NN	denotes	activity
T956	3278-3286	RB	denotes	Together
T957	3286-3287	-COMMA-	denotes	,
T958	3288-3293	DT	denotes	these
T959	3294-3302	NN	denotes	findings
T960	3303-3309	VB	denotes	reveal
T961	3310-3314	IN	denotes	that
T962	3315-3317	IN	denotes	in
T963	3318-3319	NN	denotes	B
T964	3320-3331	NN	denotes	lymphocytes
T965	3331-3332	-COMMA-	denotes	,
T966	3333-3336	NN	denotes	PKD
T967	3337-3344	NN	denotes	kinases
T968	3345-3348	VB	denotes	are
T969	3349-3352	RB	denotes	not
T970	3353-3361	JJ	denotes	critical
T971	3362-3372	NN	denotes	regulators
T972	3373-3375	IN	denotes	of
T973	3376-3380	JJ	denotes	many
T974	3381-3383	IN	denotes	of
T975	3384-3387	DT	denotes	the
T976	3388-3396	JJ	denotes	cellular
T977	3397-3406	NN	denotes	processes
T978	3407-3417	RB	denotes	previously
T979	3418-3426	VB	denotes	ascribed
T980	3427-3429	TO	denotes	to
T981	3430-3434	PRP	denotes	them
T982	3435-3437	IN	denotes	in
T983	3438-3443	JJ	denotes	other
T984	3444-3452	JJ	denotes	cellular
T985	3453-3460	NN	denotes	systems
T1675	3499-3506	NN	denotes	culture
T1676	3506-3507	-COMMA-	denotes	,
T1677	3508-3517	JJ	denotes	transient
T1678	3518-3531	NN	denotes	transfections
T1679	3532-3535	CC	denotes	and
T1680	3536-3540	NN	denotes	cell
T1681	3541-3552	NN	denotes	stimulation
T1682	3553-3556	DT	denotes	The
T1683	3557-3567	NN	denotes	generation
T1684	3567-3568	-COMMA-	denotes	,
T1685	3569-3576	NN	denotes	culture
T1686	3577-3580	CC	denotes	and
T1687	3581-3591	NN	denotes	activation
T1688	3592-3594	IN	denotes	of
T1689	3595-3602	NN	denotes	PKD1−/−
T1690	3602-3603	-COMMA-	denotes	,
T1691	3604-3611	NN	denotes	PKD3−/−
T1692	3612-3615	CC	denotes	and
T1693	3616-3625	NN	denotes	PKD1/3−/−
T1694	3626-3634	NN	denotes	knockout
T1695	3635-3639	NN	denotes	DT40
T1696	3640-3641	NN	denotes	B
T1697	3642-3646	NN	denotes	cell
T1698	3647-3652	NN	denotes	lines
T1699	3653-3657	VB	denotes	have
T1700	3658-3662	VB	denotes	been
T1701	3663-3672	VB	denotes	described
T1702	3673-3683	RB	denotes	previously
T1703	3684-3685	-LRB-	denotes	[
T1704	3685-3686	CD	denotes	1
T1705	3686-3687	-RRB-	denotes	]
T1706	3689-3694	NN	denotes	Cells
T1707	3695-3699	VB	denotes	were
T1708	3700-3705	VB	denotes	lysed
T1709	3706-3709	CC	denotes	and
T1710	3710-3717	NN	denotes	protein
T1711	3718-3726	NN	denotes	extracts
T1712	3727-3731	VB	denotes	were
T1713	3732-3740	VB	denotes	analysed
T1714	3741-3743	IN	denotes	in
T1715	3744-3751	JJ	denotes	Western
T1716	3752-3760	NN	denotes	blotting
T1717	3761-3772	NN	denotes	experiments
T1718	3773-3775	IN	denotes	as
T1719	3776-3786	RB	denotes	previously
T1720	3787-3796	VB	denotes	described
T1721	3797-3798	-LRB-	denotes	[
T1873	3914-3915	-LRB-	denotes	(
T1874	3915-3922	CD	denotes	2 × 106
T1875	3923-3928	NN	denotes	cells
T1876	3929-3932	IN	denotes	per
T1877	3933-3938	NN	denotes	point
T1878	3938-3939	-RRB-	denotes	)
T1879	3940-3944	VB	denotes	were
T1880	3945-3956	VB	denotes	resuspended
T1881	3957-3959	IN	denotes	in
T1882	3960-3966	NN	denotes	200 μl
T1883	3967-3973	NN	denotes	buffer
T1884	3974-3975	-LRB-	denotes	(
T1885	3975-3979	NN	denotes	RPMI
T1886	3980-3984	CD	denotes	1640
T1887	3985-3990	NN	denotes	media
T1888	3990-3991	-COMMA-	denotes	,
T1889	3992-3993	CD	denotes	1
T1890	3993-3994	NN	denotes	%
T1891	3995-4001	JJ	denotes	foetal
T1892	4002-4006	NN	denotes	calf
T1893	4007-4012	NN	denotes	serum
T1894	4012-4013	-RRB-	denotes	)
T1895	4014-4024	VB	denotes	containing
T1896	4025-4037	JJ	denotes	anti-chicken
T1897	4038-4040	NN	denotes	M1
T1898	4041-4051	JJ	denotes	monoclonal
T1899	4052-4060	NN	denotes	antibody
T1900	4061-4071	VB	denotes	conjugated
T1901	4072-4074	TO	denotes	to
T1902	4075-4079	NN	denotes	FITC
T1903	4080-4083	IN	denotes	for
T1904	4084-4090	NN	denotes	20 min
T1905	4091-4093	IN	denotes	on
T1906	4094-4097	NN	denotes	ice
T1907	4099-4102	DT	denotes	The
T1908	4103-4108	NN	denotes	cells
T1909	4109-4113	VB	denotes	were
T1910	4114-4120	VB	denotes	washed
T1911	4121-4126	RB	denotes	twice
T1912	4127-4130	CC	denotes	and
T1913	4131-4142	JJ	denotes	fluorescent
T1914	4143-4152	NN	denotes	intensity
T1915	4153-4156	VB	denotes	was
T1916	4157-4165	VB	denotes	analysed
T1917	4166-4168	IN	denotes	by
T1918	4169-4173	NN	denotes	flow
T1919	4174-4183	NN	denotes	cytometry
T1920	4185-4188	DT	denotes	All
T1921	4189-4196	NN	denotes	results
T1922	4197-4202	VB	denotes	shown
T1923	4203-4206	VB	denotes	are
T1924	4207-4221	JJ	denotes	representative
T1925	4222-4224	IN	denotes	of
T1926	4225-4227	IN	denotes	at
T1927	4228-4231	CD	denotes	two
T1928	4232-4234	TO	denotes	to
T1929	4235-4239	CD	denotes	four
T1930	4240-4251	JJ	denotes	independent
T1931	4252-4263	NN	denotes	experiments
T1932	4264-4270	IN	denotes	unless
T1933	4271-4280	RB	denotes	otherwise
T1934	4281-4290	VB	denotes	indicated
T2289	4315-4317	IN	denotes	of
T2290	4318-4323	NN	denotes	HSP27
T2291	4324-4339	NN	denotes	phosphorylation
T2292	4340-4342	IN	denotes	in
T2293	4343-4347	NN	denotes	DT40
T2294	4348-4349	NN	denotes	B
T2295	4350-4355	NN	denotes	cells
T2296	4356-4363	VB	denotes	lacking
T2297	4364-4374	NN	denotes	expression
T2298	4375-4377	IN	denotes	of
T2299	4378-4381	NN	denotes	PKD
T2300	4382-4388	NN	denotes	family
T2301	4389-4396	NN	denotes	kinases
T2302	4397-4401	NN	denotes	DT40
T2303	4402-4403	NN	denotes	B
T2304	4404-4409	NN	denotes	cells
T2305	4410-4417	VB	denotes	express
T2306	4418-4421	CD	denotes	two
T2307	4422-4425	NN	denotes	PKD
T2308	4426-4434	NN	denotes	isoforms
T2309	4434-4435	-COMMA-	denotes	,
T2310	4436-4440	NN	denotes	PKD1
T2311	4441-4444	CC	denotes	and
T2312	4445-4449	NN	denotes	PKD3
T2313	4449-4450	-COMMA-	denotes	,
T2314	4451-4454	CC	denotes	and
T2315	4455-4457	IN	denotes	as
T2316	4458-4468	RB	denotes	previously
T2317	4469-4478	VB	denotes	described
T2318	4479-4481	PRP	denotes	we
T2319	4482-4486	VB	denotes	have
T2320	4487-4495	RB	denotes	recently
T2321	4496-4505	VB	denotes	generated
T2322	4506-4510	NN	denotes	DT40
T2323	4511-4512	NN	denotes	B
T2324	4513-4517	NN	denotes	cell
T2325	4518-4523	NN	denotes	lines
T2326	4524-4528	WDT	denotes	that
T2327	4529-4533	VB	denotes	lack
T2328	4534-4544	NN	denotes	expression
T2329	4545-4547	IN	denotes	of
T2330	4548-4554	CC	denotes	either
T2331	4555-4559	NN	denotes	PKD1
T2332	4560-4562	CC	denotes	or
T2333	4563-4567	NN	denotes	PKD3
T2334	4568-4570	CC	denotes	or
T2335	4571-4575	DT	denotes	both
T2336	4576-4583	NN	denotes	enzymes
T2337	4584-4585	-LRB-	denotes	[
T2338	4585-4586	CD	denotes	1
T2339	4586-4587	-RRB-	denotes	]
T2340	4589-4591	IN	denotes	In
T2341	4592-4602	VB	denotes	generating
T2342	4603-4606	DT	denotes	the
T2343	4607-4613	JJ	denotes	double
T2344	4614-4622	NN	denotes	knockout
T2345	4623-4627	NN	denotes	cell
T2346	4628-4633	NN	denotes	lines
T2347	4634-4636	PRP	denotes	we
T2348	4637-4645	VB	denotes	targeted
T2349	4646-4649	DT	denotes	the
T2350	4650-4654	NN	denotes	PKD1
T2351	4655-4659	NN	denotes	loci
T2352	4660-4662	IN	denotes	in
T2353	4663-4664	DT	denotes	a
T2354	4665-4672	NN	denotes	PKD3−/−
T2355	4673-4677	NN	denotes	cell
T2356	4678-4682	NN	denotes	line
T2357	4683-4687	WDT	denotes	that
T2358	4688-4697	VB	denotes	expressed
T2359	4698-4699	DT	denotes	a
T2360	4700-4709	NN	denotes	Flag-PKD3
T2361	4710-4719	NN	denotes	transgene
T2362	4720-4725	IN	denotes	under
T2363	4726-4729	DT	denotes	the
T2364	4730-4737	NN	denotes	control
T2365	4738-4740	IN	denotes	of
T2366	4741-4742	DT	denotes	a
T2367	4743-4764	JJ	denotes	doxycycline-inducible
T2368	4765-4773	NN	denotes	promoter
T2369	4775-4780	RB	denotes	Hence
T2370	4780-4781	-COMMA-	denotes	,
T2371	4782-4784	IN	denotes	in
T2372	4785-4788	DT	denotes	the
T2373	4789-4797	NN	denotes	presence
T2374	4798-4800	IN	denotes	of
T2375	4801-4812	NN	denotes	doxycycline
T2376	4812-4813	-COMMA-	denotes	,
T2377	4814-4823	NN	denotes	Flag-PKD3
T2378	4824-4834	NN	denotes	expression
T2379	4835-4837	IN	denotes	in
T2380	4838-4844	NN	denotes	PKD1/3
T2381	4845-4851	JJ	denotes	double
T2382	4852-4860	JJ	denotes	knockout
T2383	4861-4866	NN	denotes	cells
T2384	4867-4869	VB	denotes	is
T2385	4870-4880	JJ	denotes	comparable
T2386	4881-4883	TO	denotes	to
T2387	4884-4894	JJ	denotes	endogenous
T2388	4895-4899	NN	denotes	PKD3
T2389	4900-4907	JJ	denotes	present
T2390	4908-4910	IN	denotes	in
T2391	4911-4920	JJ	denotes	wild-type
T2392	4921-4925	NN	denotes	DT40
T2393	4926-4931	NN	denotes	cells
T2394	4932-4935	CC	denotes	and
T2395	4936-4943	NN	denotes	removal
T2396	4944-4946	IN	denotes	of
T2397	4947-4958	NN	denotes	doxycycline
T2398	4959-4963	IN	denotes	from
T2399	4964-4967	DT	denotes	the
T2400	4968-4975	NN	denotes	culture
T2401	4976-4981	NN	denotes	media
T2402	4982-4985	IN	denotes	for
T2403	4986-4987	CD	denotes	5
T2404	4988-4992	NN	denotes	days
T2405	4993-5000	VB	denotes	results
T2406	5001-5003	IN	denotes	in
T2407	5004-5005	DT	denotes	a
T2408	5006-5016	RB	denotes	completely
T2409	5017-5021	JJ	denotes	null
T2410	5022-5025	NN	denotes	PKD
T2411	5026-5035	NN	denotes	phenotype
T2412	5036-5037	-LRB-	denotes	(
T2413	5037-5041	NN	denotes	Fig.
T2414	5042-5044	NN	denotes	1A
T2415	5044-5045	-RRB-	denotes	)
T2416	5047-5057	RB	denotes	Previously
T2417	5057-5058	-COMMA-	denotes	,
T2418	5059-5061	PRP	denotes	we
T2419	5062-5066	VB	denotes	have
T2420	5067-5079	VB	denotes	demonstrated
T2421	5080-5084	IN	denotes	that
T2422	5085-5100	NN	denotes	phosphorylation
T2423	5101-5104	CC	denotes	and
T2424	5105-5112	JJ	denotes	nuclear
T2425	5113-5122	NN	denotes	exclusion
T2426	5123-5125	IN	denotes	of
T2427	5126-5131	NN	denotes	class
T2428	5132-5134	CD	denotes	II
T2429	5135-5142	NN	denotes	histone
T2430	5143-5155	NN	denotes	deacetylases
T2431	5156-5157	-LRB-	denotes	(
T2432	5157-5162	NN	denotes	HDACs
T2433	5162-5163	-RRB-	denotes	)
T2434	5164-5170	IN	denotes	during
T2435	5171-5174	NN	denotes	BCR
T2436	5175-5185	NN	denotes	engagement
T2437	5186-5188	VB	denotes	is
T2438	5189-5198	JJ	denotes	defective
T2439	5199-5201	IN	denotes	in
T2440	5202-5211	NN	denotes	PKD1/3−/−
T2441	5212-5213	NN	denotes	B
T2442	5214-5219	NN	denotes	cells
T2443	5220-5223	CC	denotes	and
T2444	5224-5227	MD	denotes	can
T2445	5228-5236	VB	denotes	restored
T2446	5237-5241	IN	denotes	upon
T2447	5242-5255	NN	denotes	re-expression
T2448	5256-5258	IN	denotes	of
T2449	5259-5260	DT	denotes	a
T2450	5261-5267	JJ	denotes	single
T2451	5268-5271	NN	denotes	PKD
T2452	5272-5279	NN	denotes	isoform
T2453	5280-5281	-LRB-	denotes	[
T2454	5281-5282	CD	denotes	1
T2455	5282-5283	-RRB-	denotes	]
T2456	5285-5288	DT	denotes	The
T2457	5289-5294	JJ	denotes	small
T2458	5295-5299	NN	denotes	heat
T2459	5300-5305	NN	denotes	shock
T2460	5306-5313	NN	denotes	protein
T2461	5314-5319	NN	denotes	HSP27
T2462	5320-5323	VB	denotes	has
T2463	5324-5332	RB	denotes	recently
T2464	5333-5337	VB	denotes	been
T2465	5338-5346	VB	denotes	proposed
T2466	5347-5349	IN	denotes	as
T2467	5350-5351	DT	denotes	a
T2468	5352-5356	NN	denotes	PKD1
T2469	5357-5366	NN	denotes	substrate
T2470	5367-5368	-LRB-	denotes	[
T2471	5368-5370	CD	denotes	24
T2472	5370-5371	-RRB-	denotes	]
T2473	5372-5375	CC	denotes	and
T2474	5376-5378	PRP	denotes	we
T2475	5379-5390	RB	denotes	accordingly
T2476	5391-5399	VB	denotes	assessed
T2477	5400-5407	IN	denotes	whether
T2478	5408-5416	JJ	denotes	PKD-null
T2479	5417-5421	NN	denotes	DT40
T2480	5422-5427	NN	denotes	cells
T2481	5428-5432	VB	denotes	have
T2482	5433-5442	JJ	denotes	defective
T2483	5443-5458	NN	denotes	phosphorylation
T2484	5459-5461	IN	denotes	of
T2485	5462-5467	NN	denotes	HSP27
T2486	5468-5470	IN	denotes	on
T2487	5471-5477	NN	denotes	serine
T2488	5478-5480	CD	denotes	82
T2489	5480-5481	-COMMA-	denotes	,
T2490	5482-5485	DT	denotes	the
T2491	5486-5494	VB	denotes	proposed
T2492	5495-5499	NN	denotes	PKD1
T2493	5500-5509	NN	denotes	substrate
T2494	5510-5518	NN	denotes	sequence
T2495	5520-5522	PRP	denotes	We
T2496	5523-5532	RB	denotes	initially
T2497	5533-5545	VB	denotes	investigated
T2498	5546-5549	DT	denotes	the
T2499	5550-5560	NN	denotes	regulation
T2500	5561-5563	IN	denotes	of
T2501	5564-5569	NN	denotes	HSP27
T2502	5570-5585	NN	denotes	phosphorylation
T2503	5586-5588	IN	denotes	in
T2504	5589-5595	JJ	denotes	single
T2505	5596-5604	NN	denotes	knockout
T2506	5605-5609	NN	denotes	DT40
T2507	5610-5611	NN	denotes	B
T2508	5612-5617	NN	denotes	cells
T2509	5618-5625	VB	denotes	lacking
T2510	5626-5632	CC	denotes	either
T2511	5633-5637	NN	denotes	PKD1
T2512	5638-5640	CC	denotes	or
T2513	5641-5645	NN	denotes	PKD3
T2514	5647-5649	IN	denotes	As
T2515	5650-5655	VB	denotes	shown
T2516	5656-5658	IN	denotes	in
T2517	5659-5663	NNP	denotes	Fig.
T2518	5664-5666	NN	denotes	1B
T2519	5666-5667	-COMMA-	denotes	,
T2520	5668-5678	NN	denotes	activation
T2521	5679-5681	IN	denotes	of
T2522	5682-5685	DT	denotes	the
T2523	5686-5689	NN	denotes	BCR
T2524	5690-5692	CC	denotes	or
T2525	5693-5702	NN	denotes	treatment
T2526	5703-5707	IN	denotes	with
T2527	5708-5711	DT	denotes	the
T2528	5712-5723	JJ	denotes	DAG-mimetic
T2529	5724-5728	NN	denotes	PdBu
T2530	5729-5738	VB	denotes	increased
T2531	5739-5742	DT	denotes	the
T2532	5743-5749	NN	denotes	levels
T2533	5750-5752	IN	denotes	of
T2534	5753-5758	NN	denotes	HSP27
T2535	5759-5774	NN	denotes	phosphorylation
T2536	5775-5777	IN	denotes	at
T2537	5778-5781	NN	denotes	S82
T2538	5782-5784	IN	denotes	in
T2539	5785-5794	JJ	denotes	wild-type
T2540	5795-5799	NN	denotes	DT40
T2541	5800-5801	NN	denotes	B
T2542	5802-5807	NN	denotes	cells
T2543	5809-5812	NN	denotes	BCR
T2544	5813-5816	CC	denotes	and
T2545	5817-5824	NN	denotes	phorbol
T2546	5825-5830	NN	denotes	ester
T2547	5831-5838	NN	denotes	signals
T2548	5839-5843	VB	denotes	were
T2549	5844-5848	RB	denotes	also
T2550	5849-5853	JJ	denotes	able
T2551	5854-5856	TO	denotes	to
T2552	5857-5865	VB	denotes	increase
T2553	5866-5871	NN	denotes	HSP27
T2554	5872-5887	NN	denotes	phosphorylation
T2555	5888-5890	IN	denotes	in
T2556	5891-5895	NN	denotes	PKD1
T2557	5896-5898	CC	denotes	or
T2558	5899-5903	NN	denotes	PKD3
T2559	5904-5910	JJ	denotes	single
T2560	5911-5919	NN	denotes	knockout
T2561	5920-5924	NN	denotes	DT40
T2562	5925-5926	NN	denotes	B
T2563	5927-5932	NN	denotes	cells
T2564	5933-5934	-LRB-	denotes	(
T2565	5934-5938	NN	denotes	Fig.
T2566	5939-5941	NN	denotes	1B
T2567	5941-5942	-RRB-	denotes	)
T2568	5944-5951	RB	denotes	However
T2569	5951-5952	-COMMA-	denotes	,
T2570	5953-5957	NN	denotes	BCR-
T2571	5958-5961	CC	denotes	and
T2572	5962-5969	NN	denotes	phorbol
T2573	5970-5983	JJ	denotes	ester-induced
T2574	5984-5999	NN	denotes	phosphorylation
T2575	6000-6002	IN	denotes	of
T2576	6003-6008	NN	denotes	HSP27
T2577	6009-6011	IN	denotes	on
T2578	6012-6015	NN	denotes	S82
T2579	6016-6019	VB	denotes	was
T2580	6020-6029	VB	denotes	abolished
T2581	6030-6032	IN	denotes	in
T2582	6033-6034	NN	denotes	B
T2583	6035-6040	NN	denotes	cells
T2584	6041-6045	WDT	denotes	that
T2585	6046-6052	VB	denotes	lacked
T2586	6053-6057	CC	denotes	both
T2587	6058-6062	NN	denotes	PKD1
T2588	6063-6066	CC	denotes	and
T2589	6067-6071	NN	denotes	PKD3
T2590	6072-6073	-LRB-	denotes	(
T2591	6073-6077	NN	denotes	Fig.
T2592	6078-6080	NN	denotes	1C
T2593	6080-6081	-RRB-	denotes	)
T2594	6083-6096	RB	denotes	Significantly
T2595	6096-6097	-COMMA-	denotes	,
T2596	6098-6117	JJ	denotes	doxycycline-induced
T2597	6118-6128	NN	denotes	expression
T2598	6129-6131	IN	denotes	of
T2599	6132-6135	DT	denotes	the
T2600	6136-6145	NN	denotes	Flag-PKD3
T2601	6146-6155	NN	denotes	transgene
T2602	6156-6158	IN	denotes	in
T2603	6159-6162	DT	denotes	the
T2604	6163-6169	JJ	denotes	double
T2605	6170-6178	NN	denotes	knockout
T2606	6179-6184	NN	denotes	cells
T2607	6185-6188	VB	denotes	was
T2608	6189-6199	JJ	denotes	sufficient
T2609	6200-6202	TO	denotes	to
T2610	6203-6210	VB	denotes	restore
T2611	6211-6217	JJ	denotes	normal
T2612	6218-6228	NN	denotes	regulation
T2613	6229-6231	IN	denotes	of
T2614	6232-6237	NN	denotes	HSP27
T2615	6238-6253	NN	denotes	phosphorylation
T2616	6254-6255	-LRB-	denotes	(
T2617	6255-6259	NN	denotes	Fig.
T2618	6260-6262	NN	denotes	1C
T2619	6262-6263	-RRB-	denotes	)
T2620	6265-6267	IN	denotes	In
T2621	6268-6276	NN	denotes	contrast
T2622	6276-6277	-COMMA-	denotes	,
T2623	6278-6288	NN	denotes	expression
T2624	6289-6291	IN	denotes	of
T2625	6292-6293	DT	denotes	a
T2626	6294-6310	JJ	denotes	kinase-deficient
T2627	6311-6315	NN	denotes	PKD3
T2628	6316-6322	JJ	denotes	mutant
T2629	6323-6330	NN	denotes	protein
T2630	6331-6333	IN	denotes	in
T2631	6334-6337	DT	denotes	the
T2632	6338-6344	JJ	denotes	double
T2633	6345-6353	NN	denotes	knockout
T2634	6354-6359	NN	denotes	cells
T2635	6360-6363	VB	denotes	was
T2636	6364-6367	RB	denotes	not
T2637	6368-6372	JJ	denotes	able
T2638	6373-6375	TO	denotes	to
T2639	6376-6383	VB	denotes	restore
T2640	6384-6388	NN	denotes	BCR-
T2641	6389-6391	CC	denotes	or
T2642	6392-6399	NN	denotes	phorbol
T2643	6400-6413	JJ	denotes	ester-induced
T2644	6414-6419	NN	denotes	HSP27
T2645	6420-6435	NN	denotes	phosphorylation
T2646	6436-6437	-LRB-	denotes	(
T2647	6437-6441	NN	denotes	Fig.
T2648	6442-6444	NN	denotes	1D
T2649	6444-6445	-RRB-	denotes	)
T2650	6447-6452	RB	denotes	Hence
T2651	6452-6453	-COMMA-	denotes	,
T2652	6454-6458	NN	denotes	PKD3
T2653	6459-6461	RB	denotes	as
T2654	6462-6466	RB	denotes	well
T2655	6467-6469	IN	denotes	as
T2656	6470-6474	NN	denotes	PKD1
T2657	6475-6478	MD	denotes	can
T2658	6479-6487	VB	denotes	regulate
T2659	6488-6493	NN	denotes	HSP27
T2660	6494-6509	NN	denotes	phosphorylation
T2661	6510-6513	CC	denotes	and
T2662	6514-6516	IN	denotes	in
T2663	6517-6521	NN	denotes	DT40
T2664	6522-6523	NN	denotes	B
T2665	6524-6529	NN	denotes	cells
T2666	6530-6534	PRP	denotes	they
T2667	6535-6538	VB	denotes	are
T2668	6539-6551	RB	denotes	functionally
T2669	6552-6561	JJ	denotes	redundant
T2670	6562-6564	IN	denotes	as
T2671	6565-6570	NN	denotes	HSP27
T2672	6571-6578	NN	denotes	kinases
T3837	6595-6608	NN	denotes	proliferation
T3838	6609-6612	CC	denotes	and
T3839	6613-6621	NN	denotes	survival
T3840	6622-6624	IN	denotes	in
T3841	6625-6629	NN	denotes	DT40
T3842	6630-6631	NN	denotes	B
T3843	6632-6637	NN	denotes	cells
T3844	6638-6645	VB	denotes	lacking
T3845	6646-6656	NN	denotes	expression
T3846	6657-6659	IN	denotes	of
T3847	6660-6663	NN	denotes	PKD
T3848	6664-6670	NN	denotes	family
T3849	6671-6678	NN	denotes	kinases
T3850	6679-6682	NN	denotes	PKD
T3851	6683-6690	NN	denotes	enzymes
T3852	6691-6695	VB	denotes	have
T3853	6696-6706	RB	denotes	previously
T3854	6707-6711	VB	denotes	been
T3855	6712-6718	VB	denotes	linked
T3856	6719-6721	TO	denotes	to
T3857	6722-6725	DT	denotes	the
T3858	6726-6736	NN	denotes	regulation
T3859	6737-6739	IN	denotes	of
T3860	6740-6744	NN	denotes	cell
T3861	6745-6758	NN	denotes	proliferation
T3862	6759-6762	CC	denotes	and
T3863	6763-6771	NN	denotes	survival
T3864	6772-6773	-LRB-	denotes	(
T3865	6773-6781	VB	denotes	reviewed
T3866	6782-6784	IN	denotes	in
T3867	6785-6786	-LRB-	denotes	[
T3868	6786-6788	CD	denotes	20
T3869	6788-6789	-RRB-	denotes	]
T3870	6789-6790	-RRB-	denotes	)
T3871	6792-6794	TO	denotes	To
T3872	6795-6806	VB	denotes	investigate
T3873	6807-6810	DT	denotes	the
T3874	6811-6817	NN	denotes	effect
T3875	6818-6822	IN	denotes	that
T3876	6823-6827	NN	denotes	loss
T3877	6828-6830	IN	denotes	of
T3878	6831-6834	NN	denotes	PKD
T3879	6835-6842	NN	denotes	kinases
T3880	6843-6846	VB	denotes	had
T3881	6847-6849	IN	denotes	on
T3882	6850-6851	NN	denotes	B
T3883	6852-6856	NN	denotes	cell
T3884	6857-6865	NN	denotes	survival
T3885	6866-6872	CC	denotes	and/or
T3886	6873-6886	NN	denotes	proliferation
T3887	6887-6889	PRP	denotes	we
T3888	6890-6898	VB	denotes	cultured
T3889	6899-6908	JJ	denotes	wild-type
T3890	6909-6912	CC	denotes	and
T3891	6913-6921	JJ	denotes	PKD-null
T3892	6922-6927	NN	denotes	cells
T3893	6928-6930	IN	denotes	in
T3894	6931-6934	DT	denotes	the
T3895	6935-6943	NN	denotes	presence
T3896	6944-6945	-LRB-	denotes	(
T3897	6945-6954	NN	denotes	PKD1/3−/−
T3898	6954-6955	-COLON-	denotes	:
T3899	6956-6968	NN	denotes	Flag-PKD3+ve
T3900	6968-6969	-RRB-	denotes	)
T3901	6970-6972	CC	denotes	or
T3902	6973-6980	NN	denotes	absence
T3903	6981-6982	-LRB-	denotes	(
T3904	6982-6991	NN	denotes	PKD1/3−/−
T3905	6991-6992	-RRB-	denotes	)
T3906	6993-6995	IN	denotes	of
T3907	6996-7007	NN	denotes	doxycycline
T3908	7008-7011	CC	denotes	and
T3909	7012-7021	VB	denotes	monitored
T3910	7022-7033	JJ	denotes	exponential
T3911	7034-7040	NN	denotes	growth
T3912	7042-7044	IN	denotes	As
T3913	7045-7050	VB	denotes	shown
T3914	7051-7053	IN	denotes	in
T3915	7054-7058	NNP	denotes	Fig.
T3916	7059-7061	NN	denotes	2A
T3917	7061-7062	-COMMA-	denotes	,
T3918	7063-7072	NN	denotes	PKD1/3−/−
T3919	7073-7078	NN	denotes	cells
T3920	7079-7091	VB	denotes	proliferated
T3921	7092-7105	RB	denotes	exponentially
T3922	7106-7109	CC	denotes	and
T3923	7110-7123	NN	denotes	re-expression
T3924	7124-7126	IN	denotes	of
T3925	7127-7136	NN	denotes	Flag-PKD3
T3926	7137-7139	IN	denotes	in
T3927	7140-7145	DT	denotes	these
T3928	7146-7151	NN	denotes	cells
T3929	7152-7155	VB	denotes	had
T3930	7156-7158	DT	denotes	no
T3931	7159-7165	NN	denotes	impact
T3932	7166-7168	IN	denotes	on
T3933	7169-7172	DT	denotes	the
T3934	7173-7177	NN	denotes	rate
T3935	7178-7180	IN	denotes	of
T3936	7181-7194	NN	denotes	proliferation
T3937	7196-7207	RB	denotes	Furthermore
T3938	7207-7208	-COMMA-	denotes	,
T3939	7209-7212	DT	denotes	the
T3940	7213-7222	NN	denotes	viability
T3941	7223-7225	IN	denotes	of
T3942	7226-7235	NN	denotes	PKD1/3−/−
T3943	7236-7237	NN	denotes	B
T3944	7238-7243	NN	denotes	cells
T3945	7244-7250	IN	denotes	during
T3946	7251-7258	JJ	denotes	routine
T3947	7259-7268	NN	denotes	culturing
T3948	7269-7272	VB	denotes	was
T3949	7273-7276	RB	denotes	not
T3950	7277-7290	RB	denotes	significantly
T3951	7291-7300	JJ	denotes	different
T3952	7301-7305	IN	denotes	from
T3953	7306-7310	DT	denotes	that
T3954	7311-7313	IN	denotes	of
T3955	7314-7323	JJ	denotes	wild-type
T3956	7324-7325	NN	denotes	B
T3957	7326-7331	NN	denotes	cells
T3958	7332-7333	-LRB-	denotes	(
T3959	7333-7337	NN	denotes	data
T3960	7338-7341	RB	denotes	not
T3961	7342-7347	VB	denotes	shown
T3962	7347-7348	-RRB-	denotes	)
T3963	7350-7352	PRP	denotes	It
T3964	7353-7356	VB	denotes	was
T3965	7357-7362	VB	denotes	noted
T3966	7363-7367	IN	denotes	that
T3967	7368-7371	DT	denotes	the
T3968	7372-7382	NN	denotes	population
T3969	7383-7391	NN	denotes	doubling
T3970	7392-7396	NN	denotes	time
T3971	7397-7399	IN	denotes	of
T3972	7400-7409	NN	denotes	PKD1/3−/−
T3973	7410-7415	NN	denotes	cells
T3974	7416-7419	VB	denotes	was
T3975	7420-7428	RB	denotes	slightly
T3976	7429-7435	JJ	denotes	slower
T3977	7436-7440	IN	denotes	than
T3978	7441-7445	DT	denotes	that
T3979	7446-7448	IN	denotes	of
T3980	7449-7453	JJ	denotes	wild
T3981	7454-7458	NN	denotes	type
T3982	7459-7463	NN	denotes	DT40
T3983	7464-7469	NN	denotes	cells
T3984	7470-7471	-LRB-	denotes	(
T3985	7471-7483	CD	denotes	12.7 ± 2.8 h
T3986	7484-7490	IN	denotes	versus
T3987	7491-7503	CD	denotes	10.2 ± 0.4 h
T3988	7503-7504	-RRB-	denotes	)
T3989	7505-7508	CC	denotes	but
T3990	7509-7512	DT	denotes	the
T3991	7513-7520	NN	denotes	failure
T3992	7521-7523	IN	denotes	of
T3993	7524-7528	NN	denotes	PKD3
T3994	7529-7542	NN	denotes	re-expression
T3995	7543-7545	TO	denotes	to
T3996	7546-7552	VB	denotes	modify
T3997	7553-7556	DT	denotes	the
T3998	7557-7570	NN	denotes	proliferation
T3999	7571-7575	NN	denotes	rate
T4000	7576-7578	IN	denotes	of
T4001	7579-7588	NN	denotes	PKD1/3−/−
T4002	7589-7594	NN	denotes	cells
T4003	7595-7603	VB	denotes	suggests
T4004	7604-7608	IN	denotes	that
T4005	7609-7614	DT	denotes	these
T4006	7615-7620	JJ	denotes	small
T4007	7621-7632	NN	denotes	differences
T4008	7633-7637	VB	denotes	were
T4009	7638-7642	RB	denotes	most
T4010	7643-7649	RB	denotes	likely
T4011	7650-7653	DT	denotes	the
T4012	7654-7660	NN	denotes	result
T4013	7661-7663	IN	denotes	of
T4014	7664-7670	JJ	denotes	clonal
T4015	7671-7680	NN	denotes	variation
T4016	7681-7684	CC	denotes	and
T4017	7685-7689	VB	denotes	were
T4018	7690-7693	RB	denotes	not
T4019	7694-7700	VB	denotes	caused
T4020	7701-7713	RB	denotes	specifically
T4021	7714-7716	IN	denotes	by
T4022	7717-7721	NN	denotes	loss
T4023	7722-7724	IN	denotes	of
T4024	7725-7728	NN	denotes	PKD
T4025	7729-7736	NN	denotes	enzymes
T4026	7738-7742	RB	denotes	Thus
T4027	7742-7743	-COMMA-	denotes	,
T4028	7744-7747	NN	denotes	PKD
T4029	7748-7754	NN	denotes	family
T4030	7755-7762	NN	denotes	enzymes
T4031	7763-7766	VB	denotes	are
T4032	7767-7770	RB	denotes	not
T4033	7771-7780	JJ	denotes	essential
T4034	7781-7784	IN	denotes	for
T4035	7785-7795	VB	denotes	regulating
T4036	7796-7801	JJ	denotes	basal
T4037	7802-7810	NN	denotes	survival
T4038	7811-7814	CC	denotes	and
T4039	7815-7828	NN	denotes	proliferation
T4040	7829-7831	IN	denotes	of
T4041	7832-7836	NN	denotes	DT40
T4042	7837-7838	NN	denotes	B
T4043	7839-7844	NN	denotes	cells
T4044	7846-7849	NN	denotes	PKD
T4045	7850-7857	NN	denotes	enzymes
T4046	7857-7858	-COMMA-	denotes	,
T4047	7859-7871	RB	denotes	specifically
T4048	7872-7876	NN	denotes	PKD1
T4049	7877-7880	CC	denotes	and
T4050	7881-7885	NN	denotes	PKD2
T4051	7885-7886	-COMMA-	denotes	,
T4052	7887-7891	VB	denotes	have
T4053	7892-7902	RB	denotes	previously
T4054	7903-7907	VB	denotes	been
T4055	7908-7914	VB	denotes	linked
T4056	7915-7917	TO	denotes	to
T4057	7918-7919	DT	denotes	a
T4058	7920-7930	JJ	denotes	protective
T4059	7931-7935	NN	denotes	role
T4060	7936-7943	IN	denotes	against
T4061	7944-7953	JJ	denotes	oxidative
T4062	7954-7968	JJ	denotes	stress-induced
T4063	7969-7975	NN	denotes	injury
T4064	7976-7978	IN	denotes	in
T4065	7979-7982	NN	denotes	3T3
T4066	7983-7993	NN	denotes	fibroblast
T4067	7993-7994	-COMMA-	denotes	,
T4068	7995-7999	NN	denotes	HeLa
T4069	8000-8003	CC	denotes	and
T4070	8004-8014	JJ	denotes	epithelial
T4071	8015-8019	NN	denotes	cell
T4072	8020-8025	NN	denotes	lines
T4073	8026-8027	-LRB-	denotes	[
T4074	8027-8035	CD	denotes	17,30–32
T4075	8035-8036	-RRB-	denotes	]
T4076	8038-8040	PRP	denotes	We
T4077	8041-8050	RB	denotes	therefore
T4078	8051-8060	VB	denotes	addressed
T4079	8061-8064	DT	denotes	the
T4080	8065-8069	NN	denotes	role
T4081	8070-8072	IN	denotes	of
T4082	8073-8076	NN	denotes	PKD
T4083	8077-8083	NN	denotes	family
T4084	8084-8091	NN	denotes	kinases
T4085	8092-8094	IN	denotes	in
T4086	8095-8105	VB	denotes	regulating
T4087	8106-8107	NN	denotes	B
T4088	8108-8112	NN	denotes	cell
T4089	8113-8121	NN	denotes	survival
T4090	8122-8124	IN	denotes	in
T4091	8125-8133	NN	denotes	response
T4092	8134-8136	TO	denotes	to
T4093	8137-8146	JJ	denotes	oxidative
T4094	8147-8153	NN	denotes	stress
T4095	8154-8157	CC	denotes	and
T4096	8158-8163	JJ	denotes	other
T4097	8164-8170	NN	denotes	stress
T4098	8171-8178	NN	denotes	stimuli
T4099	8180-8182	IN	denotes	As
T4100	8183-8188	VB	denotes	shown
T4101	8189-8191	IN	denotes	in
T4102	8192-8196	NNP	denotes	Fig.
T4103	8197-8199	NN	denotes	2B
T4104	8199-8200	-COMMA-	denotes	,
T4105	8201-8205	NN	denotes	loss
T4106	8206-8208	IN	denotes	of
T4107	8209-8215	NN	denotes	PKD1/3
T4108	8216-8226	NN	denotes	expression
T4109	8227-8230	VB	denotes	had
T4110	8231-8233	DT	denotes	no
T4111	8234-8245	JJ	denotes	significant
T4112	8246-8252	NN	denotes	impact
T4113	8253-8255	IN	denotes	on
T4114	8256-8259	DT	denotes	the
T4115	8260-8268	NN	denotes	survival
T4116	8269-8271	IN	denotes	of
T4117	8272-8276	NN	denotes	DT40
T4118	8277-8278	NN	denotes	B
T4119	8279-8284	NN	denotes	cells
T4120	8285-8287	IN	denotes	in
T4121	8288-8296	NN	denotes	response
T4122	8297-8299	TO	denotes	to
T4123	8300-8313	JJ	denotes	mitochondrial
T4124	8314-8320	NN	denotes	stress
T4125	8321-8328	NN	denotes	stimuli
T4126	8329-8330	-LRB-	denotes	(
T4127	8330-8334	NN	denotes	H2O2
T4128	8335-8337	CC	denotes	or
T4129	8338-8343	NN	denotes	serum
T4130	8344-8355	NN	denotes	deprivation
T4131	8355-8356	-RRB-	denotes	)
T4132	8356-8357	-COLON-	denotes	;
T4133	8358-8361	NN	denotes	DNA
T4134	8362-8370	NN	denotes	damaging
T4135	8371-8377	NN	denotes	agents
T4136	8378-8379	-LRB-	denotes	(
T4137	8379-8388	NN	denotes	etoposide
T4138	8389-8391	CC	denotes	or
T4139	8392-8403	NN	denotes	doxorubicin
T4140	8403-8404	-RRB-	denotes	)
T4141	8404-8405	-COLON-	denotes	;
T4142	8406-8408	NN	denotes	ER
T4143	8409-8416	NN	denotes	pathway
T4144	8417-8423	NN	denotes	stress
T4145	8424-8427	IN	denotes	due
T4146	8428-8430	TO	denotes	to
T4147	8431-8438	NN	denotes	calcium
T4148	8439-8447	NN	denotes	overload
T4149	8448-8449	-LRB-	denotes	(
T4150	8449-8461	NN	denotes	thapsigargin
T4151	8461-8462	-RRB-	denotes	)
T4152	8463-8465	CC	denotes	or
T4153	8466-8475	VB	denotes	following
T4154	8476-8485	VB	denotes	prolonged
T4155	8486-8495	NN	denotes	treatment
T4156	8496-8500	IN	denotes	with
T4157	8501-8508	NN	denotes	phorbol
T4158	8509-8515	NN	denotes	esters
T4159	8516-8518	CC	denotes	or
T4160	8519-8531	NN	denotes	Trichostatin
T4161	8532-8533	NN	denotes	A
T4162	8533-8534	-COMMA-	denotes	,
T4163	8535-8537	DT	denotes	an
T4164	8538-8547	NN	denotes	inhibitor
T4165	8548-8550	IN	denotes	of
T4166	8551-8556	NN	denotes	class
T4167	8557-8561	NN	denotes	I/II
T4168	8562-8567	NN	denotes	HDACs
T4169	8569-8573	RB	denotes	Thus
T4170	8573-8574	-COMMA-	denotes	,
T4171	8575-8578	NN	denotes	PKD
T4172	8579-8586	NN	denotes	kinases
T4173	8587-8589	VB	denotes	do
T4174	8590-8593	RB	denotes	not
T4175	8594-8598	VB	denotes	play
T4176	8599-8601	DT	denotes	an
T4177	8602-8611	JJ	denotes	essential
T4178	8612-8616	NN	denotes	role
T4179	8617-8619	IN	denotes	in
T4180	8620-8630	VB	denotes	regulating
T4181	8631-8632	NN	denotes	B
T4182	8633-8637	NN	denotes	cell
T4183	8638-8646	NN	denotes	survival
T4184	8647-8649	IN	denotes	in
T4185	8650-8658	NN	denotes	response
T4186	8659-8661	TO	denotes	to
T4187	8662-8663	DT	denotes	a
T4188	8664-8669	NN	denotes	range
T4189	8670-8672	IN	denotes	of
T4190	8673-8682	JJ	denotes	different
T4191	8683-8689	NN	denotes	stress
T4192	8690-8697	NN	denotes	stimuli
T5032	8713-8721	NN	denotes	receptor
T5033	8722-8731	VB	denotes	regulated
T5034	8732-8742	NN	denotes	signalling
T5035	8743-8751	NN	denotes	pathways
T5036	8752-8754	IN	denotes	in
T5037	8755-8763	JJ	denotes	PKD-null
T5038	8764-8768	NN	denotes	DT40
T5039	8769-8770	NN	denotes	B
T5040	8771-8776	NN	denotes	cells
T5041	8777-8779	TO	denotes	To
T5042	8780-8787	RB	denotes	further
T5043	8788-8795	VB	denotes	explore
T5044	8796-8799	DT	denotes	the
T5045	8800-8812	NN	denotes	contribution
T5046	8813-8815	IN	denotes	of
T5047	8816-8819	NN	denotes	PKD
T5048	8820-8827	NN	denotes	kinases
T5049	8828-8830	TO	denotes	to
T5050	8831-8835	NN	denotes	DT40
T5051	8836-8837	NN	denotes	B
T5052	8838-8842	NN	denotes	cell
T5053	8843-8850	NN	denotes	biology
T5054	8851-8853	PRP	denotes	we
T5055	8854-8866	VB	denotes	investigated
T5056	8867-8874	IN	denotes	whether
T5057	8875-8883	JJ	denotes	specific
T5058	8884-8897	JJ	denotes	BCR-regulated
T5059	8898-8908	NN	denotes	signalling
T5060	8909-8915	NN	denotes	events
T5061	8916-8920	VB	denotes	were
T5062	8921-8930	JJ	denotes	defective
T5063	8931-8933	IN	denotes	in
T5064	8934-8937	DT	denotes	the
T5065	8938-8946	JJ	denotes	PKD-null
T5066	8947-8948	NN	denotes	B
T5067	8949-8954	NN	denotes	cells
T5068	8956-8963	JJ	denotes	Initial
T5069	8964-8975	NN	denotes	experiments
T5070	8976-8984	VB	denotes	revealed
T5071	8985-8989	IN	denotes	that
T5072	8990-8997	NN	denotes	surface
T5073	8998-9008	NN	denotes	expression
T5074	9009-9011	IN	denotes	of
T5075	9012-9015	DT	denotes	the
T5076	9016-9019	NN	denotes	BCR
T5077	9020-9023	VB	denotes	was
T5078	9024-9031	VB	denotes	reduced
T5079	9032-9034	IN	denotes	in
T5080	9035-9044	NN	denotes	PKD1/3−/−
T5081	9045-9046	-LRB-	denotes	(
T5082	9046-9049	CC	denotes	and
T5083	9050-9052	IN	denotes	in
T5084	9053-9062	NN	denotes	PKD1/3−/−
T5085	9062-9063	-COLON-	denotes	:
T5086	9063-9075	NN	denotes	Flag-PKD3+ve
T5087	9075-9076	-RRB-	denotes	)
T5088	9077-9082	NN	denotes	cells
T5089	9083-9091	VB	denotes	compared
T5090	9092-9094	TO	denotes	to
T5091	9095-9104	JJ	denotes	wild-type
T5092	9105-9109	NN	denotes	DT40
T5093	9110-9111	NN	denotes	B
T5094	9112-9117	NN	denotes	cells
T5095	9118-9119	-LRB-	denotes	(
T5096	9119-9123	NN	denotes	Fig.
T5097	9124-9126	NN	denotes	3A
T5098	9127-9130	CC	denotes	and
T5099	9131-9135	NN	denotes	data
T5100	9136-9139	RB	denotes	not
T5101	9140-9145	VB	denotes	shown
T5102	9145-9146	-RRB-	denotes	)
T5103	9148-9160	RB	denotes	Nevertheless
T5104	9160-9161	-COMMA-	denotes	,
T5105	9162-9178	NN	denotes	BCR-crosslinking
T5106	9179-9181	IN	denotes	of
T5107	9182-9191	NN	denotes	PKD1/3−/−
T5108	9192-9197	NN	denotes	cells
T5109	9198-9201	VB	denotes	was
T5110	9202-9212	JJ	denotes	sufficient
T5111	9213-9215	TO	denotes	to
T5112	9216-9222	VB	denotes	induce
T5113	9223-9226	DT	denotes	the
T5114	9227-9237	NN	denotes	activation
T5115	9238-9240	IN	denotes	of
T5116	9241-9242	DT	denotes	a
T5117	9243-9249	NN	denotes	number
T5118	9250-9252	IN	denotes	of
T5119	9253-9263	NN	denotes	signalling
T5120	9264-9272	NN	denotes	cascades
T5121	9272-9273	-COMMA-	denotes	,
T5122	9274-9281	JJ	denotes	similar
T5123	9282-9284	TO	denotes	to
T5124	9285-9289	DT	denotes	that
T5125	9290-9298	VB	denotes	observed
T5126	9299-9301	IN	denotes	in
T5127	9302-9311	JJ	denotes	wild-type
T5128	9312-9317	NN	denotes	cells
T5129	9318-9319	-LRB-	denotes	(
T5130	9319-9323	NN	denotes	Fig.
T5131	9324-9326	NN	denotes	3B
T5132	9326-9327	-RRB-	denotes	)
T5133	9329-9334	RB	denotes	Hence
T5134	9334-9335	-COMMA-	denotes	,
T5135	9336-9347	JJ	denotes	BCR-induced
T5136	9348-9358	NN	denotes	activation
T5137	9359-9361	IN	denotes	of
T5138	9362-9365	DT	denotes	the
T5139	9366-9369	NN	denotes	Akt
T5140	9369-9370	-COMMA-	denotes	,
T5141	9371-9379	NN	denotes	mTOR/p70
T5142	9380-9382	NN	denotes	S6
T5143	9383-9389	NN	denotes	kinase
T5144	9390-9391	-LRB-	denotes	(
T5145	9391-9393	IN	denotes	as
T5146	9394-9399	VB	denotes	shown
T5147	9400-9402	IN	denotes	by
T5148	9403-9405	NN	denotes	S6
T5149	9406-9415	JJ	denotes	ribosomal
T5150	9416-9423	NN	denotes	protein
T5151	9424-9439	NN	denotes	phosphorylation
T5152	9439-9440	-RRB-	denotes	)
T5153	9441-9444	CC	denotes	and
T5154	9445-9449	NN	denotes	MAPK
T5155	9450-9460	NN	denotes	signalling
T5156	9461-9469	NN	denotes	pathways
T5157	9470-9473	VB	denotes	was
T5158	9474-9481	RB	denotes	clearly
T5159	9482-9492	JJ	denotes	detectable
T5160	9493-9495	IN	denotes	in
T5161	9496-9507	JJ	denotes	PKD1/3-null
T5162	9508-9509	NN	denotes	B
T5163	9510-9515	NN	denotes	cells
T5164	9516-9517	-LRB-	denotes	(
T5165	9517-9521	NN	denotes	Fig.
T5166	9522-9524	NN	denotes	3B
T5167	9524-9525	-RRB-	denotes	)
T5168	9527-9538	RB	denotes	Furthermore
T5169	9538-9539	-COMMA-	denotes	,
T5170	9540-9548	VB	denotes	enhanced
T5171	9549-9557	NN	denotes	tyrosine
T5172	9558-9573	NN	denotes	phosphorylation
T5173	9574-9576	IN	denotes	of
T5174	9577-9585	JJ	denotes	multiple
T5175	9586-9594	JJ	denotes	cellular
T5176	9595-9603	NN	denotes	proteins
T5177	9604-9606	RB	denotes	as
T5178	9607-9611	RB	denotes	well
T5179	9612-9614	IN	denotes	as
T5180	9615-9617	DT	denotes	an
T5181	9618-9626	NN	denotes	increase
T5182	9627-9629	IN	denotes	in
T5183	9630-9643	JJ	denotes	intracellular
T5184	9644-9651	NN	denotes	calcium
T5185	9652-9658	NN	denotes	levels
T5186	9659-9662	VB	denotes	was
T5187	9663-9667	RB	denotes	also
T5188	9668-9676	VB	denotes	observed
T5189	9677-9686	VB	denotes	following
T5190	9687-9690	NN	denotes	BCR
T5191	9691-9702	NN	denotes	stimulation
T5192	9703-9705	IN	denotes	of
T5193	9706-9717	JJ	denotes	PKD1/3-null
T5194	9718-9719	NN	denotes	B
T5195	9720-9725	NN	denotes	cells
T5196	9726-9727	-LRB-	denotes	(
T5197	9727-9731	NN	denotes	data
T5198	9732-9735	RB	denotes	not
T5199	9736-9741	VB	denotes	shown
T5200	9741-9742	-RRB-	denotes	)
T5201	9744-9746	PRP	denotes	We
T5202	9747-9750	VB	denotes	did
T5203	9751-9758	VB	denotes	observe
T5204	9759-9763	IN	denotes	that
T5205	9764-9767	DT	denotes	the
T5206	9768-9776	NN	denotes	strength
T5207	9777-9779	IN	denotes	of
T5208	9780-9783	NN	denotes	BCR
T5209	9784-9785	-LRB-	denotes	(
T5210	9785-9788	CC	denotes	but
T5211	9789-9792	RB	denotes	not
T5212	9793-9800	NN	denotes	phorbol
T5213	9801-9806	NN	denotes	ester
T5214	9806-9807	-RRB-	denotes	)
T5215	9807-9815	JJ	denotes	-induced
T5216	9816-9826	NN	denotes	regulation
T5217	9827-9829	IN	denotes	of
T5218	9830-9833	DT	denotes	the
T5219	9834-9843	NN	denotes	Erk1-RSK1
T5220	9844-9854	NN	denotes	signalling
T5221	9855-9862	NN	denotes	pathway
T5222	9863-9866	VB	denotes	was
T5223	9867-9874	VB	denotes	reduced
T5224	9875-9877	IN	denotes	in
T5225	9878-9887	NN	denotes	PKD1/3−/−
T5226	9888-9889	NN	denotes	B
T5227	9890-9895	NN	denotes	cells
T5228	9896-9904	VB	denotes	compared
T5229	9905-9907	TO	denotes	to
T5230	9908-9917	JJ	denotes	wild-type
T5231	9918-9919	NN	denotes	B
T5232	9920-9925	NN	denotes	cells
T5233	9926-9927	-LRB-	denotes	(
T5234	9927-9931	NN	denotes	Fig.
T5235	9932-9934	NN	denotes	3B
T5236	9934-9935	-RRB-	denotes	)
T5237	9937-9940	CD	denotes	One
T5238	9941-9955	NN	denotes	interpretation
T5239	9956-9958	IN	denotes	of
T5240	9959-9963	DT	denotes	this
T5241	9964-9968	NN	denotes	data
T5242	9969-9971	VB	denotes	is
T5243	9972-9976	IN	denotes	that
T5244	9977-9980	NN	denotes	PKD
T5245	9981-9988	NN	denotes	enzymes
T5246	9989-9992	MD	denotes	may
T5247	9993-10001	VB	denotes	modulate
T5248	10002-10005	NN	denotes	Erk
T5249	10006-10016	NN	denotes	activation
T5250	10018-10024	RB	denotes	Indeed
T5251	10024-10025	-COMMA-	denotes	,
T5252	10026-10029	NN	denotes	PKD
T5253	10030-10037	NN	denotes	enzymes
T5254	10038-10042	VB	denotes	have
T5255	10043-10053	RB	denotes	previously
T5256	10054-10058	VB	denotes	been
T5257	10059-10065	VB	denotes	linked
T5258	10066-10068	TO	denotes	to
T5259	10069-10072	DT	denotes	the
T5260	10073-10079	NN	denotes	growth
T5261	10080-10096	JJ	denotes	factor-regulated
T5262	10097-10100	NN	denotes	Erk
T5263	10101-10111	NN	denotes	signalling
T5264	10112-10114	IN	denotes	in
T5265	10115-10125	NN	denotes	fibroblast
T5266	10126-10129	CC	denotes	and
T5267	10130-10141	JJ	denotes	endothelial
T5268	10142-10146	NN	denotes	cell
T5269	10147-10152	NN	denotes	lines
T5270	10153-10154	-LRB-	denotes	[
T5271	10154-10159	CD	denotes	33–35
T5272	10159-10160	-RRB-	denotes	]
T5273	10162-10169	RB	denotes	However
T5274	10169-10170	-COMMA-	denotes	,
T5275	10171-10182	JJ	denotes	BCR-induced
T5276	10183-10186	NN	denotes	Erk
T5277	10187-10202	NN	denotes	phosphorylation
T5278	10203-10206	VB	denotes	was
T5279	10207-10211	RB	denotes	also
T5280	10212-10219	VB	denotes	reduced
T5281	10220-10222	IN	denotes	in
T5282	10223-10243	JJ	denotes	PKD1/3−/−-Flag-PKD3+
T5283	10244-10245	NN	denotes	B
T5284	10246-10251	NN	denotes	cells
T5285	10252-10253	-LRB-	denotes	(
T5286	10253-10257	NN	denotes	data
T5287	10258-10261	RB	denotes	not
T5288	10262-10267	VB	denotes	shown
T5289	10267-10268	-RRB-	denotes	)
T5290	10269-10279	VB	denotes	suggesting
T5291	10280-10284	IN	denotes	that
T5292	10285-10292	VB	denotes	reduced
T5293	10293-10296	NN	denotes	BCR
T5294	10297-10303	NN	denotes	levels
T5295	10304-10306	IN	denotes	on
T5296	10307-10310	DT	denotes	the
T5297	10311-10318	NN	denotes	surface
T5298	10319-10321	IN	denotes	of
T5299	10322-10331	NN	denotes	PKD1/3−/−
T5300	10332-10333	-LRB-	denotes	(
T5301	10333-10336	CC	denotes	and
T5302	10337-10357	JJ	denotes	PKD1/3−/−-Flag-PKD3+
T5303	10357-10358	-RRB-	denotes	)
T5304	10359-10360	NN	denotes	B
T5305	10361-10366	NN	denotes	cells
T5306	10367-10370	MD	denotes	may
T5307	10371-10377	PRP	denotes	itself
T5308	10378-10384	VB	denotes	impact
T5309	10385-10387	IN	denotes	on
T5310	10388-10391	DT	denotes	the
T5311	10392-10400	NN	denotes	strength
T5312	10401-10403	IN	denotes	of
T5313	10404-10414	NN	denotes	activation
T5314	10415-10417	IN	denotes	of
T5315	10418-10422	DT	denotes	this
T5316	10423-10431	JJ	denotes	specific
T5317	10432-10445	JJ	denotes	intracellular
T5318	10446-10456	NN	denotes	signalling
T5319	10457-10464	NN	denotes	pathway
T5320	10466-10468	TO	denotes	To
T5321	10469-10475	VB	denotes	search
T5322	10476-10479	IN	denotes	for
T5323	10480-10485	JJ	denotes	other
T5324	10486-10495	JJ	denotes	potential
T5325	10496-10499	NN	denotes	PKD
T5326	10500-10507	NN	denotes	targets
T5327	10508-10512	WDT	denotes	that
T5328	10513-10516	MD	denotes	may
T5329	10517-10521	VB	denotes	show
T5330	10522-10531	JJ	denotes	defective
T5331	10532-10542	NN	denotes	regulation
T5332	10543-10545	IN	denotes	in
T5333	10546-10555	NN	denotes	PKD1/3−/−
T5334	10556-10560	NN	denotes	DT40
T5335	10561-10562	NN	denotes	B
T5336	10563-10568	NN	denotes	cells
T5337	10568-10569	-COMMA-	denotes	,
T5338	10570-10572	PRP	denotes	we
T5339	10573-10577	VB	denotes	used
T5340	10578-10579	DT	denotes	a
T5341	10580-10583	NN	denotes	PKD
T5342	10584-10593	NN	denotes	substrate
T5343	10594-10610	NN	denotes	phospho-antibody
T5344	10611-10615	WDT	denotes	that
T5345	10616-10626	VB	denotes	recognises
T5346	10627-10636	NN	denotes	consensus
T5347	10637-10652	NN	denotes	phosphorylation
T5348	10653-10662	NN	denotes	sequences
T5349	10663-10671	VB	denotes	targeted
T5350	10672-10674	IN	denotes	by
T5351	10675-10678	NN	denotes	PKD
T5352	10679-10686	NN	denotes	enzymes
T5353	10687-10688	-LRB-	denotes	(
T5354	10688-10697	NN	denotes	LxRxxpS/T
T5355	10697-10698	-RRB-	denotes	)
T5356	10699-10700	-LRB-	denotes	[
T5357	10700-10702	CD	denotes	36
T5358	10702-10703	-RRB-	denotes	]
T5359	10705-10707	IN	denotes	As
T5360	10708-10713	VB	denotes	shown
T5361	10714-10716	IN	denotes	in
T5362	10717-10721	NNP	denotes	Fig.
T5363	10722-10724	NNP	denotes	3C
T5364	10724-10725	-COMMA-	denotes	,
T5365	10726-10733	NN	denotes	phorbol
T5366	10734-10740	NN	denotes	ester-
T5367	10741-10744	CC	denotes	and
T5368	10745-10756	JJ	denotes	BCR-induced
T5369	10757-10772	NN	denotes	phosphorylation
T5370	10773-10775	IN	denotes	of
T5371	10776-10784	JJ	denotes	cellular
T5372	10785-10795	NN	denotes	substrates
T5373	10796-10804	VB	denotes	detected
T5374	10805-10807	IN	denotes	by
T5375	10808-10812	DT	denotes	this
T5376	10813-10829	NN	denotes	phospho-antibody
T5377	10830-10833	VB	denotes	was
T5378	10834-10841	JJ	denotes	similar
T5379	10842-10844	IN	denotes	in
T5380	10845-10854	JJ	denotes	wild-type
T5381	10855-10858	CC	denotes	and
T5382	10859-10868	NN	denotes	PKD1/3−/−
T5383	10869-10874	NN	denotes	cells
T5384	10875-10878	CC	denotes	and
T5385	10879-10881	VB	denotes	is
T5386	10882-10891	RB	denotes	therefore
T5387	10892-10903	JJ	denotes	independent
T5388	10904-10906	IN	denotes	of
T5389	10907-10910	NN	denotes	PKD
T5390	10911-10918	NN	denotes	enzymes
T5391	10920-10927	RB	denotes	However
T5392	10927-10928	-COMMA-	denotes	,
T5393	10929-10941	NN	denotes	pretreatment
T5394	10942-10944	IN	denotes	of
T5395	10945-10949	CC	denotes	both
T5396	10950-10959	JJ	denotes	wild-type
T5397	10960-10963	CC	denotes	and
T5398	10964-10973	NN	denotes	PKD1/3−/−
T5399	10974-10978	NN	denotes	DT40
T5400	10979-10980	NN	denotes	B
T5401	10981-10986	NN	denotes	cells
T5402	10987-10991	IN	denotes	with
T5403	10992-11001	NN	denotes	GF109203X
T5404	11001-11002	-COMMA-	denotes	,
T5405	11003-11004	DT	denotes	a
T5406	11005-11023	NN	denotes	bisindoylmaleimide
T5407	11024-11034	NN	denotes	derivative
T5408	11035-11039	WDT	denotes	that
T5409	11040-11048	VB	denotes	inhibits
T5410	11049-11053	NN	denotes	PKCs
T5411	11054-11063	VB	denotes	prevented
T5412	11064-11067	DT	denotes	the
T5413	11068-11077	NN	denotes	induction
T5414	11078-11080	IN	denotes	of
T5415	11081-11089	NN	denotes	proteins
T5416	11090-11094	WDT	denotes	that
T5417	11095-11102	VB	denotes	contain
T5418	11103-11117	VB	denotes	phosphorylated
T5419	11118-11126	NN	denotes	LxRxxS/T
T5420	11127-11133	NN	denotes	motifs
T5421	11135-11139	RB	denotes	Thus
T5422	11140-11144	NN	denotes	loss
T5423	11145-11147	IN	denotes	of
T5424	11148-11154	NN	denotes	PKD1/3
T5425	11155-11162	NN	denotes	enzymes
T5426	11163-11167	VB	denotes	does
T5427	11168-11171	RB	denotes	not
T5428	11172-11180	RB	denotes	globally
T5429	11181-11188	VB	denotes	disrupt
T5430	11189-11192	DT	denotes	the
T5431	11193-11208	NN	denotes	phosphorylation
T5432	11209-11211	IN	denotes	of
T5433	11212-11220	JJ	denotes	cellular
T5434	11221-11229	NN	denotes	proteins
T5435	11230-11234	WDT	denotes	that
T5436	11235-11242	VB	denotes	contain
T5437	11243-11252	NN	denotes	LxRxxpS/T
T5438	11253-11259	NN	denotes	motifs
T5439	11261-11265	DT	denotes	This
T5440	11266-11272	NN	denotes	result
T5441	11273-11275	VB	denotes	is
T5442	11276-11283	RB	denotes	perhaps
T5443	11284-11287	RB	denotes	not
T5444	11288-11298	JJ	denotes	surprising
T5445	11299-11301	IN	denotes	as
T5446	11302-11310	NN	denotes	LxRxxS/T
T5447	11311-11317	NN	denotes	motifs
T5448	11318-11322	RB	denotes	also
T5449	11323-11326	VB	denotes	act
T5450	11327-11329	IN	denotes	as
T5451	11330-11334	JJ	denotes	good
T5452	11335-11345	NN	denotes	substrates
T5453	11346-11349	IN	denotes	for
T5454	11350-11355	JJ	denotes	other
T5455	11356-11372	NN	denotes	serine/threonine
T5456	11373-11380	NN	denotes	kinases
T5457	11381-11385	JJ	denotes	such
T5458	11386-11388	IN	denotes	as
T5459	11389-11397	NN	denotes	MAPKAPK2
T5460	11399-11406	RB	denotes	However
T5461	11407-11412	DT	denotes	these
T5462	11413-11424	NN	denotes	experiments
T5463	11425-11427	VB	denotes	do
T5464	11428-11435	VB	denotes	provide
T5465	11436-11443	JJ	denotes	further
T5466	11444-11452	NN	denotes	evidence
T5467	11453-11457	IN	denotes	that
T5468	11458-11473	JJ	denotes	phosphospecific
T5469	11474-11482	NN	denotes	antisera
T5470	11483-11486	VB	denotes	are
T5471	11487-11490	RB	denotes	not
T5472	11491-11503	RB	denotes	sufficiently
T5473	11504-11513	JJ	denotes	selective
T5474	11514-11516	TO	denotes	to
T5475	11517-11519	VB	denotes	be
T5476	11520-11530	VB	denotes	designated
T5477	11531-11537	NN	denotes	kinase
T5478	11538-11546	JJ	denotes	specific
T5479	11547-11556	NN	denotes	substrate
T5480	11557-11565	NN	denotes	antisera
T5481	11567-11578	JJ	denotes	BCR-induced
T5482	11579-11589	NN	denotes	signalling
T5483	11590-11598	NN	denotes	pathways
T5484	11599-11608	VB	denotes	culminate
T5485	11609-11611	IN	denotes	in
T5486	11612-11615	DT	denotes	the
T5487	11616-11626	NN	denotes	activation
T5488	11627-11629	IN	denotes	of
T5489	11630-11634	NN	denotes	gene
T5490	11635-11648	NN	denotes	transcription
T5491	11649-11655	NN	denotes	events
T5492	11656-11660	WDT	denotes	that
T5493	11661-11668	VB	denotes	control
T5494	11669-11670	NN	denotes	B
T5495	11671-11675	NN	denotes	cell
T5496	11676-11684	NN	denotes	survival
T5497	11684-11685	-COMMA-	denotes	,
T5498	11686-11699	NN	denotes	proliferation
T5499	11700-11703	CC	denotes	and
T5500	11704-11712	NN	denotes	function
T5501	11714-11716	IN	denotes	In
T5502	11717-11721	DT	denotes	this
T5503	11722-11729	NN	denotes	context
T5504	11729-11730	-COMMA-	denotes	,
T5505	11731-11733	PRP	denotes	it
T5506	11734-11737	VB	denotes	has
T5507	11738-11742	VB	denotes	been
T5508	11743-11751	VB	denotes	proposed
T5509	11752-11756	IN	denotes	that
T5510	11757-11760	NN	denotes	PKD
T5511	11761-11767	NN	denotes	family
T5512	11768-11775	NN	denotes	members
T5513	11776-11783	NN	denotes	control
T5514	11784-11786	IN	denotes	of
T5515	11787-11791	NN	denotes	gene
T5516	11792-11805	NN	denotes	transcription
T5517	11806-11813	IN	denotes	through
T5518	11814-11824	NN	denotes	activation
T5519	11825-11827	IN	denotes	of
T5520	11828-11831	DT	denotes	the
T5521	11832-11836	NN	denotes	NFκB
T5522	11837-11850	NN	denotes	transcription
T5523	11851-11857	NN	denotes	factor
T5524	11859-11863	RB	denotes	Thus
T5525	11863-11864	-COMMA-	denotes	,
T5526	11865-11877	JJ	denotes	PKD-mediated
T5527	11878-11888	NN	denotes	activation
T5528	11889-11891	IN	denotes	of
T5529	11892-11896	NN	denotes	NFκB
T5530	11897-11903	VB	denotes	occurs
T5531	11904-11914	RB	denotes	downstream
T5532	11915-11917	IN	denotes	of
T5533	11918-11919	DT	denotes	a
T5534	11920-11927	NN	denotes	variety
T5535	11928-11930	IN	denotes	of
T5536	11931-11940	JJ	denotes	different
T5537	11941-11948	NN	denotes	signals
T5538	11948-11949	-COMMA-	denotes	,
T5539	11950-11959	VB	denotes	including
T5540	11960-11974	JJ	denotes	mROS/oxidative
T5541	11975-11981	NN	denotes	stress
T5542	11981-11982	-COMMA-	denotes	,
T5543	11983-11999	JJ	denotes	lysophosphatidic
T5544	12000-12004	NN	denotes	acid
T5545	12005-12008	CC	denotes	and
T5546	12009-12012	DT	denotes	the
T5547	12013-12020	NN	denotes	Bcr-Abl
T5548	12021-12029	NN	denotes	oncogene
T5549	12030-12031	-LRB-	denotes	[
T5550	12031-12045	CD	denotes	17,21,23,30,37
T5551	12045-12046	-RRB-	denotes	]
T5552	12048-12059	RB	denotes	Furthermore
T5553	12059-12060	-COMMA-	denotes	,
T5554	12061-12071	NN	denotes	expression
T5555	12072-12074	IN	denotes	of
T5556	12075-12077	DT	denotes	an
T5557	12078-12087	VB	denotes	activated
T5558	12088-12092	NN	denotes	PKD1
T5559	12093-12099	NN	denotes	mutant
T5560	12100-12108	VB	denotes	enhances
T5561	12109-12122	JJ	denotes	HPK1-mediated
T5562	12123-12127	NN	denotes	NFκB
T5563	12128-12138	NN	denotes	activation
T5564	12139-12140	-LRB-	denotes	[
T5565	12140-12142	CD	denotes	38
T5566	12142-12143	-RRB-	denotes	]
T5567	12145-12147	IN	denotes	In
T5568	12148-12149	NN	denotes	B
T5569	12150-12155	NN	denotes	cells
T5570	12155-12156	-COMMA-	denotes	,
T5571	12157-12161	NN	denotes	NFκB
T5572	12162-12164	VB	denotes	is
T5573	12165-12170	VB	denotes	known
T5574	12171-12173	TO	denotes	to
T5575	12174-12176	VB	denotes	be
T5576	12177-12186	VB	denotes	regulated
T5577	12187-12190	IN	denotes	via
T5578	12191-12194	NN	denotes	DAG
T5579	12195-12198	CC	denotes	and
T5580	12199-12203	NN	denotes	PKCβ
T5581	12204-12205	-LRB-	denotes	[
T5582	12205-12210	CD	denotes	39,40
T5583	12210-12211	-RRB-	denotes	]
T5584	12212-12215	CC	denotes	but
T5585	12216-12223	IN	denotes	whether
T5586	12224-12228	NN	denotes	PKDs
T5587	12229-12232	VB	denotes	are
T5588	12233-12236	JJ	denotes	key
T5589	12237-12251	NN	denotes	intermediaries
T5590	12252-12255	IN	denotes	for
T5591	12256-12260	NN	denotes	NFκB
T5592	12261-12271	NN	denotes	regulation
T5593	12272-12275	VB	denotes	has
T5594	12276-12279	RB	denotes	not
T5595	12280-12284	VB	denotes	been
T5596	12285-12293	VB	denotes	explored
T5597	12295-12298	DT	denotes	The
T5598	12299-12303	NN	denotes	data
T5599	12304-12305	-LRB-	denotes	(
T5600	12305-12309	NNP	denotes	Fig.
T5601	12310-12312	NN	denotes	4A
T5602	12312-12313	-RRB-	denotes	)
T5603	12314-12318	VB	denotes	show
T5604	12319-12323	IN	denotes	that
T5605	12324-12328	NN	denotes	NFκB
T5606	12329-12344	JJ	denotes	transcriptional
T5607	12345-12353	NN	denotes	activity
T5608	12354-12357	VB	denotes	was
T5609	12358-12366	RB	denotes	strongly
T5610	12367-12374	VB	denotes	induced
T5611	12375-12377	IN	denotes	in
T5612	12378-12382	CC	denotes	both
T5613	12383-12392	JJ	denotes	wild-type
T5614	12393-12396	CC	denotes	and
T5615	12397-12406	NN	denotes	PKD1/3−/−
T5616	12407-12411	NN	denotes	DT40
T5617	12412-12413	NN	denotes	B
T5618	12414-12419	NN	denotes	cells
T5619	12420-12422	IN	denotes	in
T5620	12423-12431	NN	denotes	response
T5621	12432-12434	TO	denotes	to
T5622	12435-12441	CC	denotes	either
T5623	12442-12449	NN	denotes	phorbol
T5624	12450-12455	NN	denotes	ester
T5625	12456-12458	CC	denotes	or
T5626	12459-12462	NN	denotes	BCR
T5627	12463-12474	NN	denotes	stimulation
T5628	12476-12478	IN	denotes	In
T5629	12479-12487	NN	denotes	contrast
T5630	12487-12488	-COMMA-	denotes	,
T5631	12489-12492	NN	denotes	BCR
T5632	12493-12496	CC	denotes	and
T5633	12497-12504	NN	denotes	phorbol
T5634	12505-12518	JJ	denotes	ester-induced
T5635	12519-12523	NN	denotes	NFκB
T5636	12524-12539	JJ	denotes	transcriptional
T5637	12540-12548	NN	denotes	activity
T5638	12549-12552	VB	denotes	was
T5639	12553-12562	VB	denotes	abolished
T5640	12563-12565	IN	denotes	in
T5641	12566-12573	NN	denotes	PKCβ−/−
T5642	12574-12578	NN	denotes	DT40
T5643	12579-12580	NN	denotes	B
T5644	12581-12586	NN	denotes	cells
T5645	12587-12588	-LRB-	denotes	(
T5646	12588-12592	NN	denotes	Fig.
T5647	12593-12595	NN	denotes	4A
T5648	12595-12596	-RRB-	denotes	)
T5649	12596-12597	-COMMA-	denotes	,
T5650	12598-12606	IN	denotes	although
T5651	12607-12613	JJ	denotes	strong
T5652	12614-12624	NN	denotes	activation
T5653	12625-12627	IN	denotes	of
T5654	12628-12631	NN	denotes	PKD
T5655	12632-12639	NN	denotes	kinases
T5656	12640-12641	-LRB-	denotes	(
T5657	12641-12643	IN	denotes	as
T5658	12644-12652	VB	denotes	assessed
T5659	12653-12655	IN	denotes	by
T5660	12656-12675	NN	denotes	autophosphorylation
T5661	12676-12678	IN	denotes	of
T5662	12679-12683	NN	denotes	PKD1
T5663	12684-12686	IN	denotes	at
T5664	12687-12691	NN	denotes	S916
T5665	12691-12692	-RRB-	denotes	)
T5666	12693-12696	VB	denotes	was
T5667	12697-12705	VB	denotes	observed
T5668	12706-12708	IN	denotes	in
T5669	12709-12712	DT	denotes	the
T5670	12713-12720	NN	denotes	PKCβ−/−
T5671	12721-12726	NN	denotes	cells
T5672	12727-12728	-LRB-	denotes	(
T5673	12728-12732	NN	denotes	Fig.
T5674	12733-12735	NN	denotes	4B
T5675	12735-12736	-RRB-	denotes	)
T5676	12738-12742	RB	denotes	Thus
T5677	12742-12743	-COMMA-	denotes	,
T5678	12744-12747	NN	denotes	PKD
T5679	12748-12755	NN	denotes	kinases
T5680	12756-12759	VB	denotes	are
T5681	12760-12767	DT	denotes	neither
T5682	12768-12777	JJ	denotes	essential
T5683	12778-12781	CC	denotes	nor
T5684	12782-12792	JJ	denotes	sufficient
T5685	12793-12795	TO	denotes	to
T5686	12796-12803	VB	denotes	mediate
T5687	12804-12815	JJ	denotes	BCR-induced
T5688	12816-12820	NN	denotes	NFκB
T5689	12821-12831	NN	denotes	activation
T5690	12832-12834	IN	denotes	in
T5691	12835-12839	NN	denotes	DT40
T5692	12840-12841	NN	denotes	B
T5693	12842-12847	NN	denotes	cells
T5694	12848-12851	CC	denotes	and
T5695	12852-12857	RB	denotes	hence
T5696	12858-12860	VB	denotes	do
T5697	12861-12864	RB	denotes	not
T5698	12865-12876	VB	denotes	participate
T5699	12877-12879	IN	denotes	in
T5700	12880-12887	NN	denotes	DAG/PKC
T5701	12888-12896	VB	denotes	mediated
T5702	12897-12904	NN	denotes	control
T5703	12905-12907	IN	denotes	of
T5704	12908-12912	NN	denotes	NFκB
T7043	0-12936	NN	denotes	40 B-lymphocyte cell line. Previously we have shown that PKDs have an essential role in regulating class II histone deacetylases in DT40 B-cells [Matthews, S.A., Liu, P., Spitaler, M., Olson, E.N., McKinsey, T.A., Cantrell, D.A. and Scharenberg, A.M. (2006) Essential role for protein kinase D family kinases in the regulation of class II histone deacetylases in B lymphocytes. Mol. Cell Biol. 26, 1569–1577]. We now show that PKDs are also required to regulate HSP27 phosphorylation in DT40 B-cells. However, in contrast to previous observations in other cell types, PKD enzymes do not regulate basic cellular processes such as proliferation or survival responses, nor NFκB transcriptional activity downstream of the B cell antigen receptor. Thus, PKDs have a selective role in DT40 B-cell biology. 1 Introduction The protein kinase D (PKD) serine/threonine kinase family has three members: PKD1, PKD2 and PKD3. Most cell types express at least two PKD isoforms but PKD enzymes are especially highly expressed in haematopoietic cells, where they are activated in response to antigen receptors stimulation [2,3]. A conserved signalling pathway linking antigen receptors to PKDs involves the activation of PLCγ and the subsequent production of diacylglycerol (DAG) which stimulates classical and/or novel protein kinase Cs (PKC) that phosphorylate two key regulatory serine residues in the activation loop of PKD kinases [3–6]. The N-terminal regulatory region of PKD enzymes contains a DAG binding domain and direct binding of DAG also contributes to PKD1 activation [7] as well as regulating the spatial location of PKD enzymes within cells [8–12]. PKD enzymes have been proposed to regulate numerous cellular functions, including cell proliferation [13–16], anti-apoptotic signals [17,18] and thymocyte development [19]. Expression of mutant catalytically inactive and constitutively activated PKDs can also modify Golgi function, cell adhesion and cell motility (reviewed in [20]). In particular, PKDs have been widely linked to the activation of the NFκB transcription factor and in regulating cell survival during oxidative stress [17,21–23]. Another recently proposed PKD1 substrate is HSP27 [24], a small heat shock protein involved in regulating cell migration and cell survival [25]. An essential role for PKD enzymes in regulating class II histone deacetylases (HDACs), enzymes that repress MEF2-dependent gene transcription, has also been demonstrated [1,26–28]. To investigate the biological role of PKDs we have generated DT40 B cell lines that lack expression of one or more members of the PKD family [1], allowing us to investigate the function(s) of PKD isoforms following B cell antigen receptor (BCR) stimulation, as well addressing the issue of functional redundancy between the different PKD family members. Previous studies have shown that PKDs are indispensable for HDAC regulation in B cells [1]. Herein we show that PKDs are also indispensable for HSP27 phosphorylation in B cells. However, PKD-null DT40 B cells are viable and proliferate normally. Moreover, loss of the entire cellular pool of PKD does not critically affect oxidative stress responses in B cells nor do PKD kinases play an essential role in regulating NFκB transcriptional activity. Together, these findings reveal that in B lymphocytes, PKD kinases are not critical regulators of many of the cellular processes previously ascribed to them in other cellular systems. 2 Materials and methods 2.1 Cell culture, transient transfections and cell stimulation The generation, culture and activation of PKD1−/−, PKD3−/− and PKD1/3−/− knockout DT40 B cell lines have been described previously [1]. Cells were lysed and protein extracts were analysed in Western blotting experiments as previously described [1]. Chloramphenicol acetyl transferase assays have been described previously [29]. 2.2 sIgM staining DT40 B cells (2 × 106 cells per point) were resuspended in 200 μl buffer (RPMI 1640 media, 1% foetal calf serum) containing anti-chicken M1 monoclonal antibody conjugated to FITC for 20 min on ice. The cells were washed twice and fluorescent intensity was analysed by flow cytometry. All results shown are representative of at two to four independent experiments unless otherwise indicated. 3 Results 3.1 Loss of HSP27 phosphorylation in DT40 B cells lacking expression of PKD family kinases DT40 B cells express two PKD isoforms, PKD1 and PKD3, and as previously described we have recently generated DT40 B cell lines that lack expression of either PKD1 or PKD3 or both enzymes [1]. In generating the double knockout cell lines we targeted the PKD1 loci in a PKD3−/− cell line that expressed a Flag-PKD3 transgene under the control of a doxycycline-inducible promoter. Hence, in the presence of doxycycline, Flag-PKD3 expression in PKD1/3 double knockout cells is comparable to endogenous PKD3 present in wild-type DT40 cells and removal of doxycycline from the culture media for 5 days results in a completely null PKD phenotype (Fig. 1A). Previously, we have demonstrated that phosphorylation and nuclear exclusion of class II histone deacetylases (HDACs) during BCR engagement is defective in PKD1/3−/− B cells and can restored upon re-expression of a single PKD isoform [1]. The small heat shock protein HSP27 has recently been proposed as a PKD1 substrate [24] and we accordingly assessed whether PKD-null DT40 cells have defective phosphorylation of HSP27 on serine 82, the proposed PKD1 substrate sequence. We initially investigated the regulation of HSP27 phosphorylation in single knockout DT40 B cells lacking either PKD1 or PKD3. As shown in Fig. 1B, activation of the BCR or treatment with the DAG-mimetic PdBu increased the levels of HSP27 phosphorylation at S82 in wild-type DT40 B cells. BCR and phorbol ester signals were also able to increase HSP27 phosphorylation in PKD1 or PKD3 single knockout DT40 B cells (Fig. 1B). However, BCR- and phorbol ester-induced phosphorylation of HSP27 on S82 was abolished in B cells that lacked both PKD1 and PKD3 (Fig. 1C). Significantly, doxycycline-induced expression of the Flag-PKD3 transgene in the double knockout cells was sufficient to restore normal regulation of HSP27 phosphorylation (Fig. 1C). In contrast, expression of a kinase-deficient PKD3 mutant protein in the double knockout cells was not able to restore BCR- or phorbol ester-induced HSP27 phosphorylation (Fig. 1D). Hence, PKD3 as well as PKD1 can regulate HSP27 phosphorylation and in DT40 B cells they are functionally redundant as HSP27 kinases. 3.2 Cellular proliferation and survival in DT40 B cells lacking expression of PKD family kinases PKD enzymes have previously been linked to the regulation of cell proliferation and survival (reviewed in [20]). To investigate the effect that loss of PKD kinases had on B cell survival and/or proliferation we cultured wild-type and PKD-null cells in the presence (PKD1/3−/−: Flag-PKD3+ve) or absence (PKD1/3−/−) of doxycycline and monitored exponential growth. As shown in Fig. 2A, PKD1/3−/− cells proliferated exponentially and re-expression of Flag-PKD3 in these cells had no impact on the rate of proliferation. Furthermore, the viability of PKD1/3−/− B cells during routine culturing was not significantly different from that of wild-type B cells (data not shown). It was noted that the population doubling time of PKD1/3−/− cells was slightly slower than that of wild type DT40 cells (12.7 ± 2.8 h versus 10.2 ± 0.4 h) but the failure of PKD3 re-expression to modify the proliferation rate of PKD1/3−/− cells suggests that these small differences were most likely the result of clonal variation and were not caused specifically by loss of PKD enzymes. Thus, PKD family enzymes are not essential for regulating basal survival and proliferation of DT40 B cells. PKD enzymes, specifically PKD1 and PKD2, have previously been linked to a protective role against oxidative stress-induced injury in 3T3 fibroblast, HeLa and epithelial cell lines [17,30–32]. We therefore addressed the role of PKD family kinases in regulating B cell survival in response to oxidative stress and other stress stimuli. As shown in Fig. 2B, loss of PKD1/3 expression had no significant impact on the survival of DT40 B cells in response to mitochondrial stress stimuli (H2O2 or serum deprivation); DNA damaging agents (etoposide or doxorubicin); ER pathway stress due to calcium overload (thapsigargin) or following prolonged treatment with phorbol esters or Trichostatin A, an inhibitor of class I/II HDACs. Thus, PKD kinases do not play an essential role in regulating B cell survival in response to a range of different stress stimuli. 3.3 Antigen receptor regulated signalling pathways in PKD-null DT40 B cells To further explore the contribution of PKD kinases to DT40 B cell biology we investigated whether specific BCR-regulated signalling events were defective in the PKD-null B cells. Initial experiments revealed that surface expression of the BCR was reduced in PKD1/3−/− (and in PKD1/3−/−:Flag-PKD3+ve) cells compared to wild-type DT40 B cells (Fig. 3A and data not shown). Nevertheless, BCR-crosslinking of PKD1/3−/− cells was sufficient to induce the activation of a number of signalling cascades, similar to that observed in wild-type cells (Fig. 3B). Hence, BCR-induced activation of the Akt, mTOR/p70 S6 kinase (as shown by S6 ribosomal protein phosphorylation) and MAPK signalling pathways was clearly detectable in PKD1/3-null B cells (Fig. 3B). Furthermore, enhanced tyrosine phosphorylation of multiple cellular proteins as well as an increase in intracellular calcium levels was also observed following BCR stimulation of PKD1/3-null B cells (data not shown). We did observe that the strength of BCR (but not phorbol ester)-induced regulation of the Erk1-RSK1 signalling pathway was reduced in PKD1/3−/− B cells compared to wild-type B cells (Fig. 3B). One interpretation of this data is that PKD enzymes may modulate Erk activation. Indeed, PKD enzymes have previously been linked to the growth factor-regulated Erk signalling in fibroblast and endothelial cell lines [33–35]. However, BCR-induced Erk phosphorylation was also reduced in PKD1/3−/−-Flag-PKD3+ B cells (data not shown) suggesting that reduced BCR levels on the surface of PKD1/3−/− (and PKD1/3−/−-Flag-PKD3+) B cells may itself impact on the strength of activation of this specific intracellular signalling pathway. To search for other potential PKD targets that may show defective regulation in PKD1/3−/− DT40 B cells, we used a PKD substrate phospho-antibody that recognises consensus phosphorylation sequences targeted by PKD enzymes (LxRxxpS/T) [36]. As shown in Fig. 3C, phorbol ester- and BCR-induced phosphorylation of cellular substrates detected by this phospho-antibody was similar in wild-type and PKD1/3−/− cells and is therefore independent of PKD enzymes. However, pretreatment of both wild-type and PKD1/3−/− DT40 B cells with GF109203X, a bisindoylmaleimide derivative that inhibits PKCs prevented the induction of proteins that contain phosphorylated LxRxxS/T motifs. Thus loss of PKD1/3 enzymes does not globally disrupt the phosphorylation of cellular proteins that contain LxRxxpS/T motifs. This result is perhaps not surprising as LxRxxS/T motifs also act as good substrates for other serine/threonine kinases such as MAPKAPK2. However these experiments do provide further evidence that phosphospecific antisera are not sufficiently selective to be designated kinase specific substrate antisera. BCR-induced signalling pathways culminate in the activation of gene transcription events that control B cell survival, proliferation and function. In this context, it has been proposed that PKD family members control of gene transcription through activation of the NFκB transcription factor. Thus, PKD-mediated activation of NFκB occurs downstream of a variety of different signals, including mROS/oxidative stress, lysophosphatidic acid and the Bcr-Abl oncogene [17,21,23,30,37]. Furthermore, expression of an activated PKD1 mutant enhances HPK1-mediated NFκB activation [38]. In B cells, NFκB is known to be regulated via DAG and PKCβ [39,40] but whether PKDs are key intermediaries for NFκB regulation has not been explored. The data (Fig. 4A) show that NFκB transcriptional activity was strongly induced in both wild-type and PKD1/3−/− DT40 B cells in response to either phorbol ester or BCR stimulation. In contrast, BCR and phorbol ester-induced NFκB transcriptional activity was abolished in PKCβ−/− DT40 B cells (Fig. 4A), although strong activation of PKD kinases (as assessed by autophosphorylation of PKD1 at S916) was observed in the PKCβ−/− cells (Fig. 4B). Thus, PKD kinases are neither essential nor sufficient to mediate BCR-induced NFκB activation in DT40 B cells and hence do not participate in DAG/PKC mediated control of NFκB. 4 Discussion Protein
T7044	12937-12943	NN	denotes	kinase
T7045	12944-12945	NN	denotes	D
T7046	12946-12952	NN	denotes	serine
T7047	12953-12960	NN	denotes	kinases
T1722	3798-3799	CD	denotes	1
T1723	3799-3800	-RRB-	denotes	]
T1724	3802-3817	NN	denotes	Chloramphenicol
T1725	3818-3824	NN	denotes	acetyl
T1726	3825-3836	NN	denotes	transferase
T1727	3837-3843	NN	denotes	assays
T1728	3844-3848	VB	denotes	have
T1729	3849-3853	VB	denotes	been
T1730	3854-3863	VB	denotes	described
T1731	3864-3874	RB	denotes	previously
T1732	3875-3876	-LRB-	denotes	[
T1733	3876-3878	CD	denotes	29
T1734	3878-3879	-RRB-	denotes	]
T1869	3892-3900	NN	denotes	staining
T1870	3901-3905	NN	denotes	DT40
T1871	3906-3907	NN	denotes	B
T1872	3908-3913	NN	denotes	cells
R21	T63	T61	arg1Of	line,B-lymphocyte
R22	T63	T62	arg1Of	line,cell
R23	T65	T66	arg1Of	we,have
R24	T65	T67	arg1Of	we,shown
R25	T67	T64	arg1Of	shown,Previously
R26	T67	T66	arg2Of	shown,have
R27	T69	T70	arg1Of	PKDs,have
R28	T70	T67	arg2Of	have,shown
R29	T70	T68	arg1Of	have,that
R30	T70	T74	arg1Of	have,in
R31	T73	T70	arg2Of	role,have
R32	T73	T71	arg1Of	role,an
R33	T73	T72	arg1Of	role,essential
R34	T75	T74	arg2Of	regulating,in
R35	T75	T80	arg1Of	regulating,in
R36	T79	T75	arg2Of	deacetylases,regulating
R37	T79	T76	arg1Of	deacetylases,class
R38	T79	T77	arg1Of	deacetylases,II
R39	T79	T78	arg1Of	deacetylases,histone
R40	T82	T80	arg2Of	B-cells,in
R41	T82	T81	arg1Of	B-cells,DT40
R42	T84	T85	arg1Of	Matthews,","
R43	T85	T87	arg1Of	",",","
R44	T86	T85	arg2Of	S.A.,","
R45	T87	T89	arg1Of	",",","
R46	T88	T87	arg2Of	Liu,","
R47	T89	T91	arg1Of	",",","
R48	T90	T89	arg2Of	P.,","
R49	T91	T93	arg1Of	",",","
R50	T92	T91	arg2Of	Spitaler,","
R51	T93	T95	arg1Of	",",","
R52	T94	T93	arg2Of	M.,","
R53	T95	T105	arg1Of	",",","
R54	T96	T97	arg1Of	Olson,","
R55	T97	T99	arg1Of	",",","
R56	T98	T97	arg2Of	E.N.,","
R57	T99	T101	arg1Of	",",","
R58	T100	T99	arg2Of	McKinsey,","
R59	T101	T103	arg1Of	",",","
R60	T102	T101	arg2Of	T.A.,","
R61	T103	T95	arg2Of	",",","
R62	T104	T103	arg2Of	Cantrell,","
R63	T105	T107	arg1Of	",",and
R64	T106	T105	arg2Of	D.A.,","
R65	T108	T109	arg1Of	Scharenberg,","
R66	T109	T107	arg2Of	",",and
R67	T110	T109	arg2Of	A.M.,","
R68	T112	T111	arg2Of	2006,(
R69	T113	T111	arg3Of	),(
R70	T115	T80	arg3Of	role,in
R71	T115	T83	arg1Of	role,[
R72	T115	T84	arg1Of	role,Matthews
R73	T115	T86	arg1Of	role,S.A.
R74	T115	T88	arg1Of	role,Liu
R75	T115	T90	arg1Of	role,P.
R76	T115	T92	arg1Of	role,Spitaler
R77	T115	T94	arg1Of	role,M.
R78	T115	T96	arg1Of	role,Olson
R79	T115	T98	arg1Of	role,E.N.
R80	T115	T100	arg1Of	role,McKinsey
R81	T115	T102	arg1Of	role,T.A.
R82	T115	T104	arg1Of	role,Cantrell
R83	T115	T106	arg1Of	role,D.A.
R84	T115	T108	arg1Of	role,Scharenberg
R85	T115	T110	arg1Of	role,A.M.
R86	T115	T111	arg1Of	role,(
R87	T115	T114	arg1Of	role,Essential
R88	T115	T116	arg1Of	role,for
R89	T115	T122	arg1Of	role,in
R90	T121	T116	arg2Of	kinases,for
R91	T121	T117	arg1Of	kinases,protein
R92	T121	T118	arg1Of	kinases,kinase
R93	T121	T119	arg1Of	kinases,D
R94	T121	T120	arg1Of	kinases,family
R95	T124	T122	arg2Of	regulation,in
R96	T124	T123	arg1Of	regulation,the
R97	T124	T125	arg1Of	regulation,of
R98	T129	T125	arg2Of	deacetylases,of
R99	T129	T126	arg1Of	deacetylases,class
R100	T129	T127	arg1Of	deacetylases,II
R101	T129	T128	arg1Of	deacetylases,histone
R102	T129	T130	arg1Of	deacetylases,in
R103	T132	T130	arg2Of	lymphocytes,in
R104	T132	T131	arg1Of	lymphocytes,B
R105	T135	T133	arg1Of	Biol.,Mol.
R106	T135	T134	arg1Of	Biol.,Cell
R107	T135	T136	arg1Of	Biol.,26
R108	T135	T137	arg1Of	Biol.,","
R109	T138	T137	arg2Of	1569–1577,","
R110	T138	T139	arg1Of	1569–1577,]
R111	T140	T142	arg1Of	We,show
R112	T142	T141	arg1Of	show,now
R113	T144	T145	arg1Of	PKDs,are
R114	T144	T147	arg2Of	PKDs,required
R115	T144	T149	arg1Of	PKDs,regulate
R116	T147	T142	arg2Of	required,show
R117	T147	T143	arg1Of	required,that
R118	T147	T145	arg2Of	required,are
R119	T147	T146	arg1Of	required,also
R120	T149	T147	arg3Of	regulate,required
R121	T149	T148	arg1Of	regulate,to
R122	T149	T152	arg1Of	regulate,in
R123	T151	T149	arg2Of	phosphorylation,regulate
R124	T151	T150	arg1Of	phosphorylation,HSP27
R125	T154	T152	arg2Of	B-cells,in
R126	T154	T153	arg1Of	B-cells,DT40
R127	T158	T157	arg2Of	contrast,in
R128	T158	T159	arg1Of	contrast,to
R129	T161	T159	arg2Of	observations,to
R130	T161	T160	arg1Of	observations,previous
R131	T161	T162	arg1Of	observations,in
R132	T165	T162	arg2Of	types,in
R133	T165	T163	arg1Of	types,other
R134	T165	T164	arg1Of	types,cell
R135	T168	T167	arg1Of	enzymes,PKD
R136	T168	T169	arg1Of	enzymes,do
R137	T168	T171	arg1Of	enzymes,regulate
R138	T171	T155	arg1Of	regulate,However
R139	T171	T156	arg1Of	regulate,","
R140	T171	T157	arg1Of	regulate,in
R141	T171	T166	arg1Of	regulate,","
R142	T171	T169	arg2Of	regulate,do
R143	T171	T170	arg1Of	regulate,not
R144	T174	T171	arg2Of	processes,regulate
R145	T174	T172	arg1Of	processes,basic
R146	T174	T173	arg1Of	processes,cellular
R147	T174	T176	arg1Of	processes,as
R148	T176	T175	arg1Of	as,such
R149	T177	T178	arg1Of	proliferation,or
R150	T178	T182	arg1Of	or,nor
R151	T180	T178	arg2Of	responses,or
R152	T180	T179	arg1Of	responses,survival
R153	T182	T176	arg2Of	nor,as
R154	T182	T181	arg1Of	nor,","
R155	T185	T182	arg2Of	activity,nor
R156	T185	T183	arg1Of	activity,NFκB
R157	T185	T184	arg1Of	activity,transcriptional
R158	T185	T186	arg1Of	activity,downstream
R159	T186	T187	arg1Of	downstream,of
R160	T192	T187	arg2Of	receptor,of
R161	T192	T188	arg1Of	receptor,the
R162	T192	T189	arg1Of	receptor,B
R163	T192	T190	arg1Of	receptor,cell
R164	T192	T191	arg1Of	receptor,antigen
R165	T195	T196	arg1Of	PKDs,have
R166	T196	T193	arg1Of	have,Thus
R167	T196	T194	arg1Of	have,","
R168	T196	T200	arg1Of	have,in
R169	T199	T196	arg2Of	role,have
R170	T199	T197	arg1Of	role,a
R171	T199	T198	arg1Of	role,selective
R172	T203	T200	arg2Of	biology,in
R173	T203	T201	arg1Of	biology,DT40
R174	T203	T202	arg1Of	biology,B-cell
R430	T535	T532	arg1Of	D,"1569–1577]. We now show that PKDs are also required to regulate HSP27 phosphorylation in DT40 B-cells. However, in contrast to previous observations in other cell types, PKD enzymes do not regulate basic cellular processes such as proliferation or survival responses, nor NFκB transcriptional activity downstream of the B cell antigen receptor. Thus, PKDs have a selective role in DT40 B-cell biology. 1 Introduction The"
R431	T535	T533	arg1Of	D,protein
R432	T535	T534	arg1Of	D,kinase
R433	T535	T536	arg1Of	D,(
R434	T537	T536	arg2Of	PKD,(
R435	T538	T536	arg3Of	),(
R436	T541	T535	arg1Of	family,D
R437	T541	T539	arg1Of	family,serine/threonine
R438	T541	T540	arg1Of	family,kinase
R439	T541	T542	arg1Of	family,has
R440	T544	T542	arg2Of	members,has
R441	T544	T543	arg1Of	members,three
R442	T544	T545	arg1Of	members,:
R443	T546	T547	arg1Of	PKD1,","
R444	T547	T549	arg1Of	",",and
R445	T548	T547	arg2Of	PKD2,","
R446	T549	T545	arg2Of	and,:
R447	T550	T549	arg2Of	PKD3,and
R448	T553	T551	arg1Of	types,Most
R449	T553	T552	arg1Of	types,cell
R450	T553	T554	arg1Of	types,express
R451	T554	T560	arg1Of	express,but
R452	T557	T555	arg1Of	two,at
R453	T557	T556	arg1Of	two,least
R454	T559	T554	arg2Of	isoforms,express
R455	T559	T557	arg1Of	isoforms,two
R456	T559	T558	arg1Of	isoforms,PKD
R457	T562	T561	arg1Of	enzymes,PKD
R458	T562	T563	arg1Of	enzymes,are
R459	T562	T566	arg2Of	enzymes,expressed
R460	T565	T564	arg1Of	highly,especially
R461	T566	T560	arg2Of	expressed,but
R462	T566	T563	arg2Of	expressed,are
R463	T566	T565	arg1Of	expressed,highly
R464	T566	T567	arg1Of	expressed,in
R465	T569	T567	arg2Of	cells,in
R466	T569	T568	arg1Of	cells,haematopoietic
R467	T569	T570	arg1Of	cells,","
R468	T569	T571	arg1Of	cells,where
R469	T572	T573	arg1Of	they,are
R470	T572	T574	arg2Of	they,activated
R471	T574	T571	arg2Of	activated,where
R472	T574	T573	arg2Of	activated,are
R473	T574	T575	arg1Of	activated,in
R474	T574	T581	arg1Of	activated,[
R475	T575	T577	arg1Of	in,to
R476	T576	T575	arg2Of	response,in
R477	T580	T575	arg3Of	stimulation,in
R478	T580	T578	arg1Of	stimulation,antigen
R479	T580	T579	arg1Of	stimulation,receptors
R480	T582	T581	arg2Of	"2,3",[
R481	T583	T581	arg3Of	],[
R482	T587	T584	arg1Of	pathway,A
R483	T587	T585	arg2Of	pathway,conserved
R484	T587	T586	arg1Of	pathway,signalling
R485	T587	T588	arg1Of	pathway,linking
R486	T587	T593	arg1Of	pathway,involves
R487	T590	T588	arg2Of	receptors,linking
R488	T590	T589	arg1Of	receptors,antigen
R489	T590	T591	arg1Of	receptors,to
R490	T592	T591	arg2Of	PKDs,to
R491	T595	T594	arg1Of	activation,the
R492	T595	T596	arg1Of	activation,of
R493	T595	T598	arg1Of	activation,and
R494	T597	T596	arg2Of	PLCγ,of
R495	T598	T593	arg2Of	and,involves
R496	T601	T598	arg2Of	production,and
R497	T601	T599	arg1Of	production,the
R498	T601	T600	arg1Of	production,subsequent
R499	T601	T602	arg1Of	production,of
R500	T601	T607	arg1Of	production,which
R501	T601	T608	arg1Of	production,stimulates
R502	T603	T602	arg2Of	diacylglycerol,of
R503	T603	T604	arg1Of	diacylglycerol,(
R504	T605	T604	arg2Of	DAG,(
R505	T606	T604	arg3Of	),(
R506	T609	T610	arg1Of	classical,and/or
R507	T611	T610	arg2Of	novel,and/or
R508	T614	T608	arg2Of	Cs,stimulates
R509	T614	T609	arg1Of	Cs,classical
R510	T614	T611	arg1Of	Cs,novel
R511	T614	T612	arg1Of	Cs,protein
R512	T614	T613	arg1Of	Cs,kinase
R513	T614	T615	arg1Of	Cs,(
R514	T614	T618	arg1Of	Cs,that
R515	T614	T619	arg1Of	Cs,phosphorylate
R516	T616	T615	arg2Of	PKC,(
R517	T617	T615	arg3Of	),(
R518	T619	T625	arg1Of	phosphorylate,in
R519	T624	T619	arg2Of	residues,phosphorylate
R520	T624	T620	arg1Of	residues,two
R521	T624	T621	arg1Of	residues,key
R522	T624	T622	arg1Of	residues,regulatory
R523	T624	T623	arg1Of	residues,serine
R524	T628	T625	arg2Of	loop,in
R525	T628	T626	arg1Of	loop,the
R526	T628	T627	arg1Of	loop,activation
R527	T628	T629	arg1Of	loop,of
R528	T628	T632	arg1Of	loop,[
R529	T631	T629	arg2Of	kinases,of
R530	T631	T630	arg1Of	kinases,PKD
R531	T633	T632	arg2Of	3–6,[
R532	T634	T632	arg3Of	],[
R533	T638	T635	arg1Of	region,The
R534	T638	T636	arg1Of	region,N-terminal
R535	T638	T637	arg1Of	region,regulatory
R536	T638	T639	arg1Of	region,of
R537	T638	T642	arg1Of	region,contains
R538	T641	T639	arg2Of	enzymes,of
R539	T641	T640	arg1Of	enzymes,PKD
R540	T642	T647	arg1Of	contains,and
R541	T646	T642	arg2Of	domain,contains
R542	T646	T643	arg1Of	domain,a
R543	T646	T644	arg1Of	domain,DAG
R544	T646	T645	arg1Of	domain,binding
R545	T649	T648	arg1Of	binding,direct
R546	T649	T650	arg1Of	binding,of
R547	T649	T653	arg1Of	binding,contributes
R548	T651	T650	arg2Of	DAG,of
R549	T653	T647	arg2Of	contributes,and
R550	T653	T652	arg1Of	contributes,also
R551	T653	T654	arg1Of	contributes,to
R552	T653	T657	arg1Of	contributes,[
R553	T653	T661	arg1Of	contributes,well
R554	T653	T662	arg1Of	contributes,as
R555	T656	T654	arg2Of	activation,to
R556	T656	T655	arg1Of	activation,PKD1
R557	T658	T657	arg2Of	7,[
R558	T659	T657	arg3Of	],[
R559	T661	T660	arg1Of	well,as
R560	T663	T662	arg2Of	regulating,as
R561	T666	T663	arg2Of	location,regulating
R562	T666	T664	arg1Of	location,the
R563	T666	T665	arg1Of	location,spatial
R564	T666	T667	arg1Of	location,of
R565	T666	T670	arg1Of	location,within
R566	T669	T667	arg2Of	enzymes,of
R567	T669	T668	arg1Of	enzymes,PKD
R568	T671	T670	arg2Of	cells,within
R569	T671	T672	arg1Of	cells,[
R570	T673	T672	arg2Of	8–12,[
R571	T674	T672	arg3Of	],[
R572	T676	T675	arg1Of	enzymes,PKD
R573	T676	T677	arg1Of	enzymes,have
R574	T676	T678	arg1Of	enzymes,been
R575	T676	T679	arg2Of	enzymes,proposed
R576	T676	T681	arg1Of	enzymes,regulate
R577	T679	T677	arg2Of	proposed,have
R578	T679	T678	arg2Of	proposed,been
R579	T681	T679	arg3Of	regulate,proposed
R580	T681	T680	arg1Of	regulate,to
R581	T684	T681	arg2Of	functions,regulate
R582	T684	T682	arg1Of	functions,numerous
R583	T684	T683	arg1Of	functions,cellular
R584	T684	T685	arg1Of	functions,","
R585	T684	T686	arg1Of	functions,including
R586	T688	T687	arg1Of	proliferation,cell
R587	T688	T689	arg1Of	proliferation,[
R588	T688	T692	arg1Of	proliferation,","
R589	T690	T689	arg2Of	13–16,[
R590	T691	T689	arg3Of	],[
R591	T692	T698	arg1Of	",",and
R592	T694	T692	arg2Of	signals,","
R593	T694	T693	arg1Of	signals,anti-apoptotic
R594	T694	T695	arg1Of	signals,[
R595	T696	T695	arg2Of	"17,18",[
R596	T697	T695	arg3Of	],[
R597	T698	T686	arg2Of	and,including
R598	T700	T698	arg2Of	development,and
R599	T700	T699	arg1Of	development,thymocyte
R600	T700	T701	arg1Of	development,[
R601	T702	T701	arg2Of	19,[
R602	T703	T701	arg3Of	],[
R603	T704	T705	arg1Of	Expression,of
R604	T704	T713	arg1Of	Expression,can
R605	T704	T715	arg1Of	Expression,modify
R606	T708	T709	arg1Of	inactive,and
R607	T710	T709	arg2Of	constitutively,and
R608	T712	T705	arg2Of	PKDs,of
R609	T712	T706	arg1Of	PKDs,mutant
R610	T712	T707	arg1Of	PKDs,catalytically
R611	T712	T708	arg1Of	PKDs,inactive
R612	T712	T710	arg1Of	PKDs,constitutively
R613	T712	T711	arg2Of	PKDs,activated
R614	T715	T713	arg2Of	modify,can
R615	T715	T714	arg1Of	modify,also
R616	T717	T716	arg1Of	function,Golgi
R617	T717	T718	arg1Of	function,","
R618	T718	T721	arg1Of	",",and
R619	T720	T718	arg2Of	adhesion,","
R620	T720	T719	arg1Of	adhesion,cell
R621	T721	T715	arg2Of	and,modify
R622	T723	T721	arg2Of	motility,and
R623	T723	T722	arg1Of	motility,cell
R624	T723	T724	arg1Of	motility,(
R625	T725	T724	arg2Of	reviewed,(
R626	T725	T726	arg1Of	reviewed,in
R627	T725	T727	arg1Of	reviewed,[
R628	T728	T727	arg2Of	20,[
R629	T729	T727	arg3Of	],[
R630	T730	T724	arg3Of	),(
R631	T732	T731	arg2Of	particular,In
R632	T734	T735	arg1Of	PKDs,have
R633	T734	T736	arg1Of	PKDs,been
R634	T734	T738	arg2Of	PKDs,linked
R635	T734	T749	arg1Of	PKDs,regulating
R636	T738	T731	arg1Of	linked,In
R637	T738	T733	arg1Of	linked,","
R638	T738	T735	arg2Of	linked,have
R639	T738	T736	arg2Of	linked,been
R640	T738	T737	arg1Of	linked,widely
R641	T738	T739	arg1Of	linked,to
R642	T738	T748	arg1Of	linked,in
R643	T739	T747	arg1Of	to,and
R644	T741	T739	arg2Of	activation,to
R645	T741	T740	arg1Of	activation,the
R646	T741	T742	arg1Of	activation,of
R647	T746	T742	arg2Of	factor,of
R648	T746	T743	arg1Of	factor,the
R649	T746	T744	arg1Of	factor,NFκB
R650	T746	T745	arg1Of	factor,transcription
R651	T748	T747	arg2Of	in,and
R652	T749	T748	arg2Of	regulating,in
R653	T749	T752	arg1Of	regulating,during
R654	T751	T749	arg2Of	survival,regulating
R655	T751	T750	arg1Of	survival,cell
R656	T754	T752	arg2Of	stress,during
R657	T754	T753	arg1Of	stress,oxidative
R658	T754	T755	arg1Of	stress,[
R659	T756	T755	arg2Of	"17,21–23",[
R660	T757	T755	arg3Of	],[
R661	T760	T759	arg1Of	proposed,recently
R662	T762	T758	arg1Of	substrate,Another
R663	T762	T760	arg1Of	substrate,proposed
R664	T762	T761	arg1Of	substrate,PKD1
R665	T762	T763	arg1Of	substrate,is
R666	T764	T763	arg2Of	HSP27,is
R667	T764	T765	arg1Of	HSP27,[
R668	T764	T768	arg1Of	HSP27,","
R669	T766	T765	arg2Of	24,[
R670	T767	T765	arg3Of	],[
R671	T773	T768	arg2Of	protein,","
R672	T773	T769	arg1Of	protein,a
R673	T773	T770	arg1Of	protein,small
R674	T773	T771	arg1Of	protein,heat
R675	T773	T772	arg1Of	protein,shock
R676	T773	T774	arg2Of	protein,involved
R677	T774	T775	arg1Of	involved,in
R678	T776	T775	arg2Of	regulating,in
R679	T776	T782	arg1Of	regulating,[
R680	T778	T777	arg1Of	migration,cell
R681	T778	T779	arg1Of	migration,and
R682	T779	T776	arg2Of	and,regulating
R683	T781	T779	arg2Of	survival,and
R684	T781	T780	arg1Of	survival,cell
R685	T783	T782	arg2Of	25,[
R686	T784	T782	arg3Of	],[
R687	T787	T785	arg1Of	role,An
R688	T787	T786	arg1Of	role,essential
R689	T787	T788	arg1Of	role,for
R690	T787	T808	arg1Of	role,has
R691	T787	T810	arg1Of	role,been
R692	T787	T811	arg2Of	role,demonstrated
R693	T790	T788	arg2Of	enzymes,for
R694	T790	T789	arg1Of	enzymes,PKD
R695	T790	T791	arg1Of	enzymes,in
R696	T792	T791	arg2Of	regulating,in
R697	T796	T792	arg2Of	deacetylases,regulating
R698	T796	T793	arg1Of	deacetylases,class
R699	T796	T794	arg1Of	deacetylases,II
R700	T796	T795	arg1Of	deacetylases,histone
R701	T796	T797	arg1Of	deacetylases,(
R702	T796	T800	arg1Of	deacetylases,","
R703	T798	T797	arg2Of	HDACs,(
R704	T799	T797	arg3Of	),(
R705	T801	T800	arg2Of	enzymes,","
R706	T801	T802	arg1Of	enzymes,that
R707	T801	T803	arg1Of	enzymes,repress
R708	T806	T803	arg2Of	transcription,repress
R709	T806	T804	arg1Of	transcription,MEF2-dependent
R710	T806	T805	arg1Of	transcription,gene
R711	T811	T807	arg1Of	demonstrated,","
R712	T811	T808	arg2Of	demonstrated,has
R713	T811	T809	arg1Of	demonstrated,also
R714	T811	T810	arg2Of	demonstrated,been
R715	T811	T812	arg1Of	demonstrated,[
R716	T813	T812	arg2Of	"1,26–28",[
R717	T814	T812	arg3Of	],[
R718	T816	T815	arg1Of	investigate,To
R719	T819	T816	arg2Of	role,investigate
R720	T819	T817	arg1Of	role,the
R721	T819	T818	arg1Of	role,biological
R722	T819	T820	arg1Of	role,of
R723	T821	T820	arg2Of	PKDs,of
R724	T822	T816	arg1Of	we,investigate
R725	T822	T823	arg1Of	we,have
R726	T822	T824	arg1Of	we,generated
R727	T824	T815	modOf	generated,To
R728	T824	T823	arg2Of	generated,have
R729	T828	T824	arg2Of	lines,generated
R730	T828	T825	arg1Of	lines,DT40
R731	T828	T826	arg1Of	lines,B
R732	T828	T827	arg1Of	lines,cell
R733	T828	T829	arg1Of	lines,that
R734	T828	T830	arg1Of	lines,lack
R735	T830	T844	arg1Of	lack,","
R736	T830	T845	modOf	lack,allowing
R737	T830	T866	arg1Of	lack,","
R738	T830	T869	modOf	lack,addressing
R739	T831	T830	arg2Of	expression,lack
R740	T831	T832	arg1Of	expression,of
R741	T833	T834	arg1Of	one,or
R742	T833	T835	arg1Of	one,more
R743	T836	T832	arg2Of	members,of
R744	T836	T833	arg1Of	members,one
R745	T836	T837	arg1Of	members,of
R746	T840	T837	arg2Of	family,of
R747	T840	T838	arg1Of	family,the
R748	T840	T839	arg1Of	family,PKD
R749	T840	T841	arg1Of	family,[
R750	T842	T841	arg2Of	1,[
R751	T843	T841	arg3Of	],[
R752	T846	T845	arg2Of	us,allowing
R753	T846	T848	arg1Of	us,investigate
R754	T848	T845	arg3Of	investigate,allowing
R755	T848	T847	arg1Of	investigate,to
R756	T850	T848	arg2Of	function,investigate
R757	T850	T849	arg1Of	function,the
R758	T850	T851	arg1Of	function,(
R759	T850	T854	arg1Of	function,of
R760	T850	T857	arg1Of	function,following
R761	T852	T851	arg2Of	s,(
R762	T853	T851	arg3Of	),(
R763	T856	T854	arg2Of	isoforms,of
R764	T856	T855	arg1Of	isoforms,PKD
R765	T863	T862	arg2Of	BCR,(
R766	T864	T862	arg3Of	),(
R767	T865	T857	arg2Of	stimulation,following
R768	T865	T858	arg1Of	stimulation,B
R769	T865	T859	arg1Of	stimulation,cell
R770	T865	T860	arg1Of	stimulation,antigen
R771	T865	T861	arg1Of	stimulation,receptor
R772	T865	T862	arg1Of	stimulation,(
R773	T869	T867	arg1Of	addressing,as
R774	T869	T868	arg1Of	addressing,well
R775	T871	T869	arg2Of	issue,addressing
R776	T871	T870	arg1Of	issue,the
R777	T871	T872	arg1Of	issue,of
R778	T874	T872	arg2Of	redundancy,of
R779	T874	T873	arg1Of	redundancy,functional
R780	T874	T875	arg1Of	redundancy,between
R781	T880	T875	arg2Of	members,between
R782	T880	T876	arg1Of	members,the
R783	T880	T877	arg1Of	members,different
R784	T880	T878	arg1Of	members,PKD
R785	T880	T879	arg1Of	members,family
R786	T882	T881	arg1Of	studies,Previous
R787	T882	T883	arg1Of	studies,have
R788	T882	T884	arg1Of	studies,shown
R789	T884	T883	arg2Of	shown,have
R790	T886	T887	arg1Of	PKDs,are
R791	T886	T888	arg1Of	PKDs,indispensable
R792	T887	T884	arg2Of	are,shown
R793	T887	T885	arg1Of	are,that
R794	T887	T895	arg1Of	are,[
R795	T888	T887	arg2Of	indispensable,are
R796	T888	T889	arg1Of	indispensable,for
R797	T891	T889	arg2Of	regulation,for
R798	T891	T890	arg1Of	regulation,HDAC
R799	T891	T892	arg1Of	regulation,in
R800	T894	T892	arg2Of	cells,in
R801	T894	T893	arg1Of	cells,B
R802	T896	T895	arg2Of	1,[
R803	T897	T895	arg3Of	],[
R804	T899	T900	arg1Of	we,show
R805	T900	T898	arg1Of	show,Herein
R806	T902	T903	arg1Of	PKDs,are
R807	T902	T905	arg1Of	PKDs,indispensable
R808	T903	T900	arg2Of	are,show
R809	T903	T901	arg1Of	are,that
R810	T903	T904	arg1Of	are,also
R811	T905	T903	arg2Of	indispensable,are
R812	T905	T906	arg1Of	indispensable,for
R813	T908	T906	arg2Of	phosphorylation,for
R814	T908	T907	arg1Of	phosphorylation,HSP27
R815	T908	T909	arg1Of	phosphorylation,in
R816	T911	T909	arg2Of	cells,in
R817	T911	T910	arg1Of	cells,B
R818	T917	T914	arg1Of	cells,PKD-null
R819	T917	T915	arg1Of	cells,DT40
R820	T917	T916	arg1Of	cells,B
R821	T917	T918	arg1Of	cells,are
R822	T917	T919	arg1Of	cells,viable
R823	T917	T921	arg1Of	cells,proliferate
R824	T918	T920	arg1Of	are,and
R825	T919	T918	arg2Of	viable,are
R826	T920	T912	arg1Of	and,However
R827	T920	T913	arg1Of	and,","
R828	T921	T920	arg2Of	proliferate,and
R829	T921	T922	arg1Of	proliferate,normally
R830	T925	T926	arg1Of	loss,of
R831	T925	T933	arg1Of	loss,does
R832	T925	T936	arg1Of	loss,affect
R833	T925	T944	arg1Of	loss,do
R834	T930	T926	arg2Of	pool,of
R835	T930	T927	arg1Of	pool,the
R836	T930	T928	arg1Of	pool,entire
R837	T930	T929	arg1Of	pool,cellular
R838	T930	T931	arg1Of	pool,of
R839	T932	T931	arg2Of	PKD,of
R840	T936	T933	arg2Of	affect,does
R841	T936	T934	arg1Of	affect,not
R842	T936	T935	arg1Of	affect,critically
R843	T936	T943	arg1Of	affect,nor
R844	T939	T936	arg2Of	responses,affect
R845	T939	T937	arg1Of	responses,oxidative
R846	T939	T938	arg1Of	responses,stress
R847	T939	T940	arg1Of	responses,in
R848	T942	T940	arg2Of	cells,in
R849	T942	T941	arg1Of	cells,B
R850	T943	T923	arg1Of	nor,Moreover
R851	T943	T924	arg1Of	nor,","
R852	T944	T943	arg2Of	do,nor
R853	T945	T944	arg2Of	PKD,do
R854	T946	T947	arg1Of	kinases,play
R855	T946	T952	arg1Of	kinases,regulating
R856	T947	T944	arg3Of	play,do
R857	T947	T951	arg1Of	play,in
R858	T950	T947	arg2Of	role,play
R859	T950	T948	arg1Of	role,an
R860	T950	T949	arg1Of	role,essential
R861	T952	T951	arg2Of	regulating,in
R862	T955	T952	arg2Of	activity,regulating
R863	T955	T953	arg1Of	activity,NFκB
R864	T955	T954	arg1Of	activity,transcriptional
R865	T959	T958	arg1Of	findings,these
R866	T959	T960	arg1Of	findings,reveal
R867	T960	T956	arg1Of	reveal,Together
R868	T960	T957	arg1Of	reveal,","
R869	T964	T962	arg2Of	lymphocytes,in
R870	T964	T963	arg1Of	lymphocytes,B
R871	T967	T966	arg1Of	kinases,PKD
R872	T967	T968	arg1Of	kinases,are
R873	T968	T960	arg2Of	are,reveal
R874	T968	T961	arg1Of	are,that
R875	T968	T962	arg1Of	are,in
R876	T968	T965	arg1Of	are,","
R877	T968	T969	arg1Of	are,not
R878	T971	T968	arg2Of	regulators,are
R879	T971	T970	arg1Of	regulators,critical
R880	T971	T972	arg1Of	regulators,of
R881	T973	T972	arg2Of	many,of
R882	T973	T974	arg1Of	many,of
R883	T977	T974	arg2Of	processes,of
R884	T977	T975	arg1Of	processes,the
R885	T977	T976	arg1Of	processes,cellular
R886	T977	T979	arg2Of	processes,ascribed
R887	T979	T978	arg1Of	ascribed,previously
R888	T979	T980	arg1Of	ascribed,to
R889	T979	T982	arg1Of	ascribed,in
R890	T981	T980	arg2Of	them,to
R891	T985	T982	arg2Of	systems,in
R892	T985	T983	arg1Of	systems,other
R893	T985	T984	arg1Of	systems,cellular
R1438	T1675	T1676	arg1Of	culture,","
R1439	T1676	T1679	arg1Of	",",and
R1440	T1678	T1676	arg2Of	transfections,","
R1441	T1678	T1677	arg1Of	transfections,transient
R1442	T1681	T1679	arg2Of	stimulation,and
R1443	T1681	T1680	arg1Of	stimulation,cell
R1444	T1683	T1684	arg1Of	generation,","
R1445	T1684	T1686	arg1Of	",",and
R1446	T1685	T1684	arg2Of	culture,","
R1447	T1686	T1682	arg1Of	and,The
R1448	T1686	T1688	arg1Of	and,of
R1449	T1686	T1699	arg1Of	and,have
R1450	T1686	T1700	arg1Of	and,been
R1451	T1686	T1701	arg2Of	and,described
R1452	T1687	T1686	arg2Of	activation,and
R1453	T1689	T1690	arg1Of	PKD1−/−,","
R1454	T1690	T1692	arg1Of	",",and
R1455	T1691	T1690	arg2Of	PKD3−/−,","
R1456	T1693	T1692	arg2Of	PKD1/3−/−,and
R1457	T1698	T1688	arg2Of	lines,of
R1458	T1698	T1689	arg1Of	lines,PKD1−/−
R1459	T1698	T1691	arg1Of	lines,PKD3−/−
R1460	T1698	T1693	arg1Of	lines,PKD1/3−/−
R1461	T1698	T1694	arg1Of	lines,knockout
R1462	T1698	T1695	arg1Of	lines,DT40
R1463	T1698	T1696	arg1Of	lines,B
R1464	T1698	T1697	arg1Of	lines,cell
R1465	T1701	T1699	arg2Of	described,have
R1466	T1701	T1700	arg2Of	described,been
R1467	T1701	T1702	arg1Of	described,previously
R1468	T1701	T1703	arg1Of	described,[
R1469	T1704	T1703	arg2Of	1,[
R1470	T1705	T1703	arg3Of	],[
R1471	T1706	T1707	arg1Of	Cells,were
R1472	T1706	T1708	arg2Of	Cells,lysed
R1473	T1708	T1707	arg2Of	lysed,were
R1474	T1708	T1709	arg1Of	lysed,and
R1475	T1711	T1710	arg1Of	extracts,protein
R1476	T1711	T1712	arg1Of	extracts,were
R1477	T1711	T1713	arg2Of	extracts,analysed
R1478	T1713	T1709	arg2Of	analysed,and
R1479	T1713	T1712	arg2Of	analysed,were
R1480	T1713	T1714	arg1Of	analysed,in
R1481	T1713	T1718	arg1Of	analysed,as
R1482	T1717	T1714	arg2Of	experiments,in
R1483	T1717	T1715	arg1Of	experiments,Western
R1484	T1717	T1716	arg1Of	experiments,blotting
R1485	T1720	T1719	arg1Of	described,previously
R1486	T1722	T1718	arg2Of	1,as
R1487	T1722	T1720	arg1Of	1,described
R1488	T1722	T1721	arg2Of	1,[
R1489	T1723	T1721	arg3Of	],[
R1490	T1727	T1724	arg1Of	assays,Chloramphenicol
R1491	T1727	T1725	arg1Of	assays,acetyl
R1492	T1727	T1726	arg1Of	assays,transferase
R1493	T1727	T1728	arg1Of	assays,have
R1494	T1727	T1729	arg1Of	assays,been
R1495	T1727	T1730	arg2Of	assays,described
R1496	T1730	T1728	arg2Of	described,have
R1497	T1730	T1729	arg2Of	described,been
R1498	T1730	T1731	arg1Of	described,previously
R1499	T1730	T1732	arg1Of	described,[
R1500	T1733	T1732	arg2Of	29,[
R1501	T1734	T1732	arg3Of	],[
R1598	T1872	T1870	arg1Of	cells,DT40
R1599	T1872	T1871	arg1Of	cells,B
R1600	T1872	T1873	arg1Of	cells,(
R1601	T1872	T1880	arg2Of	cells,resuspended
R1604	T1875	T1873	arg2Of	cells,(
R1606	T1878	T1873	arg3Of	),(
R1607	T1880	T1879	arg2Of	resuspended,were
R1608	T1880	T1881	arg1Of	resuspended,in
R1609	T1883	T1881	arg2Of	buffer,in
R1610	T1883	T1882	arg1Of	buffer,200 μl
R1611	T1883	T1884	arg1Of	buffer,(
R1613	T1887	T1884	arg2Of	media,(
R1614	T1887	T1885	arg1Of	media,RPMI
R1615	T1887	T1886	arg1Of	media,1640
R1616	T1887	T1888	arg1Of	media,","
R1618	T1893	T1888	arg2Of	serum,","
R1619	T1893	T1889	arg1Of	serum,1
R1622	T1894	T1884	arg3Of	),(
R1653	T1924	T1923	arg2Of	representative,are
R1654	T1924	T1926	arg1Of	representative,at
R1655	T1926	T1925	arg1Of	at,of
R1656	T1927	T1928	arg1Of	two,to
R1657	T1929	T1928	arg2Of	four,to
R1658	T1931	T1926	arg2Of	experiments,at
R1659	T1931	T1927	arg1Of	experiments,two
R1660	T1931	T1930	arg1Of	experiments,independent
R1661	T1934	T1932	arg2Of	indicated,unless
R1662	T1934	T1933	arg1Of	indicated,otherwise
R1889	T2291	T2289	arg2Of	phosphorylation,of
R1890	T2291	T2290	arg1Of	phosphorylation,HSP27
R1891	T2295	T2292	arg2Of	cells,in
R1892	T2295	T2293	arg1Of	cells,DT40
R1893	T2295	T2294	arg1Of	cells,B
R1894	T2295	T2296	arg1Of	cells,lacking
R1895	T2297	T2296	arg2Of	expression,lacking
R1896	T2297	T2298	arg1Of	expression,of
R1897	T2301	T2298	arg2Of	kinases,of
R1898	T2301	T2299	arg1Of	kinases,PKD
R1899	T2301	T2300	arg1Of	kinases,family
R1900	T2304	T2302	arg1Of	cells,DT40
R1901	T2304	T2303	arg1Of	cells,B
R1902	T2304	T2305	arg1Of	cells,express
R1903	T2308	T2305	arg2Of	isoforms,express
R1904	T2308	T2306	arg1Of	isoforms,two
R1905	T2308	T2307	arg1Of	isoforms,PKD
R1906	T2308	T2309	arg1Of	isoforms,","
R1907	T2310	T2311	arg1Of	PKD1,and
R1908	T2311	T2309	arg2Of	and,","
R1909	T2311	T2314	arg1Of	and,and
R1910	T2311	T2315	arg1Of	and,as
R1911	T2312	T2311	arg2Of	PKD3,and
R1912	T2314	T2313	arg1Of	and,","
R1913	T2317	T2315	arg2Of	described,as
R1914	T2317	T2316	arg1Of	described,previously
R1915	T2318	T2319	arg1Of	we,have
R1916	T2318	T2321	arg1Of	we,generated
R1917	T2321	T2317	arg3Of	generated,described
R1918	T2321	T2319	arg2Of	generated,have
R1919	T2321	T2320	arg1Of	generated,recently
R1920	T2321	T2337	arg1Of	generated,[
R1921	T2325	T2321	arg2Of	lines,generated
R1922	T2325	T2322	arg1Of	lines,DT40
R1923	T2325	T2323	arg1Of	lines,B
R1924	T2325	T2324	arg1Of	lines,cell
R1925	T2325	T2326	arg1Of	lines,that
R1926	T2325	T2327	arg1Of	lines,lack
R1927	T2328	T2329	arg1Of	expression,of
R1928	T2328	T2334	arg1Of	expression,or
R1929	T2331	T2332	arg1Of	PKD1,or
R1930	T2332	T2329	arg2Of	or,of
R1931	T2332	T2330	arg1Of	or,either
R1932	T2333	T2332	arg2Of	PKD3,or
R1933	T2334	T2327	arg2Of	or,lack
R1934	T2336	T2334	arg2Of	enzymes,or
R1935	T2336	T2335	arg1Of	enzymes,both
R1936	T2338	T2337	arg2Of	1,[
R1937	T2339	T2337	arg3Of	],[
R1938	T2341	T2340	arg2Of	generating,In
R1939	T2346	T2341	arg2Of	lines,generating
R1940	T2346	T2342	arg1Of	lines,the
R1941	T2346	T2343	arg1Of	lines,double
R1942	T2346	T2344	arg1Of	lines,knockout
R1943	T2346	T2345	arg1Of	lines,cell
R1944	T2347	T2348	arg1Of	we,targeted
R1945	T2348	T2340	arg1Of	targeted,In
R1946	T2348	T2352	arg1Of	targeted,in
R1947	T2351	T2348	arg2Of	loci,targeted
R1948	T2351	T2349	arg1Of	loci,the
R1949	T2351	T2350	arg1Of	loci,PKD1
R1950	T2356	T2352	arg2Of	line,in
R1951	T2356	T2353	arg1Of	line,a
R1952	T2356	T2354	arg1Of	line,PKD3−/−
R1953	T2356	T2355	arg1Of	line,cell
R1954	T2356	T2357	arg1Of	line,that
R1955	T2356	T2358	arg1Of	line,expressed
R1956	T2358	T2362	arg1Of	expressed,under
R1957	T2361	T2358	arg2Of	transgene,expressed
R1958	T2361	T2359	arg1Of	transgene,a
R1959	T2361	T2360	arg1Of	transgene,Flag-PKD3
R1960	T2364	T2362	arg2Of	control,under
R1961	T2364	T2363	arg1Of	control,the
R1962	T2364	T2365	arg1Of	control,of
R1963	T2368	T2365	arg2Of	promoter,of
R1964	T2368	T2366	arg1Of	promoter,a
R1965	T2368	T2367	arg1Of	promoter,doxycycline-inducible
R1966	T2373	T2371	arg2Of	presence,in
R1967	T2373	T2372	arg1Of	presence,the
R1968	T2373	T2374	arg1Of	presence,of
R1969	T2375	T2374	arg2Of	doxycycline,of
R1970	T2378	T2377	arg1Of	expression,Flag-PKD3
R1971	T2378	T2379	arg1Of	expression,in
R1972	T2378	T2384	arg1Of	expression,is
R1973	T2378	T2385	arg1Of	expression,comparable
R1974	T2383	T2379	arg2Of	cells,in
R1975	T2383	T2380	arg1Of	cells,PKD1/3
R1976	T2383	T2381	arg1Of	cells,double
R1977	T2383	T2382	arg1Of	cells,knockout
R1978	T2384	T2394	arg1Of	is,and
R1979	T2385	T2384	arg2Of	comparable,is
R1980	T2385	T2386	arg1Of	comparable,to
R1981	T2385	T2390	arg1Of	comparable,in
R1982	T2388	T2386	arg2Of	PKD3,to
R1983	T2388	T2387	arg1Of	PKD3,endogenous
R1984	T2388	T2389	arg1Of	PKD3,present
R1985	T2393	T2390	arg2Of	cells,in
R1986	T2393	T2391	arg1Of	cells,wild-type
R1987	T2393	T2392	arg1Of	cells,DT40
R1988	T2394	T2369	arg1Of	and,Hence
R1989	T2394	T2370	arg1Of	and,","
R1990	T2394	T2371	arg1Of	and,in
R1991	T2394	T2376	arg1Of	and,","
R1992	T2395	T2396	arg1Of	removal,of
R1993	T2395	T2405	arg1Of	removal,results
R1994	T2397	T2396	arg2Of	doxycycline,of
R1995	T2397	T2398	arg1Of	doxycycline,from
R1996	T2397	T2402	arg1Of	doxycycline,for
R1997	T2401	T2398	arg2Of	media,from
R1998	T2401	T2399	arg1Of	media,the
R1999	T2401	T2400	arg1Of	media,culture
R2000	T2404	T2402	arg2Of	days,for
R2001	T2404	T2403	arg1Of	days,5
R2002	T2405	T2394	arg2Of	results,and
R2003	T2405	T2406	arg1Of	results,in
R2004	T2409	T2408	arg1Of	null,completely
R2005	T2411	T2406	arg2Of	phenotype,in
R2006	T2411	T2407	arg1Of	phenotype,a
R2007	T2411	T2409	arg1Of	phenotype,null
R2008	T2411	T2410	arg1Of	phenotype,PKD
R2009	T2411	T2412	arg1Of	phenotype,(
R2010	T2414	T2412	arg2Of	1A,(
R2011	T2414	T2413	arg1Of	1A,Fig.
R2012	T2415	T2412	arg3Of	),(
R2013	T2418	T2419	arg1Of	we,have
R2014	T2418	T2420	arg1Of	we,demonstrated
R2015	T2420	T2416	arg1Of	demonstrated,Previously
R2016	T2420	T2417	arg1Of	demonstrated,","
R2017	T2420	T2419	arg2Of	demonstrated,have
R2018	T2422	T2423	arg1Of	phosphorylation,and
R2019	T2423	T2426	arg1Of	and,of
R2020	T2423	T2437	arg1Of	and,is
R2021	T2423	T2438	arg1Of	and,defective
R2022	T2423	T2444	arg1Of	and,can
R2023	T2423	T2445	arg1Of	and,restored
R2024	T2425	T2423	arg2Of	exclusion,and
R2025	T2425	T2424	arg1Of	exclusion,nuclear
R2026	T2430	T2426	arg2Of	deacetylases,of
R2027	T2430	T2427	arg1Of	deacetylases,class
R2028	T2430	T2428	arg1Of	deacetylases,II
R2029	T2430	T2429	arg1Of	deacetylases,histone
R2030	T2430	T2431	arg1Of	deacetylases,(
R2031	T2430	T2434	arg1Of	deacetylases,during
R2032	T2432	T2431	arg2Of	HDACs,(
R2033	T2433	T2431	arg3Of	),(
R2034	T2436	T2434	arg2Of	engagement,during
R2035	T2436	T2435	arg1Of	engagement,BCR
R2036	T2437	T2443	arg1Of	is,and
R2037	T2438	T2437	arg2Of	defective,is
R2038	T2438	T2439	arg1Of	defective,in
R2039	T2442	T2439	arg2Of	cells,in
R2040	T2442	T2440	arg1Of	cells,PKD1/3−/−
R2041	T2442	T2441	arg1Of	cells,B
R2042	T2443	T2420	arg2Of	and,demonstrated
R2043	T2443	T2421	arg1Of	and,that
R2044	T2445	T2443	arg2Of	restored,and
R2045	T2445	T2444	arg2Of	restored,can
R2046	T2445	T2446	arg1Of	restored,upon
R2047	T2447	T2446	arg2Of	re-expression,upon
R2048	T2447	T2448	arg1Of	re-expression,of
R2049	T2452	T2448	arg2Of	isoform,of
R2050	T2452	T2449	arg1Of	isoform,a
R2051	T2452	T2450	arg1Of	isoform,single
R2052	T2452	T2451	arg1Of	isoform,PKD
R2053	T2452	T2453	arg1Of	isoform,[
R2054	T2454	T2453	arg2Of	1,[
R2055	T2455	T2453	arg3Of	],[
R2056	T2461	T2456	arg1Of	HSP27,The
R2057	T2461	T2457	arg1Of	HSP27,small
R2058	T2461	T2458	arg1Of	HSP27,heat
R2059	T2461	T2459	arg1Of	HSP27,shock
R2060	T2461	T2460	arg1Of	HSP27,protein
R2061	T2461	T2462	arg1Of	HSP27,has
R2062	T2461	T2464	arg1Of	HSP27,been
R2063	T2461	T2465	arg2Of	HSP27,proposed
R2064	T2465	T2462	arg2Of	proposed,has
R2065	T2465	T2463	arg1Of	proposed,recently
R2066	T2465	T2464	arg2Of	proposed,been
R2067	T2465	T2466	arg1Of	proposed,as
R2068	T2465	T2470	arg1Of	proposed,[
R2069	T2465	T2473	arg1Of	proposed,and
R2070	T2469	T2466	arg2Of	substrate,as
R2071	T2469	T2467	arg1Of	substrate,a
R2072	T2469	T2468	arg1Of	substrate,PKD1
R2073	T2471	T2470	arg2Of	24,[
R2074	T2472	T2470	arg3Of	],[
R2075	T2474	T2476	arg1Of	we,assessed
R2076	T2476	T2473	arg2Of	assessed,and
R2077	T2476	T2475	arg1Of	assessed,accordingly
R2078	T2480	T2478	arg1Of	cells,PKD-null
R2079	T2480	T2479	arg1Of	cells,DT40
R2080	T2480	T2481	arg1Of	cells,have
R2081	T2481	T2476	arg2Of	have,assessed
R2082	T2481	T2477	arg1Of	have,whether
R2083	T2483	T2481	arg2Of	phosphorylation,have
R2084	T2483	T2482	arg1Of	phosphorylation,defective
R2085	T2483	T2484	arg1Of	phosphorylation,of
R2086	T2485	T2484	arg2Of	HSP27,of
R2087	T2485	T2486	arg1Of	HSP27,on
R2088	T2485	T2489	arg1Of	HSP27,","
R2089	T2487	T2486	arg2Of	serine,on
R2090	T2487	T2488	arg1Of	serine,82
R2091	T2494	T2489	arg2Of	sequence,","
R2092	T2494	T2490	arg1Of	sequence,the
R2093	T2494	T2491	arg2Of	sequence,proposed
R2094	T2494	T2492	arg1Of	sequence,PKD1
R2095	T2494	T2493	arg1Of	sequence,substrate
R2096	T2495	T2497	arg1Of	We,investigated
R2097	T2497	T2496	arg1Of	investigated,initially
R2098	T2499	T2497	arg2Of	regulation,investigated
R2099	T2499	T2498	arg1Of	regulation,the
R2100	T2499	T2500	arg1Of	regulation,of
R2101	T2499	T2503	arg1Of	regulation,in
R2102	T2502	T2500	arg2Of	phosphorylation,of
R2103	T2502	T2501	arg1Of	phosphorylation,HSP27
R2104	T2508	T2503	arg2Of	cells,in
R2105	T2508	T2504	arg1Of	cells,single
R2106	T2508	T2505	arg1Of	cells,knockout
R2107	T2508	T2506	arg1Of	cells,DT40
R2108	T2508	T2507	arg1Of	cells,B
R2109	T2508	T2509	arg1Of	cells,lacking
R2110	T2511	T2512	arg1Of	PKD1,or
R2111	T2512	T2509	arg2Of	or,lacking
R2112	T2512	T2510	arg1Of	or,either
R2113	T2513	T2512	arg2Of	PKD3,or
R2114	T2515	T2514	arg2Of	shown,As
R2115	T2515	T2516	arg1Of	shown,in
R2116	T2518	T2516	arg2Of	1B,in
R2117	T2518	T2517	arg1Of	1B,Fig.
R2118	T2520	T2521	arg1Of	activation,of
R2119	T2520	T2524	arg1Of	activation,or
R2120	T2523	T2521	arg2Of	BCR,of
R2121	T2523	T2522	arg1Of	BCR,the
R2122	T2524	T2530	arg1Of	or,increased
R2123	T2525	T2524	arg2Of	treatment,or
R2124	T2525	T2526	arg1Of	treatment,with
R2125	T2529	T2526	arg2Of	PdBu,with
R2126	T2529	T2527	arg1Of	PdBu,the
R2127	T2529	T2528	arg1Of	PdBu,DAG-mimetic
R2128	T2530	T2514	arg1Of	increased,As
R2129	T2530	T2519	arg1Of	increased,","
R2130	T2532	T2530	arg2Of	levels,increased
R2131	T2532	T2531	arg1Of	levels,the
R2132	T2532	T2533	arg1Of	levels,of
R2133	T2535	T2533	arg2Of	phosphorylation,of
R2134	T2535	T2534	arg1Of	phosphorylation,HSP27
R2135	T2535	T2536	arg1Of	phosphorylation,at
R2136	T2537	T2536	arg2Of	S82,at
R2137	T2537	T2538	arg1Of	S82,in
R2138	T2542	T2538	arg2Of	cells,in
R2139	T2542	T2539	arg1Of	cells,wild-type
R2140	T2542	T2540	arg1Of	cells,DT40
R2141	T2542	T2541	arg1Of	cells,B
R2142	T2543	T2544	arg1Of	BCR,and
R2143	T2545	T2544	arg2Of	phorbol,and
R2144	T2547	T2543	arg1Of	signals,BCR
R2145	T2547	T2545	arg1Of	signals,phorbol
R2146	T2547	T2546	arg1Of	signals,ester
R2147	T2547	T2548	arg1Of	signals,were
R2148	T2547	T2550	arg1Of	signals,able
R2149	T2547	T2552	arg1Of	signals,increase
R2150	T2548	T2549	arg1Of	were,also
R2151	T2550	T2548	arg2Of	able,were
R2152	T2552	T2550	arg2Of	increase,able
R2153	T2552	T2551	arg1Of	increase,to
R2154	T2554	T2552	arg2Of	phosphorylation,increase
R2155	T2554	T2553	arg1Of	phosphorylation,HSP27
R2156	T2554	T2555	arg1Of	phosphorylation,in
R2157	T2556	T2557	arg1Of	PKD1,or
R2158	T2558	T2557	arg2Of	PKD3,or
R2159	T2563	T2555	arg2Of	cells,in
R2160	T2563	T2556	arg1Of	cells,PKD1
R2161	T2563	T2558	arg1Of	cells,PKD3
R2162	T2563	T2559	arg1Of	cells,single
R2163	T2563	T2560	arg1Of	cells,knockout
R2164	T2563	T2561	arg1Of	cells,DT40
R2165	T2563	T2562	arg1Of	cells,B
R2166	T2563	T2564	arg1Of	cells,(
R2167	T2566	T2564	arg2Of	1B,(
R2168	T2566	T2565	arg1Of	1B,Fig.
R2169	T2567	T2564	arg3Of	),(
R2170	T2570	T2571	arg1Of	BCR-,and
R2171	T2571	T2577	arg1Of	and,on
R2172	T2571	T2579	arg1Of	and,was
R2173	T2571	T2580	arg2Of	and,abolished
R2174	T2573	T2572	arg1Of	ester-induced,phorbol
R2175	T2574	T2571	arg2Of	phosphorylation,and
R2176	T2574	T2573	arg1Of	phosphorylation,ester-induced
R2177	T2574	T2575	arg1Of	phosphorylation,of
R2178	T2576	T2575	arg2Of	HSP27,of
R2179	T2578	T2577	arg2Of	S82,on
R2180	T2580	T2568	arg1Of	abolished,However
R2181	T2580	T2569	arg1Of	abolished,","
R2182	T2580	T2579	arg2Of	abolished,was
R2183	T2580	T2581	arg1Of	abolished,in
R2184	T2583	T2581	arg2Of	cells,in
R2185	T2583	T2582	arg1Of	cells,B
R2186	T2583	T2584	arg1Of	cells,that
R2187	T2583	T2585	arg1Of	cells,lacked
R2188	T2587	T2588	arg1Of	PKD1,and
R2189	T2588	T2585	arg2Of	and,lacked
R2190	T2588	T2586	arg1Of	and,both
R2191	T2588	T2590	arg1Of	and,(
R2192	T2589	T2588	arg2Of	PKD3,and
R2193	T2592	T2590	arg2Of	1C,(
R2194	T2592	T2591	arg1Of	1C,Fig.
R2195	T2593	T2590	arg3Of	),(
R2196	T2597	T2596	arg1Of	expression,doxycycline-induced
R2197	T2597	T2598	arg1Of	expression,of
R2198	T2597	T2602	arg1Of	expression,in
R2199	T2597	T2607	arg1Of	expression,was
R2200	T2597	T2608	arg1Of	expression,sufficient
R2201	T2601	T2598	arg2Of	transgene,of
R2202	T2601	T2599	arg1Of	transgene,the
R2203	T2601	T2600	arg1Of	transgene,Flag-PKD3
R2204	T2606	T2602	arg2Of	cells,in
R2205	T2606	T2603	arg1Of	cells,the
R2206	T2606	T2604	arg1Of	cells,double
R2207	T2606	T2605	arg1Of	cells,knockout
R2208	T2607	T2594	arg1Of	was,Significantly
R2209	T2607	T2595	arg1Of	was,","
R2210	T2607	T2609	modOf	was,to
R2211	T2608	T2607	arg2Of	sufficient,was
R2212	T2610	T2609	arg1Of	restore,to
R2213	T2612	T2610	arg2Of	regulation,restore
R2214	T2612	T2611	arg1Of	regulation,normal
R2215	T2612	T2613	arg1Of	regulation,of
R2216	T2615	T2613	arg2Of	phosphorylation,of
R2217	T2615	T2614	arg1Of	phosphorylation,HSP27
R2218	T2615	T2616	arg1Of	phosphorylation,(
R2219	T2618	T2616	arg2Of	1C,(
R2220	T2618	T2617	arg1Of	1C,Fig.
R2221	T2619	T2616	arg3Of	),(
R2222	T2621	T2620	arg2Of	contrast,In
R2223	T2623	T2624	arg1Of	expression,of
R2224	T2623	T2630	arg1Of	expression,in
R2225	T2623	T2635	arg1Of	expression,was
R2226	T2623	T2637	arg1Of	expression,able
R2227	T2623	T2639	arg1Of	expression,restore
R2228	T2629	T2624	arg2Of	protein,of
R2229	T2629	T2625	arg1Of	protein,a
R2230	T2629	T2626	arg1Of	protein,kinase-deficient
R2231	T2629	T2627	arg1Of	protein,PKD3
R2232	T2629	T2628	arg1Of	protein,mutant
R2233	T2634	T2630	arg2Of	cells,in
R2234	T2634	T2631	arg1Of	cells,the
R2235	T2634	T2632	arg1Of	cells,double
R2236	T2634	T2633	arg1Of	cells,knockout
R2237	T2635	T2620	arg1Of	was,In
R2238	T2635	T2622	arg1Of	was,","
R2239	T2635	T2636	arg1Of	was,not
R2240	T2637	T2635	arg2Of	able,was
R2241	T2639	T2637	arg2Of	restore,able
R2242	T2639	T2638	arg1Of	restore,to
R2243	T2640	T2641	arg1Of	BCR-,or
R2244	T2641	T2639	arg2Of	or,restore
R2245	T2645	T2641	arg2Of	phosphorylation,or
R2246	T2645	T2642	arg1Of	phosphorylation,phorbol
R2247	T2645	T2643	arg1Of	phosphorylation,ester-induced
R2248	T2645	T2644	arg1Of	phosphorylation,HSP27
R2249	T2645	T2646	arg1Of	phosphorylation,(
R2250	T2648	T2646	arg2Of	1D,(
R2251	T2648	T2647	arg1Of	1D,Fig.
R2252	T2649	T2646	arg3Of	),(
R2253	T2652	T2655	arg1Of	PKD3,as
R2254	T2655	T2653	arg1Of	as,as
R2255	T2655	T2654	arg1Of	as,well
R2256	T2655	T2657	arg1Of	as,can
R2257	T2655	T2658	arg1Of	as,regulate
R2258	T2656	T2655	arg2Of	PKD1,as
R2259	T2658	T2657	arg2Of	regulate,can
R2260	T2658	T2661	arg1Of	regulate,and
R2261	T2660	T2658	arg2Of	phosphorylation,regulate
R2262	T2660	T2659	arg1Of	phosphorylation,HSP27
R2263	T2661	T2650	arg1Of	and,Hence
R2264	T2661	T2651	arg1Of	and,","
R2265	T2665	T2662	arg2Of	cells,in
R2266	T2665	T2663	arg1Of	cells,DT40
R2267	T2665	T2664	arg1Of	cells,B
R2268	T2666	T2667	arg1Of	they,are
R2269	T2666	T2669	arg2Of	they,redundant
R2270	T2669	T2661	arg2Of	redundant,and
R2271	T2669	T2662	arg1Of	redundant,in
R2272	T2669	T2667	arg2Of	redundant,are
R2273	T2669	T2668	arg1Of	redundant,functionally
R2274	T2669	T2670	arg1Of	redundant,as
R2275	T2672	T2670	arg2Of	kinases,as
R2276	T2672	T2671	arg1Of	kinases,HSP27
R3056	T3837	T3838	arg1Of	proliferation,and
R3058	T3838	T3840	arg1Of	and,in
R3059	T3839	T3838	arg2Of	survival,and
R3060	T3843	T3840	arg2Of	cells,in
R3061	T3843	T3841	arg1Of	cells,DT40
R3062	T3843	T3842	arg1Of	cells,B
R3063	T3843	T3844	arg1Of	cells,lacking
R3064	T3845	T3844	arg2Of	expression,lacking
R3065	T3845	T3846	arg1Of	expression,of
R3066	T3849	T3846	arg2Of	kinases,of
R3067	T3849	T3847	arg1Of	kinases,PKD
R3068	T3849	T3848	arg1Of	kinases,family
R3069	T3851	T3850	arg1Of	enzymes,PKD
R3070	T3851	T3852	arg1Of	enzymes,have
R3071	T3851	T3854	arg1Of	enzymes,been
R3072	T3851	T3855	arg2Of	enzymes,linked
R3073	T3855	T3852	arg2Of	linked,have
R3074	T3855	T3853	arg1Of	linked,previously
R3075	T3855	T3854	arg2Of	linked,been
R3076	T3855	T3856	arg1Of	linked,to
R3077	T3858	T3856	arg2Of	regulation,to
R3078	T3858	T3857	arg1Of	regulation,the
R3079	T3858	T3859	arg1Of	regulation,of
R3080	T3861	T3862	arg1Of	proliferation,and
R3081	T3862	T3859	arg2Of	and,of
R3082	T3862	T3860	arg1Of	and,cell
R3083	T3862	T3864	arg1Of	and,(
R3084	T3863	T3862	arg2Of	survival,and
R3085	T3865	T3864	arg2Of	reviewed,(
R3086	T3865	T3866	arg1Of	reviewed,in
R3087	T3865	T3867	arg1Of	reviewed,[
R3088	T3868	T3867	arg2Of	20,[
R3089	T3869	T3867	arg3Of	],[
R3090	T3870	T3864	arg3Of	),(
R3091	T3872	T3871	arg1Of	investigate,To
R3092	T3874	T3872	arg2Of	effect,investigate
R3093	T3874	T3873	arg1Of	effect,the
R3094	T3876	T3877	arg1Of	loss,of
R3095	T3876	T3880	arg1Of	loss,had
R3096	T3879	T3877	arg2Of	kinases,of
R3097	T3879	T3878	arg1Of	kinases,PKD
R3098	T3880	T3874	arg2Of	had,effect
R3099	T3880	T3875	arg1Of	had,that
R3100	T3880	T3881	arg1Of	had,on
R3101	T3884	T3885	arg1Of	survival,and/or
R3102	T3885	T3881	arg2Of	and/or,on
R3103	T3885	T3882	arg1Of	and/or,B
R3104	T3885	T3883	arg1Of	and/or,cell
R3105	T3886	T3885	arg2Of	proliferation,and/or
R3106	T3887	T3872	arg1Of	we,investigate
R3107	T3887	T3888	arg1Of	we,cultured
R3108	T3888	T3871	modOf	cultured,To
R3109	T3888	T3893	arg1Of	cultured,in
R3110	T3889	T3890	arg1Of	wild-type,and
R3111	T3891	T3890	arg2Of	PKD-null,and
R3112	T3892	T3888	arg2Of	cells,cultured
R3113	T3892	T3889	arg1Of	cells,wild-type
R3114	T3892	T3891	arg1Of	cells,PKD-null
R3115	T3895	T3893	arg2Of	presence,in
R3116	T3895	T3894	arg1Of	presence,the
R3117	T3895	T3896	arg1Of	presence,(
R3118	T3897	T3896	arg2Of	PKD1/3−/−,(
R3119	T3898	T3896	arg3Of	:,(
R3120	T3899	T3900	arg1Of	Flag-PKD3+ve,)
R3121	T3899	T3901	arg1Of	Flag-PKD3+ve,or
R3122	T3901	T3909	arg1Of	or,monitored
R3123	T3902	T3901	arg2Of	absence,or
R3124	T3902	T3903	arg1Of	absence,(
R3125	T3902	T3906	arg1Of	absence,of
R3126	T3904	T3903	arg2Of	PKD1/3−/−,(
R3127	T3905	T3903	arg3Of	),(
R3128	T3907	T3906	arg2Of	doxycycline,of
R3129	T3909	T3908	arg1Of	monitored,and
R3130	T3911	T3909	arg2Of	growth,monitored
R3131	T3911	T3910	arg1Of	growth,exponential
R3132	T3913	T3912	arg2Of	shown,As
R3133	T3913	T3914	arg1Of	shown,in
R3134	T3916	T3914	arg2Of	2A,in
R3135	T3916	T3915	arg1Of	2A,Fig.
R3136	T3919	T3918	arg1Of	cells,PKD1/3−/−
R3137	T3919	T3920	arg1Of	cells,proliferated
R3138	T3920	T3921	arg1Of	proliferated,exponentially
R3139	T3920	T3922	arg1Of	proliferated,and
R3140	T3922	T3912	arg1Of	and,As
R3141	T3922	T3917	arg1Of	and,","
R3142	T3923	T3924	arg1Of	re-expression,of
R3143	T3923	T3926	arg1Of	re-expression,in
R3144	T3923	T3929	arg1Of	re-expression,had
R3145	T3925	T3924	arg2Of	Flag-PKD3,of
R3146	T3928	T3926	arg2Of	cells,in
R3147	T3928	T3927	arg1Of	cells,these
R3148	T3929	T3922	arg2Of	had,and
R3149	T3931	T3929	arg2Of	impact,had
R3150	T3931	T3930	arg1Of	impact,no
R3151	T3931	T3932	arg1Of	impact,on
R3152	T3934	T3932	arg2Of	rate,on
R3153	T3934	T3933	arg1Of	rate,the
R3154	T3934	T3935	arg1Of	rate,of
R3155	T3936	T3935	arg2Of	proliferation,of
R3156	T3940	T3939	arg1Of	viability,the
R3157	T3940	T3941	arg1Of	viability,of
R3158	T3940	T3945	arg1Of	viability,during
R3159	T3940	T3948	arg1Of	viability,was
R3160	T3940	T3951	arg1Of	viability,different
R3161	T3944	T3941	arg2Of	cells,of
R3162	T3944	T3942	arg1Of	cells,PKD1/3−/−
R3163	T3944	T3943	arg1Of	cells,B
R3164	T3947	T3945	arg2Of	culturing,during
R3165	T3947	T3946	arg1Of	culturing,routine
R3166	T3948	T3937	arg1Of	was,Furthermore
R3167	T3948	T3938	arg1Of	was,","
R3168	T3948	T3949	arg1Of	was,not
R3169	T3951	T3948	arg2Of	different,was
R3170	T3951	T3950	arg1Of	different,significantly
R3171	T3951	T3952	arg1Of	different,from
R3172	T3953	T3952	arg2Of	that,from
R3173	T3953	T3954	arg1Of	that,of
R3174	T3957	T3954	arg2Of	cells,of
R3175	T3957	T3955	arg1Of	cells,wild-type
R3176	T3957	T3956	arg1Of	cells,B
R3177	T3957	T3958	arg1Of	cells,(
R3178	T3959	T3958	arg2Of	data,(
R3179	T3959	T3961	arg2Of	data,shown
R3180	T3961	T3960	arg1Of	shown,not
R3181	T3962	T3958	arg3Of	),(
R3182	T3963	T3964	arg1Of	It,was
R3183	T3963	T3965	arg2Of	It,noted
R3184	T3965	T3964	arg2Of	noted,was
R3185	T3970	T3967	arg1Of	time,the
R3186	T3970	T3968	arg1Of	time,population
R3187	T3970	T3969	arg1Of	time,doubling
R3188	T3970	T3971	arg1Of	time,of
R3189	T3970	T3974	arg1Of	time,was
R3190	T3970	T3976	arg1Of	time,slower
R3191	T3973	T3971	arg2Of	cells,of
R3192	T3973	T3972	arg1Of	cells,PKD1/3−/−
R3193	T3974	T3989	arg1Of	was,but
R3194	T3976	T3974	arg2Of	slower,was
R3195	T3976	T3975	arg1Of	slower,slightly
R3196	T3976	T3977	arg1Of	slower,than
R3197	T3978	T3977	arg2Of	that,than
R3198	T3978	T3979	arg1Of	that,of
R3199	T3983	T3979	arg2Of	cells,of
R3200	T3983	T3980	arg1Of	cells,wild
R3201	T3983	T3981	arg1Of	cells,type
R3202	T3983	T3982	arg1Of	cells,DT40
R3203	T3983	T3984	arg1Of	cells,(
R3204	T3985	T3984	arg2Of	12.7 ± 2.8 h,(
R3205	T3985	T3986	arg1Of	12.7 ± 2.8 h,versus
R3206	T3987	T3986	arg2Of	10.2 ± 0.4 h,versus
R3207	T3988	T3984	arg3Of	),(
R3208	T3989	T3965	arg3Of	but,noted
R3209	T3989	T3966	arg1Of	but,that
R3210	T3991	T3990	arg1Of	failure,the
R3211	T3991	T3992	arg1Of	failure,of
R3212	T3991	T3995	modOf	failure,to
R3213	T3991	T4003	arg1Of	failure,suggests
R3214	T3994	T3992	arg2Of	re-expression,of
R3215	T3994	T3993	arg1Of	re-expression,PKD3
R3216	T3996	T3995	arg1Of	modify,to
R3217	T3999	T3996	arg2Of	rate,modify
R3218	T3999	T3997	arg1Of	rate,the
R3219	T3999	T3998	arg1Of	rate,proliferation
R3220	T3999	T4000	arg1Of	rate,of
R3221	T4002	T4000	arg2Of	cells,of
R3222	T4002	T4001	arg1Of	cells,PKD1/3−/−
R3223	T4003	T3989	arg2Of	suggests,but
R3224	T4007	T4005	arg1Of	differences,these
R3225	T4007	T4006	arg1Of	differences,small
R3226	T4007	T4008	arg1Of	differences,were
R3227	T4007	T4017	arg1Of	differences,were
R3228	T4007	T4019	arg2Of	differences,caused
R3229	T4008	T4010	arg1Of	were,likely
R3230	T4008	T4016	arg1Of	were,and
R3231	T4010	T4009	arg1Of	likely,most
R3232	T4012	T4008	arg2Of	result,were
R3233	T4012	T4011	arg1Of	result,the
R3234	T4012	T4013	arg1Of	result,of
R3235	T4015	T4013	arg2Of	variation,of
R3236	T4015	T4014	arg1Of	variation,clonal
R3237	T4016	T4003	arg2Of	and,suggests
R3238	T4016	T4004	arg1Of	and,that
R3239	T4019	T4016	arg2Of	caused,and
R3240	T4019	T4017	arg2Of	caused,were
R3241	T4019	T4018	arg1Of	caused,not
R3242	T4019	T4020	arg1Of	caused,specifically
R3243	T4022	T4019	arg1Of	loss,caused
R3244	T4022	T4021	arg2Of	loss,by
R3245	T4022	T4023	arg1Of	loss,of
R3246	T4025	T4023	arg2Of	enzymes,of
R3247	T4025	T4024	arg1Of	enzymes,PKD
R3248	T4030	T4028	arg1Of	enzymes,PKD
R3249	T4030	T4029	arg1Of	enzymes,family
R3250	T4030	T4031	arg1Of	enzymes,are
R3251	T4030	T4033	arg1Of	enzymes,essential
R3252	T4031	T4026	arg1Of	are,Thus
R3253	T4031	T4027	arg1Of	are,","
R3254	T4031	T4032	arg1Of	are,not
R3255	T4033	T4031	arg2Of	essential,are
R3256	T4033	T4034	arg1Of	essential,for
R3257	T4035	T4034	arg2Of	regulating,for
R3258	T4037	T4036	arg1Of	survival,basal
R3259	T4037	T4038	arg1Of	survival,and
R3260	T4038	T4035	arg2Of	and,regulating
R3261	T4039	T4038	arg2Of	proliferation,and
R3262	T4039	T4040	arg1Of	proliferation,of
R3263	T4043	T4040	arg2Of	cells,of
R3264	T4043	T4041	arg1Of	cells,DT40
R3265	T4043	T4042	arg1Of	cells,B
R3266	T4045	T4044	arg1Of	enzymes,PKD
R3267	T4045	T4046	arg1Of	enzymes,","
R3268	T4045	T4052	arg1Of	enzymes,have
R3269	T4045	T4054	arg1Of	enzymes,been
R3270	T4045	T4055	arg2Of	enzymes,linked
R3271	T4048	T4049	arg1Of	PKD1,and
R3272	T4049	T4046	arg2Of	and,","
R3273	T4049	T4047	arg1Of	and,specifically
R3274	T4050	T4049	arg2Of	PKD2,and
R3275	T4055	T4051	arg1Of	linked,","
R3276	T4055	T4052	arg2Of	linked,have
R3277	T4055	T4053	arg1Of	linked,previously
R3278	T4055	T4054	arg2Of	linked,been
R3279	T4055	T4056	arg1Of	linked,to
R3280	T4059	T4056	arg2Of	role,to
R3281	T4059	T4057	arg1Of	role,a
R3282	T4059	T4058	arg1Of	role,protective
R3283	T4059	T4060	arg1Of	role,against
R3284	T4062	T4061	arg1Of	stress-induced,oxidative
R3285	T4063	T4060	arg2Of	injury,against
R3286	T4063	T4062	arg1Of	injury,stress-induced
R3287	T4063	T4064	arg1Of	injury,in
R3288	T4066	T4067	arg1Of	fibroblast,","
R3289	T4068	T4067	arg2Of	HeLa,","
R3290	T4072	T4064	arg2Of	lines,in
R3291	T4072	T4065	arg1Of	lines,3T3
R3292	T4072	T4066	arg1Of	lines,fibroblast
R3293	T4072	T4068	arg1Of	lines,HeLa
R3294	T4072	T4069	arg1Of	lines,and
R3295	T4072	T4070	arg1Of	lines,epithelial
R3296	T4072	T4071	arg1Of	lines,cell
R3297	T4072	T4073	arg1Of	lines,[
R3298	T4074	T4073	arg2Of	"17,30–32",[
R3299	T4075	T4073	arg3Of	],[
R3300	T4076	T4078	arg1Of	We,addressed
R3301	T4078	T4077	arg1Of	addressed,therefore
R3302	T4080	T4078	arg2Of	role,addressed
R3303	T4080	T4079	arg1Of	role,the
R3304	T4080	T4081	arg1Of	role,of
R3305	T4080	T4085	arg1Of	role,in
R3306	T4084	T4081	arg2Of	kinases,of
R3307	T4084	T4082	arg1Of	kinases,PKD
R3308	T4084	T4083	arg1Of	kinases,family
R3309	T4086	T4085	arg2Of	regulating,in
R3310	T4086	T4090	arg1Of	regulating,in
R3311	T4089	T4086	arg2Of	survival,regulating
R3312	T4089	T4087	arg1Of	survival,B
R3313	T4089	T4088	arg1Of	survival,cell
R3314	T4090	T4092	arg1Of	in,to
R3315	T4091	T4090	arg2Of	response,in
R3316	T4094	T4093	arg1Of	stress,oxidative
R3317	T4094	T4095	arg1Of	stress,and
R3318	T4095	T4090	arg3Of	and,in
R3319	T4098	T4095	arg2Of	stimuli,and
R3320	T4098	T4096	arg1Of	stimuli,other
R3321	T4098	T4097	arg1Of	stimuli,stress
R3322	T4100	T4099	arg2Of	shown,As
R3323	T4100	T4101	arg1Of	shown,in
R3324	T4103	T4101	arg2Of	2B,in
R3325	T4103	T4102	arg1Of	2B,Fig.
R3326	T4105	T4106	arg1Of	loss,of
R3327	T4105	T4109	arg1Of	loss,had
R3328	T4108	T4106	arg2Of	expression,of
R3329	T4108	T4107	arg1Of	expression,PKD1/3
R3330	T4109	T4099	arg1Of	had,As
R3331	T4109	T4104	arg1Of	had,","
R3332	T4109	T4113	arg1Of	had,on
R3333	T4109	T4120	arg1Of	had,in
R3334	T4109	T4153	arg1Of	had,following
R3335	T4112	T4109	arg2Of	impact,had
R3336	T4112	T4110	arg1Of	impact,no
R3337	T4112	T4111	arg1Of	impact,significant
R3338	T4115	T4113	arg2Of	survival,on
R3339	T4115	T4114	arg1Of	survival,the
R3340	T4115	T4116	arg1Of	survival,of
R3341	T4119	T4116	arg2Of	cells,of
R3342	T4119	T4117	arg1Of	cells,DT40
R3343	T4119	T4118	arg1Of	cells,B
R3344	T4120	T4122	arg1Of	in,to
R3345	T4120	T4152	arg1Of	in,or
R3346	T4121	T4120	arg2Of	response,in
R3347	T4125	T4123	arg1Of	stimuli,mitochondrial
R3348	T4125	T4124	arg1Of	stimuli,stress
R3349	T4125	T4126	arg1Of	stimuli,(
R3350	T4125	T4132	arg1Of	stimuli,;
R3351	T4127	T4128	arg1Of	H2O2,or
R3352	T4128	T4126	arg2Of	or,(
R3353	T4130	T4128	arg2Of	deprivation,or
R3354	T4130	T4129	arg1Of	deprivation,serum
R3355	T4131	T4126	arg3Of	),(
R3356	T4132	T4141	arg1Of	;,;
R3357	T4135	T4132	arg2Of	agents,;
R3358	T4135	T4133	arg1Of	agents,DNA
R3359	T4135	T4134	arg1Of	agents,damaging
R3360	T4135	T4136	arg1Of	agents,(
R3361	T4137	T4138	arg1Of	etoposide,or
R3362	T4138	T4136	arg2Of	or,(
R3363	T4139	T4138	arg2Of	doxorubicin,or
R3364	T4140	T4136	arg3Of	),(
R3365	T4141	T4120	arg3Of	;,in
R3366	T4144	T4141	arg2Of	stress,;
R3367	T4144	T4142	arg1Of	stress,ER
R3368	T4144	T4143	arg1Of	stress,pathway
R3369	T4144	T4145	arg1Of	stress,due
R3370	T4145	T4146	arg1Of	due,to
R3371	T4148	T4145	arg2Of	overload,due
R3372	T4148	T4147	arg1Of	overload,calcium
R3373	T4148	T4149	arg1Of	overload,(
R3374	T4150	T4149	arg2Of	thapsigargin,(
R3375	T4151	T4149	arg3Of	),(
R3376	T4153	T4152	arg2Of	following,or
R3377	T4155	T4153	arg2Of	treatment,following
R3378	T4155	T4154	arg2Of	treatment,prolonged
R3379	T4155	T4156	arg1Of	treatment,with
R3380	T4158	T4157	arg1Of	esters,phorbol
R3381	T4158	T4159	arg1Of	esters,or
R3382	T4159	T4156	arg2Of	or,with
R3383	T4159	T4162	arg1Of	or,","
R3384	T4161	T4159	arg2Of	A,or
R3385	T4161	T4160	arg1Of	A,Trichostatin
R3386	T4164	T4162	arg2Of	inhibitor,","
R3387	T4164	T4163	arg1Of	inhibitor,an
R3388	T4164	T4165	arg1Of	inhibitor,of
R3389	T4168	T4165	arg2Of	HDACs,of
R3390	T4168	T4166	arg1Of	HDACs,class
R3391	T4168	T4167	arg1Of	HDACs,I/II
R3392	T4172	T4171	arg1Of	kinases,PKD
R3393	T4172	T4173	arg1Of	kinases,do
R3394	T4172	T4175	arg1Of	kinases,play
R3395	T4175	T4169	arg1Of	play,Thus
R3396	T4175	T4170	arg1Of	play,","
R3397	T4175	T4173	arg2Of	play,do
R3398	T4175	T4174	arg1Of	play,not
R3399	T4175	T4179	arg1Of	play,in
R3400	T4178	T4175	arg2Of	role,play
R3401	T4178	T4176	arg1Of	role,an
R3402	T4178	T4177	arg1Of	role,essential
R3403	T4180	T4179	arg2Of	regulating,in
R3404	T4180	T4184	arg1Of	regulating,in
R3405	T4183	T4180	arg2Of	survival,regulating
R3406	T4183	T4181	arg1Of	survival,B
R3407	T4183	T4182	arg1Of	survival,cell
R3408	T4184	T4186	arg1Of	in,to
R3409	T4185	T4184	arg2Of	response,in
R3410	T4188	T4184	arg3Of	range,in
R3411	T4188	T4187	arg1Of	range,a
R3412	T4188	T4189	arg1Of	range,of
R3413	T4192	T4189	arg2Of	stimuli,of
R3414	T4192	T4190	arg1Of	stimuli,different
R3415	T4192	T4191	arg1Of	stimuli,stress
R3932	T5032	T5033	arg1Of	receptor,regulated
R3933	T5035	T5033	arg2Of	pathways,regulated
R3934	T5035	T5034	arg1Of	pathways,signalling
R3935	T5035	T5036	arg1Of	pathways,in
R3936	T5040	T5036	arg2Of	cells,in
R3937	T5040	T5037	arg1Of	cells,PKD-null
R3938	T5040	T5038	arg1Of	cells,DT40
R3939	T5040	T5039	arg1Of	cells,B
R3940	T5043	T5041	arg1Of	explore,To
R3941	T5043	T5042	arg1Of	explore,further
R3942	T5045	T5043	arg2Of	contribution,explore
R3943	T5045	T5044	arg1Of	contribution,the
R3944	T5045	T5046	arg1Of	contribution,of
R3945	T5045	T5049	arg1Of	contribution,to
R3946	T5048	T5046	arg2Of	kinases,of
R3947	T5048	T5047	arg1Of	kinases,PKD
R3948	T5053	T5049	arg2Of	biology,to
R3949	T5053	T5050	arg1Of	biology,DT40
R3950	T5053	T5051	arg1Of	biology,B
R3951	T5053	T5052	arg1Of	biology,cell
R3952	T5054	T5043	arg1Of	we,explore
R3953	T5054	T5055	arg1Of	we,investigated
R3954	T5055	T5041	modOf	investigated,To
R3955	T5058	T5057	arg1Of	BCR-regulated,specific
R3956	T5060	T5058	arg1Of	events,BCR-regulated
R3957	T5060	T5059	arg1Of	events,signalling
R3958	T5060	T5061	arg1Of	events,were
R3959	T5060	T5062	arg1Of	events,defective
R3960	T5061	T5055	arg2Of	were,investigated
R3961	T5061	T5056	arg1Of	were,whether
R3962	T5062	T5061	arg2Of	defective,were
R3963	T5062	T5063	arg1Of	defective,in
R3964	T5067	T5063	arg2Of	cells,in
R3965	T5067	T5064	arg1Of	cells,the
R3966	T5067	T5065	arg1Of	cells,PKD-null
R3967	T5067	T5066	arg1Of	cells,B
R3968	T5069	T5068	arg1Of	experiments,Initial
R3969	T5069	T5070	arg1Of	experiments,revealed
R3970	T5073	T5072	arg1Of	expression,surface
R3971	T5073	T5074	arg1Of	expression,of
R3972	T5073	T5077	arg1Of	expression,was
R3973	T5073	T5078	arg2Of	expression,reduced
R3974	T5076	T5074	arg2Of	BCR,of
R3975	T5076	T5075	arg1Of	BCR,the
R3976	T5078	T5070	arg2Of	reduced,revealed
R3977	T5078	T5071	arg1Of	reduced,that
R3978	T5078	T5077	arg2Of	reduced,was
R3979	T5078	T5079	arg1Of	reduced,in
R3980	T5078	T5089	arg1Of	reduced,compared
R3981	T5080	T5081	arg1Of	PKD1/3−/−,(
R3982	T5083	T5081	arg2Of	in,(
R3983	T5083	T5082	arg1Of	in,and
R3984	T5084	T5083	arg2Of	PKD1/3−/−,in
R3985	T5084	T5085	arg1Of	PKD1/3−/−,:
R3986	T5084	T5086	arg1Of	PKD1/3−/−,Flag-PKD3+ve
R3987	T5087	T5081	arg3Of	),(
R3988	T5088	T5079	arg2Of	cells,in
R3989	T5088	T5080	arg1Of	cells,PKD1/3−/−
R3990	T5090	T5089	arg2Of	to,compared
R3991	T5094	T5090	arg2Of	cells,to
R3992	T5094	T5091	arg1Of	cells,wild-type
R3993	T5094	T5092	arg1Of	cells,DT40
R3994	T5094	T5093	arg1Of	cells,B
R3995	T5094	T5095	arg1Of	cells,(
R3996	T5097	T5096	arg1Of	3A,Fig.
R3997	T5097	T5098	arg1Of	3A,and
R3998	T5098	T5095	arg2Of	and,(
R3999	T5099	T5098	arg2Of	data,and
R4000	T5099	T5101	arg2Of	data,shown
R4001	T5101	T5100	arg1Of	shown,not
R4002	T5102	T5095	arg3Of	),(
R4003	T5105	T5106	arg1Of	BCR-crosslinking,of
R4004	T5105	T5109	arg1Of	BCR-crosslinking,was
R4005	T5105	T5110	arg1Of	BCR-crosslinking,sufficient
R4006	T5105	T5112	arg1Of	BCR-crosslinking,induce
R4007	T5108	T5106	arg2Of	cells,of
R4008	T5108	T5107	arg1Of	cells,PKD1/3−/−
R4009	T5109	T5103	arg1Of	was,Nevertheless
R4010	T5109	T5104	arg1Of	was,","
R4011	T5110	T5109	arg2Of	sufficient,was
R4012	T5112	T5110	arg2Of	induce,sufficient
R4013	T5112	T5111	arg1Of	induce,to
R4014	T5114	T5112	arg2Of	activation,induce
R4015	T5114	T5113	arg1Of	activation,the
R4016	T5114	T5115	arg1Of	activation,of
R4017	T5117	T5115	arg2Of	number,of
R4018	T5117	T5116	arg1Of	number,a
R4019	T5117	T5118	arg1Of	number,of
R4020	T5117	T5121	arg1Of	number,","
R4021	T5117	T5122	arg1Of	number,similar
R4022	T5120	T5118	arg2Of	cascades,of
R4023	T5120	T5119	arg1Of	cascades,signalling
R4024	T5122	T5123	arg1Of	similar,to
R4025	T5124	T5123	arg2Of	that,to
R4026	T5124	T5125	arg2Of	that,observed
R4027	T5125	T5126	arg1Of	observed,in
R4028	T5128	T5126	arg2Of	cells,in
R4029	T5128	T5127	arg1Of	cells,wild-type
R4030	T5128	T5129	arg1Of	cells,(
R4031	T5131	T5129	arg2Of	3B,(
R4032	T5131	T5130	arg1Of	3B,Fig.
R4033	T5132	T5129	arg3Of	),(
R4034	T5136	T5135	arg1Of	activation,BCR-induced
R4035	T5136	T5137	arg1Of	activation,of
R4036	T5136	T5140	arg1Of	activation,","
R4037	T5139	T5137	arg2Of	Akt,of
R4038	T5139	T5138	arg1Of	Akt,the
R4039	T5140	T5153	arg1Of	",",and
R4040	T5143	T5140	arg2Of	kinase,","
R4041	T5143	T5141	arg1Of	kinase,mTOR/p70
R4042	T5143	T5142	arg1Of	kinase,S6
R4043	T5143	T5144	arg1Of	kinase,(
R4044	T5143	T5145	arg1Of	kinase,as
R4045	T5143	T5152	arg1Of	kinase,)
R4046	T5146	T5145	arg2Of	shown,as
R4047	T5151	T5146	arg1Of	phosphorylation,shown
R4048	T5151	T5147	arg2Of	phosphorylation,by
R4049	T5151	T5148	arg1Of	phosphorylation,S6
R4050	T5151	T5149	arg1Of	phosphorylation,ribosomal
R4051	T5151	T5150	arg1Of	phosphorylation,protein
R4052	T5153	T5157	arg1Of	and,was
R4053	T5153	T5159	arg1Of	and,detectable
R4054	T5156	T5153	arg2Of	pathways,and
R4055	T5156	T5154	arg1Of	pathways,MAPK
R4056	T5156	T5155	arg1Of	pathways,signalling
R4057	T5157	T5133	arg1Of	was,Hence
R4058	T5157	T5134	arg1Of	was,","
R4059	T5159	T5157	arg2Of	detectable,was
R4060	T5159	T5158	arg1Of	detectable,clearly
R4061	T5159	T5160	arg1Of	detectable,in
R4062	T5163	T5160	arg2Of	cells,in
R4063	T5163	T5161	arg1Of	cells,PKD1/3-null
R4064	T5163	T5162	arg1Of	cells,B
R4065	T5163	T5164	arg1Of	cells,(
R4066	T5166	T5164	arg2Of	3B,(
R4067	T5166	T5165	arg1Of	3B,Fig.
R4068	T5167	T5164	arg3Of	),(
R4069	T5172	T5170	arg2Of	phosphorylation,enhanced
R4070	T5172	T5171	arg1Of	phosphorylation,tyrosine
R4071	T5172	T5173	arg1Of	phosphorylation,of
R4072	T5172	T5179	arg1Of	phosphorylation,as
R4073	T5176	T5173	arg2Of	proteins,of
R4074	T5176	T5174	arg1Of	proteins,multiple
R4075	T5176	T5175	arg1Of	proteins,cellular
R4076	T5179	T5177	arg1Of	as,as
R4077	T5179	T5178	arg1Of	as,well
R4078	T5179	T5186	arg1Of	as,was
R4079	T5179	T5188	arg2Of	as,observed
R4080	T5181	T5179	arg2Of	increase,as
R4081	T5181	T5180	arg1Of	increase,an
R4082	T5181	T5182	arg1Of	increase,in
R4083	T5185	T5182	arg2Of	levels,in
R4084	T5185	T5183	arg1Of	levels,intracellular
R4085	T5185	T5184	arg1Of	levels,calcium
R4086	T5188	T5168	arg1Of	observed,Furthermore
R4087	T5188	T5169	arg1Of	observed,","
R4088	T5188	T5186	arg2Of	observed,was
R4089	T5188	T5187	arg1Of	observed,also
R4090	T5188	T5189	arg1Of	observed,following
R4091	T5191	T5189	arg2Of	stimulation,following
R4092	T5191	T5190	arg1Of	stimulation,BCR
R4093	T5191	T5192	arg1Of	stimulation,of
R4094	T5195	T5192	arg2Of	cells,of
R4095	T5195	T5193	arg1Of	cells,PKD1/3-null
R4096	T5195	T5194	arg1Of	cells,B
R4097	T5195	T5196	arg1Of	cells,(
R4098	T5197	T5196	arg2Of	data,(
R4099	T5197	T5199	arg2Of	data,shown
R4100	T5199	T5198	arg1Of	shown,not
R4101	T5200	T5196	arg3Of	),(
R4102	T5201	T5202	arg1Of	We,did
R4103	T5201	T5203	arg1Of	We,observe
R4104	T5203	T5202	arg2Of	observe,did
R4105	T5206	T5205	arg1Of	strength,the
R4106	T5206	T5207	arg1Of	strength,of
R4107	T5206	T5222	arg1Of	strength,was
R4108	T5206	T5223	arg2Of	strength,reduced
R4109	T5208	T5209	arg1Of	BCR,(
R4110	T5210	T5211	arg1Of	but,not
R4111	T5213	T5209	arg2Of	ester,(
R4112	T5213	T5210	arg1Of	ester,but
R4113	T5213	T5212	arg1Of	ester,phorbol
R4114	T5214	T5209	arg3Of	),(
R4115	T5216	T5207	arg2Of	regulation,of
R4116	T5216	T5208	arg1Of	regulation,BCR
R4117	T5216	T5215	arg1Of	regulation,-induced
R4118	T5216	T5217	arg1Of	regulation,of
R4119	T5221	T5217	arg2Of	pathway,of
R4120	T5221	T5218	arg1Of	pathway,the
R4121	T5221	T5219	arg1Of	pathway,Erk1-RSK1
R4122	T5221	T5220	arg1Of	pathway,signalling
R4123	T5223	T5203	arg2Of	reduced,observe
R4124	T5223	T5204	arg1Of	reduced,that
R4125	T5223	T5222	arg2Of	reduced,was
R4126	T5223	T5224	arg1Of	reduced,in
R4127	T5223	T5228	arg1Of	reduced,compared
R4128	T5227	T5224	arg2Of	cells,in
R4129	T5227	T5225	arg1Of	cells,PKD1/3−/−
R4130	T5227	T5226	arg1Of	cells,B
R4131	T5229	T5228	arg2Of	to,compared
R4132	T5232	T5229	arg2Of	cells,to
R4133	T5232	T5230	arg1Of	cells,wild-type
R4134	T5232	T5231	arg1Of	cells,B
R4135	T5232	T5233	arg1Of	cells,(
R4136	T5235	T5233	arg2Of	3B,(
R4137	T5235	T5234	arg1Of	3B,Fig.
R4138	T5236	T5233	arg3Of	),(
R4139	T5238	T5237	arg1Of	interpretation,One
R4140	T5238	T5239	arg1Of	interpretation,of
R4141	T5238	T5242	arg1Of	interpretation,is
R4142	T5241	T5239	arg2Of	data,of
R4143	T5241	T5240	arg1Of	data,this
R4144	T5245	T5244	arg1Of	enzymes,PKD
R4145	T5245	T5246	arg1Of	enzymes,may
R4146	T5245	T5247	arg1Of	enzymes,modulate
R4147	T5247	T5242	arg2Of	modulate,is
R4148	T5247	T5243	arg1Of	modulate,that
R4149	T5247	T5246	arg2Of	modulate,may
R4150	T5249	T5247	arg2Of	activation,modulate
R4151	T5249	T5248	arg1Of	activation,Erk
R4152	T5253	T5252	arg1Of	enzymes,PKD
R4153	T5253	T5254	arg1Of	enzymes,have
R4154	T5253	T5256	arg1Of	enzymes,been
R4155	T5253	T5257	arg2Of	enzymes,linked
R4156	T5257	T5250	arg1Of	linked,Indeed
R4157	T5257	T5251	arg1Of	linked,","
R4158	T5257	T5254	arg2Of	linked,have
R4159	T5257	T5255	arg1Of	linked,previously
R4160	T5257	T5256	arg2Of	linked,been
R4161	T5257	T5258	arg1Of	linked,to
R4162	T5257	T5264	arg1Of	linked,in
R4163	T5263	T5258	arg2Of	signalling,to
R4164	T5263	T5259	arg1Of	signalling,the
R4165	T5263	T5260	arg1Of	signalling,growth
R4166	T5263	T5261	arg1Of	signalling,factor-regulated
R4167	T5263	T5262	arg1Of	signalling,Erk
R4168	T5265	T5266	arg1Of	fibroblast,and
R4169	T5266	T5264	arg2Of	and,in
R4170	T5269	T5266	arg2Of	lines,and
R4171	T5269	T5267	arg1Of	lines,endothelial
R4172	T5269	T5268	arg1Of	lines,cell
R4173	T5269	T5270	arg1Of	lines,[
R4174	T5271	T5270	arg2Of	33–35,[
R4175	T5272	T5270	arg3Of	],[
R4176	T5277	T5275	arg1Of	phosphorylation,BCR-induced
R4177	T5277	T5276	arg1Of	phosphorylation,Erk
R4178	T5277	T5278	arg1Of	phosphorylation,was
R4179	T5277	T5280	arg2Of	phosphorylation,reduced
R4180	T5280	T5273	arg1Of	reduced,However
R4181	T5280	T5274	arg1Of	reduced,","
R4182	T5280	T5278	arg2Of	reduced,was
R4183	T5280	T5279	arg1Of	reduced,also
R4184	T5280	T5281	arg1Of	reduced,in
R4185	T5280	T5290	modOf	reduced,suggesting
R4186	T5284	T5281	arg2Of	cells,in
R4187	T5284	T5282	arg1Of	cells,PKD1/3−/−-Flag-PKD3+
R4188	T5284	T5283	arg1Of	cells,B
R4189	T5284	T5285	arg1Of	cells,(
R4190	T5286	T5285	arg2Of	data,(
R4191	T5286	T5288	arg2Of	data,shown
R4192	T5288	T5287	arg1Of	shown,not
R4193	T5289	T5285	arg3Of	),(
R4194	T5294	T5292	arg2Of	levels,reduced
R4195	T5294	T5293	arg1Of	levels,BCR
R4196	T5294	T5295	arg1Of	levels,on
R4197	T5294	T5306	arg1Of	levels,may
R4198	T5294	T5308	arg1Of	levels,impact
R4199	T5297	T5295	arg2Of	surface,on
R4200	T5297	T5296	arg1Of	surface,the
R4201	T5297	T5298	arg1Of	surface,of
R4202	T5299	T5300	arg1Of	PKD1/3−/−,(
R4203	T5302	T5300	arg2Of	PKD1/3−/−-Flag-PKD3+,(
R4204	T5302	T5301	arg1Of	PKD1/3−/−-Flag-PKD3+,and
R4205	T5303	T5300	arg3Of	),(
R4206	T5305	T5298	arg2Of	cells,of
R4207	T5305	T5299	arg1Of	cells,PKD1/3−/−
R4208	T5305	T5304	arg1Of	cells,B
R4209	T5308	T5290	arg2Of	impact,suggesting
R4210	T5308	T5291	arg1Of	impact,that
R4211	T5308	T5306	arg2Of	impact,may
R4212	T5308	T5307	arg1Of	impact,itself
R4213	T5308	T5309	arg1Of	impact,on
R4214	T5311	T5309	arg2Of	strength,on
R4215	T5311	T5310	arg1Of	strength,the
R4216	T5311	T5312	arg1Of	strength,of
R4217	T5313	T5312	arg2Of	activation,of
R4218	T5313	T5314	arg1Of	activation,of
R4219	T5319	T5314	arg2Of	pathway,of
R4220	T5319	T5315	arg1Of	pathway,this
R4221	T5319	T5316	arg1Of	pathway,specific
R4222	T5319	T5317	arg1Of	pathway,intracellular
R4223	T5319	T5318	arg1Of	pathway,signalling
R4224	T5321	T5320	arg1Of	search,To
R4225	T5321	T5322	arg1Of	search,for
R4226	T5326	T5322	arg2Of	targets,for
R4227	T5326	T5323	arg1Of	targets,other
R4228	T5326	T5324	arg1Of	targets,potential
R4229	T5326	T5325	arg1Of	targets,PKD
R4230	T5326	T5327	arg1Of	targets,that
R4231	T5326	T5328	arg1Of	targets,may
R4232	T5326	T5329	arg1Of	targets,show
R4233	T5329	T5328	arg2Of	show,may
R4234	T5329	T5332	arg1Of	show,in
R4235	T5331	T5329	arg2Of	regulation,show
R4236	T5331	T5330	arg1Of	regulation,defective
R4237	T5336	T5332	arg2Of	cells,in
R4238	T5336	T5333	arg1Of	cells,PKD1/3−/−
R4239	T5336	T5334	arg1Of	cells,DT40
R4240	T5336	T5335	arg1Of	cells,B
R4241	T5338	T5321	arg1Of	we,search
R4242	T5338	T5339	arg1Of	we,used
R4243	T5339	T5320	modOf	used,To
R4244	T5339	T5337	arg1Of	used,","
R4245	T5343	T5339	arg2Of	phospho-antibody,used
R4246	T5343	T5340	arg1Of	phospho-antibody,a
R4247	T5343	T5341	arg1Of	phospho-antibody,PKD
R4248	T5343	T5342	arg1Of	phospho-antibody,substrate
R4249	T5343	T5344	arg1Of	phospho-antibody,that
R4250	T5343	T5345	arg1Of	phospho-antibody,recognises
R4251	T5348	T5345	arg2Of	sequences,recognises
R4252	T5348	T5346	arg1Of	sequences,consensus
R4253	T5348	T5347	arg1Of	sequences,phosphorylation
R4254	T5348	T5349	arg2Of	sequences,targeted
R4255	T5349	T5356	arg1Of	targeted,[
R4256	T5352	T5349	arg1Of	enzymes,targeted
R4257	T5352	T5350	arg2Of	enzymes,by
R4258	T5352	T5351	arg1Of	enzymes,PKD
R4259	T5352	T5353	arg1Of	enzymes,(
R4260	T5354	T5353	arg2Of	LxRxxpS/T,(
R4261	T5355	T5353	arg3Of	),(
R4262	T5357	T5356	arg2Of	36,[
R4263	T5358	T5356	arg3Of	],[
R4264	T5360	T5359	arg2Of	shown,As
R4265	T5360	T5361	arg1Of	shown,in
R4266	T5363	T5361	arg2Of	3C,in
R4267	T5363	T5362	arg1Of	3C,Fig.
R4268	T5366	T5365	arg1Of	ester-,phorbol
R4269	T5366	T5367	arg1Of	ester-,and
R4270	T5368	T5367	arg2Of	BCR-induced,and
R4271	T5369	T5366	arg1Of	phosphorylation,ester-
R4272	T5369	T5368	arg1Of	phosphorylation,BCR-induced
R4273	T5369	T5370	arg1Of	phosphorylation,of
R4274	T5369	T5377	arg1Of	phosphorylation,was
R4275	T5369	T5378	arg1Of	phosphorylation,similar
R4276	T5369	T5385	arg1Of	phosphorylation,is
R4277	T5369	T5387	arg1Of	phosphorylation,independent
R4278	T5372	T5370	arg2Of	substrates,of
R4279	T5372	T5371	arg1Of	substrates,cellular
R4280	T5372	T5373	arg2Of	substrates,detected
R4281	T5376	T5373	arg1Of	phospho-antibody,detected
R4282	T5376	T5374	arg2Of	phospho-antibody,by
R4283	T5376	T5375	arg1Of	phospho-antibody,this
R4284	T5377	T5384	arg1Of	was,and
R4285	T5378	T5377	arg2Of	similar,was
R4286	T5378	T5379	arg1Of	similar,in
R4287	T5380	T5381	arg1Of	wild-type,and
R4288	T5381	T5379	arg2Of	and,in
R4289	T5383	T5381	arg2Of	cells,and
R4290	T5383	T5382	arg1Of	cells,PKD1/3−/−
R4291	T5384	T5359	arg1Of	and,As
R4292	T5384	T5364	arg1Of	and,","
R4293	T5385	T5384	arg2Of	is,and
R4294	T5385	T5386	arg1Of	is,therefore
R4295	T5387	T5385	arg2Of	independent,is
R4296	T5387	T5388	arg1Of	independent,of
R4297	T5390	T5388	arg2Of	enzymes,of
R4298	T5390	T5389	arg1Of	enzymes,PKD
R4299	T5393	T5394	arg1Of	pretreatment,of
R4300	T5393	T5402	arg1Of	pretreatment,with
R4301	T5393	T5411	arg1Of	pretreatment,prevented
R4302	T5401	T5394	arg2Of	cells,of
R4303	T5401	T5395	arg1Of	cells,both
R4304	T5401	T5396	arg1Of	cells,wild-type
R4305	T5401	T5397	arg1Of	cells,and
R4306	T5401	T5398	arg1Of	cells,PKD1/3−/−
R4307	T5401	T5399	arg1Of	cells,DT40
R4308	T5401	T5400	arg1Of	cells,B
R4309	T5403	T5402	arg2Of	GF109203X,with
R4310	T5403	T5404	arg1Of	GF109203X,","
R4311	T5407	T5404	arg2Of	derivative,","
R4312	T5407	T5405	arg1Of	derivative,a
R4313	T5407	T5406	arg1Of	derivative,bisindoylmaleimide
R4314	T5407	T5408	arg1Of	derivative,that
R4315	T5407	T5409	arg1Of	derivative,inhibits
R4316	T5410	T5409	arg2Of	PKCs,inhibits
R4317	T5411	T5391	arg1Of	prevented,However
R4318	T5411	T5392	arg1Of	prevented,","
R4319	T5413	T5411	arg2Of	induction,prevented
R4320	T5413	T5412	arg1Of	induction,the
R4321	T5413	T5414	arg1Of	induction,of
R4322	T5415	T5414	arg2Of	proteins,of
R4323	T5415	T5416	arg1Of	proteins,that
R4324	T5415	T5417	arg1Of	proteins,contain
R4325	T5420	T5417	arg2Of	motifs,contain
R4326	T5420	T5418	arg2Of	motifs,phosphorylated
R4327	T5420	T5419	arg1Of	motifs,LxRxxS/T
R4328	T5422	T5423	arg1Of	loss,of
R4329	T5422	T5426	arg1Of	loss,does
R4330	T5422	T5429	arg1Of	loss,disrupt
R4331	T5425	T5423	arg2Of	enzymes,of
R4332	T5425	T5424	arg1Of	enzymes,PKD1/3
R4333	T5429	T5421	arg1Of	disrupt,Thus
R4334	T5429	T5426	arg2Of	disrupt,does
R4335	T5429	T5427	arg1Of	disrupt,not
R4336	T5429	T5428	arg1Of	disrupt,globally
R4337	T5431	T5429	arg2Of	phosphorylation,disrupt
R4338	T5431	T5430	arg1Of	phosphorylation,the
R4339	T5431	T5432	arg1Of	phosphorylation,of
R4340	T5434	T5432	arg2Of	proteins,of
R4341	T5434	T5433	arg1Of	proteins,cellular
R4342	T5434	T5435	arg1Of	proteins,that
R4343	T5434	T5436	arg1Of	proteins,contain
R4344	T5438	T5436	arg2Of	motifs,contain
R4345	T5438	T5437	arg1Of	motifs,LxRxxpS/T
R4346	T5440	T5439	arg1Of	result,This
R4347	T5440	T5441	arg1Of	result,is
R4348	T5440	T5444	arg1Of	result,surprising
R4349	T5441	T5443	arg1Of	is,not
R4350	T5441	T5445	arg1Of	is,as
R4351	T5443	T5442	arg1Of	not,perhaps
R4352	T5444	T5441	arg2Of	surprising,is
R4353	T5447	T5446	arg1Of	motifs,LxRxxS/T
R4354	T5447	T5449	arg1Of	motifs,act
R4355	T5449	T5445	arg2Of	act,as
R4356	T5449	T5448	arg1Of	act,also
R4357	T5449	T5450	arg1Of	act,as
R4358	T5452	T5450	arg2Of	substrates,as
R4359	T5452	T5451	arg1Of	substrates,good
R4360	T5452	T5453	arg1Of	substrates,for
R4361	T5456	T5453	arg2Of	kinases,for
R4362	T5456	T5454	arg1Of	kinases,other
R4363	T5456	T5455	arg1Of	kinases,serine/threonine
R4364	T5456	T5458	arg1Of	kinases,as
R4365	T5458	T5457	arg1Of	as,such
R4366	T5459	T5458	arg2Of	MAPKAPK2,as
R4367	T5462	T5461	arg1Of	experiments,these
R4368	T5462	T5463	arg1Of	experiments,do
R4369	T5462	T5464	arg1Of	experiments,provide
R4370	T5464	T5460	arg1Of	provide,However
R4371	T5464	T5463	arg2Of	provide,do
R4372	T5466	T5464	arg2Of	evidence,provide
R4373	T5466	T5465	arg1Of	evidence,further
R4374	T5469	T5468	arg1Of	antisera,phosphospecific
R4375	T5469	T5470	arg1Of	antisera,are
R4376	T5469	T5473	arg1Of	antisera,selective
R4377	T5470	T5466	arg2Of	are,evidence
R4378	T5470	T5467	arg1Of	are,that
R4379	T5470	T5471	arg1Of	are,not
R4380	T5473	T5470	arg2Of	selective,are
R4381	T5473	T5472	arg1Of	selective,sufficiently
R4382	T5473	T5474	modOf	selective,to
R4383	T5476	T5474	arg1Of	designated,to
R4384	T5476	T5475	arg2Of	designated,be
R4385	T5478	T5477	arg1Of	specific,kinase
R4386	T5480	T5476	arg3Of	antisera,designated
R4387	T5480	T5478	arg1Of	antisera,specific
R4388	T5480	T5479	arg1Of	antisera,substrate
R4389	T5483	T5481	arg1Of	pathways,BCR-induced
R4390	T5483	T5482	arg1Of	pathways,signalling
R4391	T5483	T5484	arg1Of	pathways,culminate
R4392	T5484	T5485	arg1Of	culminate,in
R4393	T5487	T5485	arg2Of	activation,in
R4394	T5487	T5486	arg1Of	activation,the
R4395	T5487	T5488	arg1Of	activation,of
R4396	T5491	T5488	arg2Of	events,of
R4397	T5491	T5489	arg1Of	events,gene
R4398	T5491	T5490	arg1Of	events,transcription
R4399	T5491	T5492	arg1Of	events,that
R4400	T5491	T5493	arg1Of	events,control
R4401	T5496	T5497	arg1Of	survival,","
R4402	T5497	T5499	arg1Of	",",and
R4403	T5498	T5497	arg2Of	proliferation,","
R4404	T5499	T5493	arg2Of	and,control
R4405	T5499	T5494	arg1Of	and,B
R4406	T5499	T5495	arg1Of	and,cell
R4407	T5500	T5499	arg2Of	function,and
R4408	T5503	T5501	arg2Of	context,In
R4409	T5503	T5502	arg1Of	context,this
R4410	T5508	T5501	arg1Of	proposed,In
R4411	T5508	T5504	arg1Of	proposed,","
R4412	T5508	T5506	arg2Of	proposed,has
R4413	T5508	T5507	arg2Of	proposed,been
R4414	T5508	T5517	arg1Of	proposed,through
R4415	T5513	T5505	arg1Of	control,it
R4416	T5513	T5506	arg1Of	control,has
R4417	T5513	T5507	arg1Of	control,been
R4418	T5513	T5508	arg2Of	control,proposed
R4419	T5513	T5509	arg1Of	control,that
R4420	T5513	T5510	arg1Of	control,PKD
R4421	T5513	T5511	arg1Of	control,family
R4422	T5513	T5512	arg1Of	control,members
R4423	T5513	T5514	arg1Of	control,of
R4424	T5516	T5514	arg2Of	transcription,of
R4425	T5516	T5515	arg1Of	transcription,gene
R4426	T5518	T5517	arg2Of	activation,through
R4427	T5518	T5519	arg1Of	activation,of
R4428	T5523	T5519	arg2Of	factor,of
R4429	T5523	T5520	arg1Of	factor,the
R4430	T5523	T5521	arg1Of	factor,NFκB
R4431	T5523	T5522	arg1Of	factor,transcription
R4432	T5527	T5526	arg1Of	activation,PKD-mediated
R4433	T5527	T5528	arg1Of	activation,of
R4434	T5527	T5530	arg1Of	activation,occurs
R4435	T5529	T5528	arg2Of	NFκB,of
R4436	T5530	T5524	arg1Of	occurs,Thus
R4437	T5530	T5525	arg1Of	occurs,","
R4438	T5530	T5531	arg1Of	occurs,downstream
R4439	T5531	T5532	arg1Of	downstream,of
R4440	T5534	T5532	arg2Of	variety,of
R4441	T5534	T5533	arg1Of	variety,a
R4442	T5534	T5535	arg1Of	variety,of
R4443	T5537	T5535	arg2Of	signals,of
R4444	T5537	T5536	arg1Of	signals,different
R4445	T5537	T5538	arg1Of	signals,","
R4446	T5537	T5539	arg1Of	signals,including
R4447	T5541	T5540	arg1Of	stress,mROS/oxidative
R4448	T5541	T5542	arg1Of	stress,","
R4449	T5542	T5545	arg1Of	",",and
R4450	T5544	T5542	arg2Of	acid,","
R4451	T5544	T5543	arg1Of	acid,lysophosphatidic
R4452	T5545	T5539	arg2Of	and,including
R4453	T5547	T5546	arg1Of	Bcr-Abl,the
R4454	T5548	T5545	arg2Of	oncogene,and
R4455	T5548	T5547	arg1Of	oncogene,Bcr-Abl
R4456	T5548	T5549	arg1Of	oncogene,[
R4457	T5550	T5549	arg2Of	"17,21,23,30,37",[
R4458	T5551	T5549	arg3Of	],[
R4459	T5554	T5555	arg1Of	expression,of
R4460	T5554	T5560	arg1Of	expression,enhances
R4461	T5559	T5555	arg2Of	mutant,of
R4462	T5559	T5556	arg1Of	mutant,an
R4463	T5559	T5557	arg2Of	mutant,activated
R4464	T5559	T5558	arg1Of	mutant,PKD1
R4465	T5560	T5552	arg1Of	enhances,Furthermore
R4466	T5560	T5553	arg1Of	enhances,","
R4467	T5560	T5564	arg1Of	enhances,[
R4468	T5563	T5560	arg2Of	activation,enhances
R4469	T5563	T5561	arg1Of	activation,HPK1-mediated
R4470	T5563	T5562	arg1Of	activation,NFκB
R4471	T5565	T5564	arg2Of	38,[
R4472	T5566	T5564	arg3Of	],[
R4473	T5569	T5567	arg2Of	cells,In
R4474	T5569	T5568	arg1Of	cells,B
R4475	T5571	T5572	arg1Of	NFκB,is
R4476	T5571	T5573	arg2Of	NFκB,known
R4477	T5571	T5575	arg1Of	NFκB,be
R4478	T5571	T5576	arg2Of	NFκB,regulated
R4479	T5573	T5572	arg2Of	known,is
R4480	T5573	T5584	arg1Of	known,but
R4481	T5576	T5573	arg3Of	regulated,known
R4482	T5576	T5574	arg1Of	regulated,to
R4483	T5576	T5575	arg2Of	regulated,be
R4484	T5576	T5577	arg1Of	regulated,via
R4485	T5576	T5581	arg1Of	regulated,[
R4486	T5578	T5579	arg1Of	DAG,and
R4487	T5579	T5577	arg2Of	and,via
R4488	T5580	T5579	arg2Of	PKCβ,and
R4489	T5582	T5581	arg2Of	"39,40",[
R4490	T5583	T5581	arg3Of	],[
R4491	T5584	T5567	arg1Of	but,In
R4492	T5584	T5570	arg1Of	but,","
R4493	T5586	T5587	arg1Of	PKDs,are
R4494	T5587	T5585	arg1Of	are,whether
R4495	T5587	T5593	arg1Of	are,has
R4496	T5587	T5595	arg1Of	are,been
R4497	T5587	T5596	arg2Of	are,explored
R4498	T5589	T5587	arg2Of	intermediaries,are
R4499	T5589	T5588	arg1Of	intermediaries,key
R4500	T5589	T5590	arg1Of	intermediaries,for
R4501	T5592	T5590	arg2Of	regulation,for
R4502	T5592	T5591	arg1Of	regulation,NFκB
R4503	T5596	T5584	arg2Of	explored,but
R4504	T5596	T5593	arg2Of	explored,has
R4505	T5596	T5594	arg1Of	explored,not
R4506	T5596	T5595	arg2Of	explored,been
R4507	T5598	T5597	arg1Of	data,The
R4508	T5598	T5599	arg1Of	data,(
R4509	T5598	T5603	arg1Of	data,show
R4510	T5601	T5599	arg2Of	4A,(
R4511	T5601	T5600	arg1Of	4A,Fig.
R4512	T5602	T5599	arg3Of	),(
R4513	T5607	T5605	arg1Of	activity,NFκB
R4514	T5607	T5606	arg1Of	activity,transcriptional
R4515	T5607	T5608	arg1Of	activity,was
R4516	T5607	T5610	arg2Of	activity,induced
R4517	T5610	T5603	arg2Of	induced,show
R4518	T5610	T5604	arg1Of	induced,that
R4519	T5610	T5608	arg2Of	induced,was
R4520	T5610	T5609	arg1Of	induced,strongly
R4521	T5610	T5611	arg1Of	induced,in
R4522	T5610	T5619	arg1Of	induced,in
R4523	T5618	T5611	arg2Of	cells,in
R4524	T5618	T5612	arg1Of	cells,both
R4525	T5618	T5613	arg1Of	cells,wild-type
R4526	T5618	T5614	arg1Of	cells,and
R4527	T5618	T5615	arg1Of	cells,PKD1/3−/−
R4528	T5618	T5616	arg1Of	cells,DT40
R4529	T5618	T5617	arg1Of	cells,B
R4530	T5620	T5619	arg2Of	response,in
R4531	T5620	T5621	arg1Of	response,to
R4532	T5624	T5623	arg1Of	ester,phorbol
R4533	T5624	T5625	arg1Of	ester,or
R4534	T5625	T5621	arg2Of	or,to
R4535	T5625	T5622	arg1Of	or,either
R4536	T5627	T5625	arg2Of	stimulation,or
R4537	T5627	T5626	arg1Of	stimulation,BCR
R4538	T5629	T5628	arg2Of	contrast,In
R4539	T5631	T5666	arg1Of	BCR,was
R4540	T5631	T5667	arg2Of	BCR,observed
R4541	T5634	T5632	arg1Of	ester-induced,and
R4542	T5634	T5633	arg1Of	ester-induced,phorbol
R4543	T5637	T5634	arg1Of	activity,ester-induced
R4544	T5637	T5635	arg1Of	activity,NFκB
R4545	T5637	T5636	arg1Of	activity,transcriptional
R4546	T5637	T5638	arg1Of	activity,was
R4547	T5637	T5639	arg2Of	activity,abolished
R4548	T5639	T5638	arg2Of	abolished,was
R4549	T5639	T5640	arg1Of	abolished,in
R4550	T5639	T5649	arg1Of	abolished,","
R4551	T5639	T5650	arg1Of	abolished,although
R4552	T5639	T5656	arg1Of	abolished,(
R4553	T5644	T5640	arg2Of	cells,in
R4554	T5644	T5641	arg1Of	cells,PKCβ−/−
R4555	T5644	T5642	arg1Of	cells,DT40
R4556	T5644	T5643	arg1Of	cells,B
R4557	T5644	T5645	arg1Of	cells,(
R4558	T5647	T5645	arg2Of	4A,(
R4559	T5647	T5646	arg1Of	4A,Fig.
R4560	T5648	T5645	arg3Of	),(
R4561	T5652	T5650	arg2Of	activation,although
R4562	T5652	T5651	arg1Of	activation,strong
R4563	T5652	T5653	arg1Of	activation,of
R4564	T5655	T5653	arg2Of	kinases,of
R4565	T5655	T5654	arg1Of	kinases,PKD
R4566	T5657	T5656	arg2Of	as,(
R4567	T5658	T5657	arg2Of	assessed,as
R4568	T5658	T5659	arg1Of	assessed,by
R4569	T5660	T5659	arg2Of	autophosphorylation,by
R4570	T5660	T5661	arg1Of	autophosphorylation,of
R4571	T5660	T5663	arg1Of	autophosphorylation,at
R4572	T5662	T5661	arg2Of	PKD1,of
R4573	T5664	T5663	arg2Of	S916,at
R4574	T5665	T5656	arg3Of	),(
R4575	T5667	T5628	arg1Of	observed,In
R4576	T5667	T5630	arg1Of	observed,","
R4577	T5667	T5638	modOf	observed,was
R4578	T5667	T5666	arg2Of	observed,was
R4579	T5667	T5668	arg1Of	observed,in
R4580	T5671	T5668	arg2Of	cells,in
R4581	T5671	T5669	arg1Of	cells,the
R4582	T5671	T5670	arg1Of	cells,PKCβ−/−
R4583	T5671	T5672	arg1Of	cells,(
R4584	T5674	T5672	arg2Of	4B,(
R4585	T5674	T5673	arg1Of	4B,Fig.
R4586	T5675	T5672	arg3Of	),(
R4587	T5679	T5678	arg1Of	kinases,PKD
R4588	T5679	T5680	arg1Of	kinases,are
R4589	T5679	T5682	arg1Of	kinases,essential
R4590	T5679	T5684	arg1Of	kinases,sufficient
R4591	T5679	T5686	arg1Of	kinases,mediate
R4592	T5679	T5696	arg1Of	kinases,do
R4593	T5679	T5698	arg1Of	kinases,participate
R4594	T5680	T5694	arg1Of	are,and
R4595	T5682	T5683	arg1Of	essential,nor
R4596	T5683	T5680	arg2Of	nor,are
R4597	T5683	T5681	arg1Of	nor,neither
R4598	T5684	T5683	arg2Of	sufficient,nor
R4599	T5686	T5682	arg2Of	mediate,essential
R4600	T5686	T5684	arg2Of	mediate,sufficient
R4601	T5686	T5685	arg1Of	mediate,to
R4602	T5689	T5686	arg2Of	activation,mediate
R4603	T5689	T5687	arg1Of	activation,BCR-induced
R4604	T5689	T5688	arg1Of	activation,NFκB
R4605	T5689	T5690	arg1Of	activation,in
R4606	T5693	T5690	arg2Of	cells,in
R4607	T5693	T5691	arg1Of	cells,DT40
R4608	T5693	T5692	arg1Of	cells,B
R4609	T5694	T5676	arg1Of	and,Thus
R4610	T5694	T5677	arg1Of	and,","
R4611	T5698	T5694	arg2Of	participate,and
R4612	T5698	T5695	arg1Of	participate,hence
R4613	T5698	T5696	arg2Of	participate,do
R4614	T5698	T5697	arg1Of	participate,not
R4615	T5698	T5699	arg1Of	participate,in
R4616	T5702	T5699	arg2Of	control,in
R4617	T5702	T5700	arg1Of	control,DAG/PKC
R4618	T5702	T5701	arg2Of	control,mediated
R4619	T5702	T5703	arg1Of	control,of
R4620	T5704	T5703	arg2Of	NFκB,of
R5531	T7047	T7043	arg1Of	kinases,"40 B-lymphocyte cell line. Previously we have shown that PKDs have an essential role in regulating class II histone deacetylases in DT40 B-cells [Matthews, S.A., Liu, P., Spitaler, M., Olson, E.N., McKinsey, T.A., Cantrell, D.A. and Scharenberg, A.M. (2006) Essential role for protein kinase D family kinases in the regulation of class II histone deacetylases in B lymphocytes. Mol. Cell Biol. 26, 1569–1577]. We now show that PKDs are also required to regulate HSP27 phosphorylation in DT40 B-cells. However, in contrast to previous observations in other cell types, PKD enzymes do not regulate basic cellular processes such as proliferation or survival responses, nor NFκB transcriptional activity downstream of the B cell antigen receptor. Thus, PKDs have a selective role in DT40 B-cell biology. 1 Introduction The protein kinase D (PKD) serine/threonine kinase family has three members: PKD1, PKD2 and PKD3. Most cell types express at least two PKD isoforms but PKD enzymes are especially highly expressed in haematopoietic cells, where they are activated in response to antigen receptors stimulation [2,3]. A conserved signalling pathway linking antigen receptors to PKDs involves the activation of PLCγ and the subsequent production of diacylglycerol (DAG) which stimulates classical and/or novel protein kinase Cs (PKC) that phosphorylate two key regulatory serine residues in the activation loop of PKD kinases [3–6]. The N-terminal regulatory region of PKD enzymes contains a DAG binding domain and direct binding of DAG also contributes to PKD1 activation [7] as well as regulating the spatial location of PKD enzymes within cells [8–12]. PKD enzymes have been proposed to regulate numerous cellular functions, including cell proliferation [13–16], anti-apoptotic signals [17,18] and thymocyte development [19]. Expression of mutant catalytically inactive and constitutively activated PKDs can also modify Golgi function, cell adhesion and cell motility (reviewed in [20]). In particular, PKDs have been widely linked to the activation of the NFκB transcription factor and in regulating cell survival during oxidative stress [17,21–23]. Another recently proposed PKD1 substrate is HSP27 [24], a small heat shock protein involved in regulating cell migration and cell survival [25]. An essential role for PKD enzymes in regulating class II histone deacetylases (HDACs), enzymes that repress MEF2-dependent gene transcription, has also been demonstrated [1,26–28]. To investigate the biological role of PKDs we have generated DT40 B cell lines that lack expression of one or more members of the PKD family [1], allowing us to investigate the function(s) of PKD isoforms following B cell antigen receptor (BCR) stimulation, as well addressing the issue of functional redundancy between the different PKD family members. Previous studies have shown that PKDs are indispensable for HDAC regulation in B cells [1]. Herein we show that PKDs are also indispensable for HSP27 phosphorylation in B cells. However, PKD-null DT40 B cells are viable and proliferate normally. Moreover, loss of the entire cellular pool of PKD does not critically affect oxidative stress responses in B cells nor do PKD kinases play an essential role in regulating NFκB transcriptional activity. Together, these findings reveal that in B lymphocytes, PKD kinases are not critical regulators of many of the cellular processes previously ascribed to them in other cellular systems. 2 Materials and methods 2.1 Cell culture, transient transfections and cell stimulation The generation, culture and activation of PKD1−/−, PKD3−/− and PKD1/3−/− knockout DT40 B cell lines have been described previously [1]. Cells were lysed and protein extracts were analysed in Western blotting experiments as previously described [1]. Chloramphenicol acetyl transferase assays have been described previously [29]. 2.2 sIgM staining DT40 B cells (2 × 106 cells per point) were resuspended in 200 μl buffer (RPMI 1640 media, 1% foetal calf serum) containing anti-chicken M1 monoclonal antibody conjugated to FITC for 20 min on ice. The cells were washed twice and fluorescent intensity was analysed by flow cytometry. All results shown are representative of at two to four independent experiments unless otherwise indicated. 3 Results 3.1 Loss of HSP27 phosphorylation in DT40 B cells lacking expression of PKD family kinases DT40 B cells express two PKD isoforms, PKD1 and PKD3, and as previously described we have recently generated DT40 B cell lines that lack expression of either PKD1 or PKD3 or both enzymes [1]. In generating the double knockout cell lines we targeted the PKD1 loci in a PKD3−/− cell line that expressed a Flag-PKD3 transgene under the control of a doxycycline-inducible promoter. Hence, in the presence of doxycycline, Flag-PKD3 expression in PKD1/3 double knockout cells is comparable to endogenous PKD3 present in wild-type DT40 cells and removal of doxycycline from the culture media for 5 days results in a completely null PKD phenotype (Fig. 1A). Previously, we have demonstrated that phosphorylation and nuclear exclusion of class II histone deacetylases (HDACs) during BCR engagement is defective in PKD1/3−/− B cells and can restored upon re-expression of a single PKD isoform [1]. The small heat shock protein HSP27 has recently been proposed as a PKD1 substrate [24] and we accordingly assessed whether PKD-null DT40 cells have defective phosphorylation of HSP27 on serine 82, the proposed PKD1 substrate sequence. We initially investigated the regulation of HSP27 phosphorylation in single knockout DT40 B cells lacking either PKD1 or PKD3. As shown in Fig. 1B, activation of the BCR or treatment with the DAG-mimetic PdBu increased the levels of HSP27 phosphorylation at S82 in wild-type DT40 B cells. BCR and phorbol ester signals were also able to increase HSP27 phosphorylation in PKD1 or PKD3 single knockout DT40 B cells (Fig. 1B). However, BCR- and phorbol ester-induced phosphorylation of HSP27 on S82 was abolished in B cells that lacked both PKD1 and PKD3 (Fig. 1C). Significantly, doxycycline-induced expression of the Flag-PKD3 transgene in the double knockout cells was sufficient to restore normal regulation of HSP27 phosphorylation (Fig. 1C). In contrast, expression of a kinase-deficient PKD3 mutant protein in the double knockout cells was not able to restore BCR- or phorbol ester-induced HSP27 phosphorylation (Fig. 1D). Hence, PKD3 as well as PKD1 can regulate HSP27 phosphorylation and in DT40 B cells they are functionally redundant as HSP27 kinases. 3.2 Cellular proliferation and survival in DT40 B cells lacking expression of PKD family kinases PKD enzymes have previously been linked to the regulation of cell proliferation and survival (reviewed in [20]). To investigate the effect that loss of PKD kinases had on B cell survival and/or proliferation we cultured wild-type and PKD-null cells in the presence (PKD1/3−/−: Flag-PKD3+ve) or absence (PKD1/3−/−) of doxycycline and monitored exponential growth. As shown in Fig. 2A, PKD1/3−/− cells proliferated exponentially and re-expression of Flag-PKD3 in these cells had no impact on the rate of proliferation. Furthermore, the viability of PKD1/3−/− B cells during routine culturing was not significantly different from that of wild-type B cells (data not shown). It was noted that the population doubling time of PKD1/3−/− cells was slightly slower than that of wild type DT40 cells (12.7 ± 2.8 h versus 10.2 ± 0.4 h) but the failure of PKD3 re-expression to modify the proliferation rate of PKD1/3−/− cells suggests that these small differences were most likely the result of clonal variation and were not caused specifically by loss of PKD enzymes. Thus, PKD family enzymes are not essential for regulating basal survival and proliferation of DT40 B cells. PKD enzymes, specifically PKD1 and PKD2, have previously been linked to a protective role against oxidative stress-induced injury in 3T3 fibroblast, HeLa and epithelial cell lines [17,30–32]. We therefore addressed the role of PKD family kinases in regulating B cell survival in response to oxidative stress and other stress stimuli. As shown in Fig. 2B, loss of PKD1/3 expression had no significant impact on the survival of DT40 B cells in response to mitochondrial stress stimuli (H2O2 or serum deprivation); DNA damaging agents (etoposide or doxorubicin); ER pathway stress due to calcium overload (thapsigargin) or following prolonged treatment with phorbol esters or Trichostatin A, an inhibitor of class I/II HDACs. Thus, PKD kinases do not play an essential role in regulating B cell survival in response to a range of different stress stimuli. 3.3 Antigen receptor regulated signalling pathways in PKD-null DT40 B cells To further explore the contribution of PKD kinases to DT40 B cell biology we investigated whether specific BCR-regulated signalling events were defective in the PKD-null B cells. Initial experiments revealed that surface expression of the BCR was reduced in PKD1/3−/− (and in PKD1/3−/−:Flag-PKD3+ve) cells compared to wild-type DT40 B cells (Fig. 3A and data not shown). Nevertheless, BCR-crosslinking of PKD1/3−/− cells was sufficient to induce the activation of a number of signalling cascades, similar to that observed in wild-type cells (Fig. 3B). Hence, BCR-induced activation of the Akt, mTOR/p70 S6 kinase (as shown by S6 ribosomal protein phosphorylation) and MAPK signalling pathways was clearly detectable in PKD1/3-null B cells (Fig. 3B). Furthermore, enhanced tyrosine phosphorylation of multiple cellular proteins as well as an increase in intracellular calcium levels was also observed following BCR stimulation of PKD1/3-null B cells (data not shown). We did observe that the strength of BCR (but not phorbol ester)-induced regulation of the Erk1-RSK1 signalling pathway was reduced in PKD1/3−/− B cells compared to wild-type B cells (Fig. 3B). One interpretation of this data is that PKD enzymes may modulate Erk activation. Indeed, PKD enzymes have previously been linked to the growth factor-regulated Erk signalling in fibroblast and endothelial cell lines [33–35]. However, BCR-induced Erk phosphorylation was also reduced in PKD1/3−/−-Flag-PKD3+ B cells (data not shown) suggesting that reduced BCR levels on the surface of PKD1/3−/− (and PKD1/3−/−-Flag-PKD3+) B cells may itself impact on the strength of activation of this specific intracellular signalling pathway. To search for other potential PKD targets that may show defective regulation in PKD1/3−/− DT40 B cells, we used a PKD substrate phospho-antibody that recognises consensus phosphorylation sequences targeted by PKD enzymes (LxRxxpS/T) [36]. As shown in Fig. 3C, phorbol ester- and BCR-induced phosphorylation of cellular substrates detected by this phospho-antibody was similar in wild-type and PKD1/3−/− cells and is therefore independent of PKD enzymes. However, pretreatment of both wild-type and PKD1/3−/− DT40 B cells with GF109203X, a bisindoylmaleimide derivative that inhibits PKCs prevented the induction of proteins that contain phosphorylated LxRxxS/T motifs. Thus loss of PKD1/3 enzymes does not globally disrupt the phosphorylation of cellular proteins that contain LxRxxpS/T motifs. This result is perhaps not surprising as LxRxxS/T motifs also act as good substrates for other serine/threonine kinases such as MAPKAPK2. However these experiments do provide further evidence that phosphospecific antisera are not sufficiently selective to be designated kinase specific substrate antisera. BCR-induced signalling pathways culminate in the activation of gene transcription events that control B cell survival, proliferation and function. In this context, it has been proposed that PKD family members control of gene transcription through activation of the NFκB transcription factor. Thus, PKD-mediated activation of NFκB occurs downstream of a variety of different signals, including mROS/oxidative stress, lysophosphatidic acid and the Bcr-Abl oncogene [17,21,23,30,37]. Furthermore, expression of an activated PKD1 mutant enhances HPK1-mediated NFκB activation [38]. In B cells, NFκB is known to be regulated via DAG and PKCβ [39,40] but whether PKDs are key intermediaries for NFκB regulation has not been explored. The data (Fig. 4A) show that NFκB transcriptional activity was strongly induced in both wild-type and PKD1/3−/− DT40 B cells in response to either phorbol ester or BCR stimulation. In contrast, BCR and phorbol ester-induced NFκB transcriptional activity was abolished in PKCβ−/− DT40 B cells (Fig. 4A), although strong activation of PKD kinases (as assessed by autophosphorylation of PKD1 at S916) was observed in the PKCβ−/− cells (Fig. 4B). Thus, PKD kinases are neither essential nor sufficient to mediate BCR-induced NFκB activation in DT40 B cells and hence do not participate in DAG/PKC mediated control of NFκB. 4 Discussion Protein"
R5532	T7047	T7044	arg1Of	kinases,kinase
R5533	T7047	T7045	arg1Of	kinases,D
R5534	T7047	T7046	arg1Of	kinases,serine
R1597	T1872	T1879	arg1Of	cells,were
R1602	T1875	T1874	arg1Of	cells,2 × 106
R1603	T1875	T1876	arg1Of	cells,per
R1605	T1877	T1876	arg2Of	point,per
R1612	T1883	T1895	arg1Of	buffer,containing
R1617	T1889	T1890	arg1Of	1,%
R1620	T1893	T1891	arg1Of	serum,foetal
R1621	T1893	T1892	arg1Of	serum,calf
R1623	T1899	T1895	arg2Of	antibody,containing
R1624	T1899	T1896	arg1Of	antibody,anti-chicken
R1625	T1899	T1897	arg1Of	antibody,M1
R1626	T1899	T1898	arg1Of	antibody,monoclonal
R1627	T1899	T1900	arg2Of	antibody,conjugated
R1628	T1900	T1901	arg1Of	conjugated,to
R1629	T1902	T1901	arg2Of	FITC,to
R1630	T1902	T1903	arg1Of	FITC,for
R1631	T1904	T1903	arg2Of	20 min,for
R1632	T1904	T1905	arg1Of	20 min,on
R1633	T1906	T1905	arg2Of	ice,on
R1634	T1908	T1907	arg1Of	cells,The
R1635	T1908	T1909	arg1Of	cells,were
R1636	T1908	T1910	arg2Of	cells,washed
R1637	T1910	T1909	arg2Of	washed,were
R1638	T1910	T1911	arg1Of	washed,twice
R1639	T1910	T1912	arg1Of	washed,and
R1640	T1914	T1913	arg1Of	intensity,fluorescent
R1641	T1914	T1915	arg1Of	intensity,was
R1642	T1914	T1916	arg2Of	intensity,analysed
R1643	T1916	T1912	arg2Of	analysed,and
R1644	T1916	T1915	arg2Of	analysed,was
R1645	T1919	T1916	arg1Of	cytometry,analysed
R1646	T1919	T1917	arg2Of	cytometry,by
R1647	T1919	T1918	arg1Of	cytometry,flow
R1648	T1921	T1920	arg1Of	results,All
R1649	T1921	T1922	arg2Of	results,shown
R1650	T1921	T1923	arg1Of	results,are
R1651	T1921	T1924	arg1Of	results,representative
R1652	T1923	T1932	arg1Of	are,unless

bionlp-st-ge-2016-coref

Id	Subject	Object	Predicate	Lexical cue
T2673	4418-4434	Anaphor	denotes	two PKD isoforms
T2674	4436-4440	Antecedent	denotes	PKD1
T2675	4445-4449	Antecedent	denotes	PKD3
R2277	T2673	T2674	boundBy	two PKD isoforms,PKD1
R2278	T2673	T2675	boundBy	two PKD isoforms,PKD3

bionlp-st-ge-2016-spacy-parsed

Id	Subject	Object	Predicate	Lexical cue
T247	3-15	NNP	denotes	B-lymphocyte
T248	16-20	NN	denotes	cell
T249	21-25	NN	denotes	line
T250	25-26	.	denotes	.
T251	27-37	RB	denotes	Previously
T252	38-40	PRP	denotes	we
T253	41-45	VBP	denotes	have
T254	46-51	VBN	denotes	shown
T255	52-56	IN	denotes	that
T256	57-61	NNS	denotes	PKDs
T257	62-66	VBP	denotes	have
T258	67-69	DT	denotes	an
T259	70-79	JJ	denotes	essential
T260	80-84	NN	denotes	role
T261	85-87	IN	denotes	in
T262	88-98	VBG	denotes	regulating
T263	99-104	NN	denotes	class
T264	105-107	NNP	denotes	II
T265	108-115	NN	denotes	histone
T266	116-128	NNS	denotes	deacetylases
T267	129-131	IN	denotes	in
T268	132-136	NNP	denotes	DT40
T269	137-144	NNPS	denotes	B-cells
T270	145-146	NNP	denotes	[
T271	146-154	NNP	denotes	Matthews
T272	154-155	,	denotes	,
T273	156-160	NNP	denotes	S.A.
T274	160-161	,	denotes	,
T275	162-165	NNP	denotes	Liu
T276	165-166	,	denotes	,
T277	167-169	NNP	denotes	P.
T278	169-170	,	denotes	,
T279	171-179	NNP	denotes	Spitaler
T280	179-180	,	denotes	,
T281	181-183	NNP	denotes	M.
T282	183-184	,	denotes	,
T283	185-190	NNP	denotes	Olson
T284	190-191	,	denotes	,
T285	192-196	NNP	denotes	E.N.
T286	196-197	,	denotes	,
T287	198-206	NNP	denotes	McKinsey
T288	206-207	,	denotes	,
T289	208-212	NNP	denotes	T.A.
T290	212-213	,	denotes	,
T291	214-222	NNP	denotes	Cantrell
T292	222-223	,	denotes	,
T293	224-228	NNP	denotes	D.A.
T294	229-232	CC	denotes	and
T295	233-244	NNP	denotes	Scharenberg
T296	244-245	,	denotes	,
T297	246-250	NNP	denotes	A.M.
T298	251-252	-LRB-	denotes	(
T299	252-256	CD	denotes	2006
T300	256-257	-RRB-	denotes	)
T301	258-267	JJ	denotes	Essential
T302	268-272	NN	denotes	role
T303	273-276	IN	denotes	for
T304	277-284	NN	denotes	protein
T305	285-291	NN	denotes	kinase
T306	292-293	NNP	denotes	D
T307	294-300	NN	denotes	family
T308	301-308	NNS	denotes	kinases
T309	309-311	IN	denotes	in
T310	312-315	DT	denotes	the
T311	316-326	NN	denotes	regulation
T312	327-329	IN	denotes	of
T313	330-335	NN	denotes	class
T314	336-338	NNP	denotes	II
T315	339-346	NN	denotes	histone
T316	347-359	NNS	denotes	deacetylases
T317	360-362	IN	denotes	in
T318	363-364	NNP	denotes	B
T319	365-376	NNS	denotes	lymphocytes
T320	376-377	.	denotes	.
T321	378-381	NNP	denotes	Mol
T322	381-382	.	denotes	.
T323	383-387	NNP	denotes	Cell
T324	388-392	NNP	denotes	Biol
T325	392-393	.	denotes	.
T326	394-396	CD	denotes	26
T327	396-397	,	denotes	,
T328	398-402	CD	denotes	1569
T329	403-407	CD	denotes	1577
T330	407-408	NNP	denotes	]
T331	408-409	.	denotes	.
T332	410-412	PRP	denotes	We
T333	413-416	RB	denotes	now
T334	417-421	VBP	denotes	show
T335	422-426	IN	denotes	that
T336	427-431	NNS	denotes	PKDs
T337	432-435	VBP	denotes	are
T338	436-440	RB	denotes	also
T339	441-449	VBN	denotes	required
T340	450-452	TO	denotes	to
T341	453-461	VB	denotes	regulate
T342	462-467	NNP	denotes	HSP27
T343	468-483	NN	denotes	phosphorylation
T344	484-486	IN	denotes	in
T345	487-491	NNP	denotes	DT40
T346	492-499	NNPS	denotes	B-cells
T347	499-500	.	denotes	.
T348	501-508	RB	denotes	However
T349	508-509	,	denotes	,
T350	510-512	IN	denotes	in
T351	513-521	NN	denotes	contrast
T352	522-524	TO	denotes	to
T353	525-533	JJ	denotes	previous
T354	534-546	NNS	denotes	observations
T355	547-549	IN	denotes	in
T356	550-555	JJ	denotes	other
T357	556-560	NN	denotes	cell
T358	561-566	NNS	denotes	types
T359	566-567	,	denotes	,
T360	568-571	NNP	denotes	PKD
T361	572-579	VBZ	denotes	enzymes
T362	580-582	VB	denotes	do
T363	583-586	RB	denotes	not
T364	587-595	VB	denotes	regulate
T365	596-601	JJ	denotes	basic
T366	602-610	JJ	denotes	cellular
T367	611-620	NNS	denotes	processes
T368	621-625	JJ	denotes	such
T369	626-628	IN	denotes	as
T370	629-642	NN	denotes	proliferation
T371	643-645	CC	denotes	or
T372	646-654	NN	denotes	survival
T373	655-664	NNS	denotes	responses
T374	664-665	,	denotes	,
T375	666-669	CC	denotes	nor
T376	670-674	NNP	denotes	NFκB
T377	675-690	JJ	denotes	transcriptional
T378	691-699	NN	denotes	activity
T379	700-710	JJ	denotes	downstream
T380	711-713	IN	denotes	of
T381	714-717	DT	denotes	the
T382	718-719	NNP	denotes	B
T383	720-724	NN	denotes	cell
T384	725-732	NN	denotes	antigen
T385	733-741	NN	denotes	receptor
T386	741-742	.	denotes	.
T387	743-747	RB	denotes	Thus
T388	747-748	,	denotes	,
T389	749-753	NNS	denotes	PKDs
T390	754-758	VBP	denotes	have
T391	759-760	DT	denotes	a
T392	761-770	JJ	denotes	selective
T393	771-775	NN	denotes	role
T394	776-778	IN	denotes	in
T395	779-783	NNP	denotes	DT40
T396	784-790	NNP	denotes	B-cell
T397	791-798	NN	denotes	biology
T398	798-799	.	denotes	.
T1008	398-820	JJ	denotes	1569–1577]. We now show that PKDs are also required to regulate HSP27 phosphorylation in DT40 B-cells. However, in contrast to previous observations in other cell types, PKD enzymes do not regulate basic cellular processes such as proliferation or survival responses, nor NFκB transcriptional activity downstream of the B cell antigen receptor. Thus, PKDs have a selective role in DT40 B-cell biology. 1 Introduction The
T1009	821-828	NN	denotes	protein
T1010	829-835	NN	denotes	kinase
T1011	836-837	NNP	denotes	D
T1012	838-839	-LRB-	denotes	(
T1013	839-842	NNP	denotes	PKD
T1014	842-843	-RRB-	denotes	)
T1015	844-860	JJ	denotes	serine/threonine
T1016	861-867	NN	denotes	kinase
T1017	868-874	NN	denotes	family
T1018	875-878	VBZ	denotes	has
T1019	879-884	CD	denotes	three
T1020	885-892	NNS	denotes	members
T1021	892-893	:	denotes	:
T1022	894-898	NNP	denotes	PKD1
T1023	898-899	,	denotes	,
T1024	900-904	NNP	denotes	PKD2
T1025	905-908	CC	denotes	and
T1026	909-913	NNP	denotes	PKD3
T1027	913-914	.	denotes	.
T1028	915-919	JJS	denotes	Most
T1029	920-924	NN	denotes	cell
T1030	925-930	NNS	denotes	types
T1031	931-938	VBP	denotes	express
T1032	939-941	IN	denotes	at
T1033	942-947	JJS	denotes	least
T1034	948-951	CD	denotes	two
T1035	952-955	NNP	denotes	PKD
T1036	956-964	NNS	denotes	isoforms
T1037	965-968	CC	denotes	but
T1038	969-972	NNP	denotes	PKD
T1039	973-980	NNS	denotes	enzymes
T1040	981-984	VBP	denotes	are
T1041	985-995	RB	denotes	especially
T1042	996-1002	RB	denotes	highly
T1043	1003-1012	VBN	denotes	expressed
T1044	1013-1015	IN	denotes	in
T1045	1016-1030	JJ	denotes	haematopoietic
T1046	1031-1036	NNS	denotes	cells
T1047	1036-1037	,	denotes	,
T1048	1038-1043	WRB	denotes	where
T1049	1044-1048	PRP	denotes	they
T1050	1049-1052	VBP	denotes	are
T1051	1053-1062	VBN	denotes	activated
T1052	1063-1065	IN	denotes	in
T1053	1066-1074	NN	denotes	response
T1054	1075-1077	TO	denotes	to
T1055	1078-1085	NN	denotes	antigen
T1056	1086-1095	NNS	denotes	receptors
T1057	1096-1107	NN	denotes	stimulation
T1058	1108-1109	NNP	denotes	[
T1059	1109-1112	CD	denotes	2,3
T1060	1112-1113	NNP	denotes	]
T1061	1113-1114	.	denotes	.
T1062	1115-1116	DT	denotes	A
T1063	1117-1126	JJ	denotes	conserved
T1064	1127-1137	JJ	denotes	signalling
T1065	1138-1145	NN	denotes	pathway
T1066	1146-1153	VBG	denotes	linking
T1067	1154-1161	NN	denotes	antigen
T1068	1162-1171	NNS	denotes	receptors
T1069	1172-1174	TO	denotes	to
T1070	1175-1179	NNS	denotes	PKDs
T1071	1180-1188	VBZ	denotes	involves
T1072	1189-1192	DT	denotes	the
T1073	1193-1203	NN	denotes	activation
T1074	1204-1206	IN	denotes	of
T1075	1207-1211	NNP	denotes	PLCγ
T1076	1212-1215	CC	denotes	and
T1077	1216-1219	DT	denotes	the
T1078	1220-1230	JJ	denotes	subsequent
T1079	1231-1241	NN	denotes	production
T1080	1242-1244	IN	denotes	of
T1081	1245-1259	NN	denotes	diacylglycerol
T1082	1260-1261	-LRB-	denotes	(
T1083	1261-1264	NNP	denotes	DAG
T1084	1264-1265	-RRB-	denotes	)
T1085	1266-1271	WDT	denotes	which
T1086	1272-1282	VBZ	denotes	stimulates
T1087	1283-1292	JJ	denotes	classical
T1088	1293-1299	CC	denotes	and/or
T1089	1300-1305	JJ	denotes	novel
T1090	1306-1313	NN	denotes	protein
T1091	1314-1320	NN	denotes	kinase
T1092	1321-1323	NNS	denotes	Cs
T1093	1324-1325	-LRB-	denotes	(
T1094	1325-1328	NNP	denotes	PKC
T1095	1328-1329	-RRB-	denotes	)
T1096	1330-1334	WDT	denotes	that
T1097	1335-1348	VBP	denotes	phosphorylate
T1098	1349-1352	CD	denotes	two
T1099	1353-1356	JJ	denotes	key
T1100	1357-1367	JJ	denotes	regulatory
T1101	1368-1374	NN	denotes	serine
T1102	1375-1383	NNS	denotes	residues
T1103	1384-1386	IN	denotes	in
T1104	1387-1390	DT	denotes	the
T1105	1391-1401	NN	denotes	activation
T1106	1402-1406	NN	denotes	loop
T1107	1407-1409	IN	denotes	of
T1108	1410-1413	NNP	denotes	PKD
T1109	1414-1421	VBZ	denotes	kinases
T1110	1422-1423	NNP	denotes	[
T1111	1423-1424	CD	denotes	3
T1112	1425-1426	CD	denotes	6
T1113	1426-1427	NNP	denotes	]
T1114	1427-1428	.	denotes	.
T1115	1429-1432	DT	denotes	The
T1116	1433-1443	JJ	denotes	N-terminal
T1117	1444-1454	JJ	denotes	regulatory
T1118	1455-1461	NN	denotes	region
T1119	1462-1464	IN	denotes	of
T1120	1465-1468	NNP	denotes	PKD
T1121	1469-1476	VBZ	denotes	enzymes
T1122	1477-1485	VBZ	denotes	contains
T1123	1486-1487	DT	denotes	a
T1124	1488-1491	NNP	denotes	DAG
T1125	1492-1499	JJ	denotes	binding
T1126	1500-1506	NN	denotes	domain
T1127	1507-1510	CC	denotes	and
T1128	1511-1517	JJ	denotes	direct
T1129	1518-1525	JJ	denotes	binding
T1130	1526-1528	IN	denotes	of
T1131	1529-1532	NNP	denotes	DAG
T1132	1533-1537	RB	denotes	also
T1133	1538-1549	VBZ	denotes	contributes
T1134	1550-1552	TO	denotes	to
T1135	1553-1557	CD	denotes	PKD1
T1136	1558-1568	NN	denotes	activation
T1137	1569-1570	NN	denotes	[
T1138	1570-1571	CD	denotes	7
T1139	1571-1572	NNP	denotes	]
T1140	1573-1575	RB	denotes	as
T1141	1576-1580	RB	denotes	well
T1142	1581-1583	IN	denotes	as
T1143	1584-1594	VBG	denotes	regulating
T1144	1595-1598	DT	denotes	the
T1145	1599-1606	JJ	denotes	spatial
T1146	1607-1615	NN	denotes	location
T1147	1616-1618	IN	denotes	of
T1148	1619-1622	NNP	denotes	PKD
T1149	1623-1630	VBZ	denotes	enzymes
T1150	1631-1637	IN	denotes	within
T1151	1638-1643	NNS	denotes	cells
T1152	1644-1645	VBP	denotes	[
T1153	1645-1646	CD	denotes	8
T1154	1647-1649	CD	denotes	12
T1155	1649-1650	NN	denotes	]
T1156	1650-1651	.	denotes	.
T1157	1652-1655	NNP	denotes	PKD
T1158	1656-1663	NNS	denotes	enzymes
T1159	1664-1668	VBP	denotes	have
T1160	1669-1673	VBN	denotes	been
T1161	1674-1682	VBN	denotes	proposed
T1162	1683-1685	TO	denotes	to
T1163	1686-1694	VB	denotes	regulate
T1164	1695-1703	JJ	denotes	numerous
T1165	1704-1712	JJ	denotes	cellular
T1166	1713-1722	NNS	denotes	functions
T1167	1722-1723	,	denotes	,
T1168	1724-1733	VBG	denotes	including
T1169	1734-1738	NN	denotes	cell
T1170	1739-1752	NN	denotes	proliferation
T1171	1753-1754	NNP	denotes	[
T1172	1754-1756	CD	denotes	13
T1173	1757-1759	CD	denotes	16
T1174	1759-1760	NNP	denotes	]
T1175	1760-1761	,	denotes	,
T1176	1762-1776	JJ	denotes	anti-apoptotic
T1177	1777-1784	NNS	denotes	signals
T1178	1785-1786	NNP	denotes	[
T1179	1786-1791	CD	denotes	17,18
T1180	1791-1792	NNP	denotes	]
T1181	1793-1796	CC	denotes	and
T1182	1797-1806	JJ	denotes	thymocyte
T1183	1807-1818	NN	denotes	development
T1184	1819-1820	NNP	denotes	[
T1185	1820-1822	CD	denotes	19
T1186	1822-1823	NNP	denotes	]
T1187	1823-1824	.	denotes	.
T1188	1825-1835	NN	denotes	Expression
T1189	1836-1838	IN	denotes	of
T1190	1839-1845	JJ	denotes	mutant
T1191	1846-1859	RB	denotes	catalytically
T1192	1860-1868	JJ	denotes	inactive
T1193	1869-1872	CC	denotes	and
T1194	1873-1887	RB	denotes	constitutively
T1195	1888-1897	VBN	denotes	activated
T1196	1898-1902	NNS	denotes	PKDs
T1197	1903-1906	MD	denotes	can
T1198	1907-1911	RB	denotes	also
T1199	1912-1918	VB	denotes	modify
T1200	1919-1924	NNP	denotes	Golgi
T1201	1925-1933	NN	denotes	function
T1202	1933-1934	,	denotes	,
T1203	1935-1939	NN	denotes	cell
T1204	1940-1948	NN	denotes	adhesion
T1205	1949-1952	CC	denotes	and
T1206	1953-1957	NN	denotes	cell
T1207	1958-1966	NN	denotes	motility
T1208	1967-1968	-LRB-	denotes	(
T1209	1968-1976	VBN	denotes	reviewed
T1210	1977-1979	IN	denotes	in
T1211	1980-1981	NNP	denotes	[
T1212	1981-1983	CD	denotes	20
T1213	1983-1984	NNP	denotes	]
T1214	1984-1985	-RRB-	denotes	)
T1215	1985-1986	.	denotes	.
T1216	1987-1989	IN	denotes	In
T1217	1990-2000	JJ	denotes	particular
T1218	2000-2001	,	denotes	,
T1219	2002-2006	NNS	denotes	PKDs
T1220	2007-2011	VBP	denotes	have
T1221	2012-2016	VBN	denotes	been
T1222	2017-2023	RB	denotes	widely
T1223	2024-2030	VBN	denotes	linked
T1224	2031-2033	TO	denotes	to
T1225	2034-2037	DT	denotes	the
T1226	2038-2048	NN	denotes	activation
T1227	2049-2051	IN	denotes	of
T1228	2052-2055	DT	denotes	the
T1229	2056-2060	NNP	denotes	NFκB
T1230	2061-2074	NN	denotes	transcription
T1231	2075-2081	NN	denotes	factor
T1232	2082-2085	CC	denotes	and
T1233	2086-2088	IN	denotes	in
T1234	2089-2099	VBG	denotes	regulating
T1235	2100-2104	NN	denotes	cell
T1236	2105-2113	NN	denotes	survival
T1237	2114-2120	IN	denotes	during
T1238	2121-2130	JJ	denotes	oxidative
T1239	2131-2137	NN	denotes	stress
T1240	2138-2139	NNP	denotes	[
T1241	2139-2144	CD	denotes	17,21
T1242	2145-2147	CD	denotes	23
T1243	2147-2148	NNP	denotes	]
T1244	2148-2149	.	denotes	.
T1245	2150-2157	DT	denotes	Another
T1246	2158-2166	RB	denotes	recently
T1247	2167-2175	VBN	denotes	proposed
T1248	2176-2180	NNP	denotes	PKD1
T1249	2181-2190	NN	denotes	substrate
T1250	2191-2193	VBZ	denotes	is
T1251	2194-2199	NNP	denotes	HSP27
T1252	2200-2201	NNP	denotes	[
T1253	2201-2203	CD	denotes	24
T1254	2203-2204	NNP	denotes	]
T1255	2204-2205	,	denotes	,
T1256	2206-2207	DT	denotes	a
T1257	2208-2213	JJ	denotes	small
T1258	2214-2218	NN	denotes	heat
T1259	2219-2224	NN	denotes	shock
T1260	2225-2232	NN	denotes	protein
T1261	2233-2241	VBN	denotes	involved
T1262	2242-2244	IN	denotes	in
T1263	2245-2255	VBG	denotes	regulating
T1264	2256-2260	NN	denotes	cell
T1265	2261-2270	NN	denotes	migration
T1266	2271-2274	CC	denotes	and
T1267	2275-2279	NN	denotes	cell
T1268	2280-2288	NN	denotes	survival
T1269	2289-2290	NNP	denotes	[
T1270	2290-2292	CD	denotes	25
T1271	2292-2293	NNP	denotes	]
T1272	2293-2294	.	denotes	.
T1273	2295-2297	DT	denotes	An
T1274	2298-2307	JJ	denotes	essential
T1275	2308-2312	NN	denotes	role
T1276	2313-2316	IN	denotes	for
T1277	2317-2320	NNP	denotes	PKD
T1278	2321-2328	VBZ	denotes	enzymes
T1279	2329-2331	IN	denotes	in
T1280	2332-2342	VBG	denotes	regulating
T1281	2343-2348	NN	denotes	class
T1282	2349-2351	NNP	denotes	II
T1283	2352-2359	NN	denotes	histone
T1284	2360-2372	NNS	denotes	deacetylases
T1285	2373-2374	-LRB-	denotes	(
T1286	2374-2379	NNS	denotes	HDACs
T1287	2379-2380	-RRB-	denotes	)
T1288	2380-2381	,	denotes	,
T1289	2382-2389	VBZ	denotes	enzymes
T1290	2390-2394	IN	denotes	that
T1291	2395-2402	VBZ	denotes	repress
T1292	2403-2417	JJ	denotes	MEF2-dependent
T1293	2418-2422	NN	denotes	gene
T1294	2423-2436	NN	denotes	transcription
T1295	2436-2437	,	denotes	,
T1296	2438-2441	VBZ	denotes	has
T1297	2442-2446	RB	denotes	also
T1298	2447-2451	VBN	denotes	been
T1299	2452-2464	VBN	denotes	demonstrated
T1300	2465-2466	NNP	denotes	[
T1301	2466-2470	CD	denotes	1,26
T1302	2471-2473	CD	denotes	28
T1303	2473-2474	NN	denotes	]
T1304	2474-2475	.	denotes	.
T1305	2476-2478	TO	denotes	To
T1306	2479-2490	VB	denotes	investigate
T1307	2491-2494	DT	denotes	the
T1308	2495-2505	JJ	denotes	biological
T1309	2506-2510	NN	denotes	role
T1310	2511-2513	IN	denotes	of
T1311	2514-2518	NNS	denotes	PKDs
T1312	2519-2521	PRP	denotes	we
T1313	2522-2526	VBP	denotes	have
T1314	2527-2536	VBN	denotes	generated
T1315	2537-2541	NNP	denotes	DT40
T1316	2542-2543	NNP	denotes	B
T1317	2544-2548	NN	denotes	cell
T1318	2549-2554	NNS	denotes	lines
T1319	2555-2559	WDT	denotes	that
T1320	2560-2564	VBP	denotes	lack
T1321	2565-2575	NN	denotes	expression
T1322	2576-2578	IN	denotes	of
T1323	2579-2582	CD	denotes	one
T1324	2583-2585	CC	denotes	or
T1325	2586-2590	JJR	denotes	more
T1326	2591-2598	NNS	denotes	members
T1327	2599-2601	IN	denotes	of
T1328	2602-2605	DT	denotes	the
T1329	2606-2609	NNP	denotes	PKD
T1330	2610-2616	NN	denotes	family
T1331	2617-2618	NNP	denotes	[
T1332	2618-2619	CD	denotes	1
T1333	2619-2620	NNP	denotes	]
T1334	2620-2621	,	denotes	,
T1335	2622-2630	VBG	denotes	allowing
T1336	2631-2633	PRP	denotes	us
T1337	2634-2636	TO	denotes	to
T1338	2637-2648	VB	denotes	investigate
T1339	2649-2652	DT	denotes	the
T1340	2653-2661	NN	denotes	function
T1341	2661-2662	-LRB-	denotes	(
T1342	2662-2663	PRP	denotes	s
T1343	2663-2664	-RRB-	denotes	)
T1344	2665-2667	IN	denotes	of
T1345	2668-2671	NNP	denotes	PKD
T1346	2672-2680	VBZ	denotes	isoforms
T1347	2681-2690	VBG	denotes	following
T1348	2691-2692	NNP	denotes	B
T1349	2693-2697	NN	denotes	cell
T1350	2698-2705	NN	denotes	antigen
T1351	2706-2714	NN	denotes	receptor
T1352	2715-2716	-LRB-	denotes	(
T1353	2716-2719	NNP	denotes	BCR
T1354	2719-2720	-RRB-	denotes	)
T1355	2721-2732	NN	denotes	stimulation
T1356	2732-2733	,	denotes	,
T1357	2734-2736	RB	denotes	as
T1358	2737-2741	RB	denotes	well
T1359	2742-2752	VBG	denotes	addressing
T1360	2753-2756	DT	denotes	the
T1361	2757-2762	NN	denotes	issue
T1362	2763-2765	IN	denotes	of
T1363	2766-2776	JJ	denotes	functional
T1364	2777-2787	NN	denotes	redundancy
T1365	2788-2795	IN	denotes	between
T1366	2796-2799	DT	denotes	the
T1367	2800-2809	JJ	denotes	different
T1368	2810-2813	NNP	denotes	PKD
T1369	2814-2820	NN	denotes	family
T1370	2821-2828	NNS	denotes	members
T1371	2828-2829	.	denotes	.
T1372	2830-2838	JJ	denotes	Previous
T1373	2839-2846	NNS	denotes	studies
T1374	2847-2851	VBP	denotes	have
T1375	2852-2857	VBN	denotes	shown
T1376	2858-2862	IN	denotes	that
T1377	2863-2867	NNS	denotes	PKDs
T1378	2868-2871	VBP	denotes	are
T1379	2872-2885	JJ	denotes	indispensable
T1380	2886-2889	IN	denotes	for
T1381	2890-2894	NNP	denotes	HDAC
T1382	2895-2905	NN	denotes	regulation
T1383	2906-2908	IN	denotes	in
T1384	2909-2910	NNP	denotes	B
T1385	2911-2916	NNS	denotes	cells
T1386	2917-2918	NNP	denotes	[
T1387	2918-2919	CD	denotes	1
T1388	2919-2920	NNP	denotes	]
T1389	2920-2921	.	denotes	.
T1390	2922-2928	NNP	denotes	Herein
T1391	2929-2931	PRP	denotes	we
T1392	2932-2936	VBP	denotes	show
T1393	2937-2941	IN	denotes	that
T1394	2942-2946	NNS	denotes	PKDs
T1395	2947-2950	VBP	denotes	are
T1396	2951-2955	RB	denotes	also
T1397	2956-2969	JJ	denotes	indispensable
T1398	2970-2973	IN	denotes	for
T1399	2974-2979	NNP	denotes	HSP27
T1400	2980-2995	NN	denotes	phosphorylation
T1401	2996-2998	IN	denotes	in
T1402	2999-3000	NNP	denotes	B
T1403	3001-3006	NNS	denotes	cells
T1404	3006-3007	.	denotes	.
T1405	3008-3015	RB	denotes	However
T1406	3015-3016	,	denotes	,
T1407	3017-3025	NNP	denotes	PKD-null
T1408	3026-3030	NNP	denotes	DT40
T1409	3031-3032	NNP	denotes	B
T1410	3033-3038	NNS	denotes	cells
T1411	3039-3042	VBP	denotes	are
T1412	3043-3049	JJ	denotes	viable
T1413	3050-3053	CC	denotes	and
T1414	3054-3065	VB	denotes	proliferate
T1415	3066-3074	RB	denotes	normally
T1416	3074-3075	.	denotes	.
T1417	3076-3084	RB	denotes	Moreover
T1418	3084-3085	,	denotes	,
T1419	3086-3090	NN	denotes	loss
T1420	3091-3093	IN	denotes	of
T1421	3094-3097	DT	denotes	the
T1422	3098-3104	JJ	denotes	entire
T1423	3105-3113	JJ	denotes	cellular
T1424	3114-3118	NN	denotes	pool
T1425	3119-3121	IN	denotes	of
T1426	3122-3125	NNP	denotes	PKD
T1427	3126-3130	VBZ	denotes	does
T1428	3131-3134	RB	denotes	not
T1429	3135-3145	RB	denotes	critically
T1430	3146-3152	VB	denotes	affect
T1431	3153-3162	JJ	denotes	oxidative
T1432	3163-3169	NN	denotes	stress
T1433	3170-3179	NNS	denotes	responses
T1434	3180-3182	IN	denotes	in
T1435	3183-3184	NNP	denotes	B
T1436	3185-3190	NNS	denotes	cells
T1437	3191-3194	CC	denotes	nor
T1438	3195-3197	VBP	denotes	do
T1439	3198-3201	NNP	denotes	PKD
T1440	3202-3209	VBZ	denotes	kinases
T1441	3210-3214	VB	denotes	play
T1442	3215-3217	DT	denotes	an
T1443	3218-3227	JJ	denotes	essential
T1444	3228-3232	NN	denotes	role
T1445	3233-3235	IN	denotes	in
T1446	3236-3246	VBG	denotes	regulating
T1447	3247-3251	NNP	denotes	NFκB
T1448	3252-3267	JJ	denotes	transcriptional
T1449	3268-3276	NN	denotes	activity
T1450	3276-3277	.	denotes	.
T1451	3278-3286	RB	denotes	Together
T1452	3286-3287	,	denotes	,
T1453	3288-3293	DT	denotes	these
T1454	3294-3302	NNS	denotes	findings
T1455	3303-3309	VBP	denotes	reveal
T1456	3310-3314	IN	denotes	that
T1457	3315-3317	IN	denotes	in
T1458	3318-3319	NNP	denotes	B
T1459	3320-3331	NNS	denotes	lymphocytes
T1460	3331-3332	,	denotes	,
T1461	3333-3336	NNP	denotes	PKD
T1462	3337-3344	NNS	denotes	kinases
T1463	3345-3348	VBP	denotes	are
T1464	3349-3352	RB	denotes	not
T1465	3353-3361	JJ	denotes	critical
T1466	3362-3372	NNS	denotes	regulators
T1467	3373-3375	IN	denotes	of
T1468	3376-3380	JJ	denotes	many
T1469	3381-3383	IN	denotes	of
T1470	3384-3387	DT	denotes	the
T1471	3388-3396	JJ	denotes	cellular
T1472	3397-3406	NNS	denotes	processes
T1473	3407-3417	RB	denotes	previously
T1474	3418-3426	VBD	denotes	ascribed
T1475	3427-3429	TO	denotes	to
T1476	3430-3434	PRP	denotes	them
T1477	3435-3437	IN	denotes	in
T1478	3438-3443	JJ	denotes	other
T1479	3444-3452	JJ	denotes	cellular
T1480	3453-3460	NNS	denotes	systems
T1481	3460-3461	.	denotes	.
T1743	3494-3498	NNP	denotes	Cell
T1744	3499-3506	NN	denotes	culture
T1745	3506-3507	,	denotes	,
T1746	3508-3517	NN	denotes	transient
T1747	3518-3531	NNS	denotes	transfections
T1748	3532-3535	CC	denotes	and
T1749	3536-3540	NN	denotes	cell
T1750	3541-3552	NN	denotes	stimulation
T1751	3553-3556	DT	denotes	The
T1752	3557-3567	NN	denotes	generation
T1753	3567-3568	,	denotes	,
T1754	3569-3576	NN	denotes	culture
T1755	3577-3580	CC	denotes	and
T1756	3581-3591	NN	denotes	activation
T1757	3592-3594	IN	denotes	of
T1758	3595-3599	CD	denotes	PKD1
T1759	3599-3600	CD	denotes	−
T1760	3600-3601	NN	denotes	/
T1761	3601-3602	NN	denotes	−
T1762	3602-3603	,	denotes	,
T1763	3604-3608	NNP	denotes	PKD3
T1764	3608-3609	NNP	denotes	−
T1765	3609-3610	VBD	denotes	/
T1766	3610-3611	CD	denotes	−
T1767	3612-3615	CC	denotes	and
T1768	3616-3622	CD	denotes	PKD1/3
T1769	3622-3623	CD	denotes	−
T1770	3623-3624	NN	denotes	/
T1771	3624-3625	NN	denotes	−
T1772	3626-3634	NN	denotes	knockout
T1773	3635-3639	NNP	denotes	DT40
T1774	3640-3641	NNP	denotes	B
T1775	3642-3646	NN	denotes	cell
T1776	3647-3652	NNS	denotes	lines
T1777	3653-3657	VBP	denotes	have
T1778	3658-3662	VBN	denotes	been
T1779	3663-3672	VBN	denotes	described
T1780	3673-3683	RB	denotes	previously
T1781	3684-3685	NNP	denotes	[
T1782	3685-3686	CD	denotes	1
T1783	3686-3687	NNP	denotes	]
T1784	3687-3688	.	denotes	.
T1785	3689-3694	NNS	denotes	Cells
T1786	3695-3699	VBD	denotes	were
T1787	3700-3705	VBN	denotes	lysed
T1788	3706-3709	CC	denotes	and
T1789	3710-3717	NN	denotes	protein
T1790	3718-3726	NNS	denotes	extracts
T1791	3727-3731	VBD	denotes	were
T1792	3732-3740	VBN	denotes	analysed
T1793	3741-3743	IN	denotes	in
T1794	3744-3751	JJ	denotes	Western
T1795	3752-3760	VBG	denotes	blotting
T1796	3761-3772	NNS	denotes	experiments
T1797	3773-3775	IN	denotes	as
T1798	3776-3786	RB	denotes	previously
T1799	3787-3796	VBN	denotes	described
T1800	3797-3798	NNP	denotes	[
T1801	3798-3799	CD	denotes	1
T1802	3799-3800	NNP	denotes	]
T1803	3800-3801	.	denotes	.
T1804	3802-3817	NNP	denotes	Chloramphenicol
T1805	3818-3824	NN	denotes	acetyl
T1806	3825-3836	NN	denotes	transferase
T1807	3837-3843	NNS	denotes	assays
T1808	3844-3848	VBP	denotes	have
T1809	3849-3853	VBN	denotes	been
T1810	3854-3863	VBN	denotes	described
T1811	3864-3874	RB	denotes	previously
T1812	3875-3876	NNP	denotes	[
T1813	3876-3878	CD	denotes	29
T1814	3878-3879	NNP	denotes	]
T1815	3879-3880	.	denotes	.
T1940	3887-3891	JJ	denotes	sIgM
T1941	3892-3900	VBG	denotes	staining
T1942	3901-3905	NNP	denotes	DT40
T1943	3906-3907	NNP	denotes	B
T1944	3908-3913	NNS	denotes	cells
T1945	3914-3915	-LRB-	denotes	(
T1946	3915-3916	CD	denotes	2
T1947	3917-3918	CD	denotes	×
T1948	3919-3922	CD	denotes	106
T1949	3923-3928	NNS	denotes	cells
T1950	3929-3932	IN	denotes	per
T1951	3933-3938	NN	denotes	point
T1952	3938-3939	-RRB-	denotes	)
T1953	3940-3944	VBD	denotes	were
T1954	3945-3956	VBN	denotes	resuspended
T1955	3957-3959	IN	denotes	in
T1956	3960-3963	CD	denotes	200
T1957	3964-3966	NN	denotes	μl
T1958	3967-3973	NN	denotes	buffer
T1959	3974-3975	-LRB-	denotes	(
T1960	3975-3979	NNP	denotes	RPMI
T1961	3980-3984	CD	denotes	1640
T1962	3985-3990	NNS	denotes	media
T1963	3990-3991	,	denotes	,
T1964	3992-3993	CD	denotes	1
T1965	3993-3994	NN	denotes	%
T1966	3995-4001	JJ	denotes	foetal
T1967	4002-4006	NN	denotes	calf
T1968	4007-4012	NN	denotes	serum
T1969	4012-4013	-RRB-	denotes	)
T1970	4014-4024	VBG	denotes	containing
T1971	4025-4037	JJ	denotes	anti-chicken
T1972	4038-4040	CD	denotes	M1
T1973	4041-4051	JJ	denotes	monoclonal
T1974	4052-4060	NN	denotes	antibody
T1975	4061-4071	VBN	denotes	conjugated
T1976	4072-4074	TO	denotes	to
T1977	4075-4079	NNP	denotes	FITC
T1978	4080-4083	IN	denotes	for
T1979	4084-4086	CD	denotes	20
T1980	4087-4090	NN	denotes	min
T1981	4091-4093	IN	denotes	on
T1982	4094-4097	NN	denotes	ice
T1983	4097-4098	.	denotes	.
T1984	4099-4102	DT	denotes	The
T1985	4103-4108	NNS	denotes	cells
T1986	4109-4113	VBD	denotes	were
T1987	4114-4120	VBN	denotes	washed
T1988	4121-4126	RB	denotes	twice
T1989	4127-4130	CC	denotes	and
T1990	4131-4142	JJ	denotes	fluorescent
T1991	4143-4152	NN	denotes	intensity
T1992	4153-4156	VBD	denotes	was
T1993	4157-4165	VBN	denotes	analysed
T1994	4166-4168	IN	denotes	by
T1995	4169-4173	NN	denotes	flow
T1996	4174-4183	NN	denotes	cytometry
T1997	4183-4184	.	denotes	.
T1998	4185-4188	DT	denotes	All
T1999	4189-4196	NNS	denotes	results
T2000	4197-4202	VBN	denotes	shown
T2001	4203-4206	VBP	denotes	are
T2002	4207-4221	NN	denotes	representative
T2003	4222-4224	IN	denotes	of
T2004	4225-4227	IN	denotes	at
T2005	4228-4231	CD	denotes	two
T2006	4232-4234	TO	denotes	to
T2007	4235-4239	CD	denotes	four
T2008	4240-4251	JJ	denotes	independent
T2009	4252-4263	NNS	denotes	experiments
T2010	4264-4270	IN	denotes	unless
T2011	4271-4280	RB	denotes	otherwise
T2012	4281-4290	VBN	denotes	indicated
T2013	4290-4291	.	denotes	.
T2731	4310-4314	NN	denotes	Loss
T2732	4315-4317	IN	denotes	of
T2733	4318-4323	NNP	denotes	HSP27
T2734	4324-4339	NN	denotes	phosphorylation
T2735	4340-4342	IN	denotes	in
T2736	4343-4347	NNP	denotes	DT40
T2737	4348-4349	NNP	denotes	B
T2738	4350-4355	NNS	denotes	cells
T2739	4356-4363	VBG	denotes	lacking
T2740	4364-4374	NN	denotes	expression
T2741	4375-4377	IN	denotes	of
T2742	4378-4381	NNP	denotes	PKD
T2743	4382-4388	NN	denotes	family
T2744	4389-4396	VBZ	denotes	kinases
T2745	4397-4401	NNP	denotes	DT40
T2746	4402-4403	NNP	denotes	B
T2747	4404-4409	NNS	denotes	cells
T2748	4410-4417	VBP	denotes	express
T2749	4418-4421	CD	denotes	two
T2750	4422-4425	NNP	denotes	PKD
T2751	4426-4434	NNS	denotes	isoforms
T2752	4434-4435	,	denotes	,
T2753	4436-4440	NNP	denotes	PKD1
T2754	4441-4444	CC	denotes	and
T2755	4445-4449	NNP	denotes	PKD3
T2756	4449-4450	,	denotes	,
T2757	4451-4454	CC	denotes	and
T2758	4455-4457	IN	denotes	as
T2759	4458-4468	RB	denotes	previously
T2760	4469-4478	VBN	denotes	described
T2761	4479-4481	PRP	denotes	we
T2762	4482-4486	VBP	denotes	have
T2763	4487-4495	RB	denotes	recently
T2764	4496-4505	VBN	denotes	generated
T2765	4506-4510	NNP	denotes	DT40
T2766	4511-4512	NNP	denotes	B
T2767	4513-4517	NN	denotes	cell
T2768	4518-4523	NNS	denotes	lines
T2769	4524-4528	WDT	denotes	that
T2770	4529-4533	VBP	denotes	lack
T2771	4534-4544	NN	denotes	expression
T2772	4545-4547	IN	denotes	of
T2773	4548-4554	DT	denotes	either
T2774	4555-4559	CD	denotes	PKD1
T2775	4560-4562	CC	denotes	or
T2776	4563-4567	CD	denotes	PKD3
T2777	4568-4570	CC	denotes	or
T2778	4571-4575	DT	denotes	both
T2779	4576-4583	NNS	denotes	enzymes
T2780	4584-4585	VBP	denotes	[
T2781	4585-4586	CD	denotes	1
T2782	4586-4587	NNP	denotes	]
T2783	4587-4588	.	denotes	.
T2784	4589-4591	IN	denotes	In
T2785	4592-4602	VBG	denotes	generating
T2786	4603-4606	DT	denotes	the
T2787	4607-4613	JJ	denotes	double
T2788	4614-4622	NN	denotes	knockout
T2789	4623-4627	NN	denotes	cell
T2790	4628-4633	NNS	denotes	lines
T2791	4634-4636	PRP	denotes	we
T2792	4637-4645	VBD	denotes	targeted
T2793	4646-4649	DT	denotes	the
T2794	4650-4654	NNP	denotes	PKD1
T2795	4655-4659	NN	denotes	loci
T2796	4660-4662	IN	denotes	in
T2797	4663-4664	DT	denotes	a
T2798	4665-4669	NNP	denotes	PKD3
T2799	4669-4670	NNP	denotes	−
T2800	4670-4671	VBD	denotes	/
T2801	4671-4672	CD	denotes	−
T2802	4673-4677	NN	denotes	cell
T2803	4678-4682	NN	denotes	line
T2804	4683-4687	WDT	denotes	that
T2805	4688-4697	VBD	denotes	expressed
T2806	4698-4699	DT	denotes	a
T2807	4700-4709	NN	denotes	Flag-PKD3
T2808	4710-4719	NN	denotes	transgene
T2809	4720-4725	IN	denotes	under
T2810	4726-4729	DT	denotes	the
T2811	4730-4737	NN	denotes	control
T2812	4738-4740	IN	denotes	of
T2813	4741-4742	DT	denotes	a
T2814	4743-4764	JJ	denotes	doxycycline-inducible
T2815	4765-4773	NN	denotes	promoter
T2816	4773-4774	.	denotes	.
T2817	4775-4780	RB	denotes	Hence
T2818	4780-4781	,	denotes	,
T2819	4782-4784	IN	denotes	in
T2820	4785-4788	DT	denotes	the
T2821	4789-4797	NN	denotes	presence
T2822	4798-4800	IN	denotes	of
T2823	4801-4812	NN	denotes	doxycycline
T2824	4812-4813	,	denotes	,
T2825	4814-4823	NN	denotes	Flag-PKD3
T2826	4824-4834	NN	denotes	expression
T2827	4835-4837	IN	denotes	in
T2828	4838-4844	CD	denotes	PKD1/3
T2829	4845-4851	JJ	denotes	double
T2830	4852-4860	NN	denotes	knockout
T2831	4861-4866	NNS	denotes	cells
T2832	4867-4869	VBZ	denotes	is
T2833	4870-4880	JJ	denotes	comparable
T2834	4881-4883	TO	denotes	to
T2835	4884-4894	JJ	denotes	endogenous
T2836	4895-4899	JJ	denotes	PKD3
T2837	4900-4907	NN	denotes	present
T2838	4908-4910	IN	denotes	in
T2839	4911-4920	JJ	denotes	wild-type
T2840	4921-4925	NNP	denotes	DT40
T2841	4926-4931	NNS	denotes	cells
T2842	4932-4935	CC	denotes	and
T2843	4936-4943	NN	denotes	removal
T2844	4944-4946	IN	denotes	of
T2845	4947-4958	NN	denotes	doxycycline
T2846	4959-4963	IN	denotes	from
T2847	4964-4967	DT	denotes	the
T2848	4968-4975	NN	denotes	culture
T2849	4976-4981	NNS	denotes	media
T2850	4982-4985	IN	denotes	for
T2851	4986-4987	CD	denotes	5
T2852	4988-4992	NNS	denotes	days
T2853	4993-5000	NNS	denotes	results
T2854	5001-5003	IN	denotes	in
T2855	5004-5005	DT	denotes	a
T2856	5006-5016	RB	denotes	completely
T2857	5017-5021	JJ	denotes	null
T2858	5022-5025	NNP	denotes	PKD
T2859	5026-5035	NN	denotes	phenotype
T2860	5036-5037	-LRB-	denotes	(
T2861	5037-5041	NNP	denotes	Fig.
T2862	5042-5044	NNP	denotes	1A
T2863	5044-5045	-RRB-	denotes	)
T2864	5045-5046	.	denotes	.
T2865	5047-5057	RB	denotes	Previously
T2866	5057-5058	,	denotes	,
T2867	5059-5061	PRP	denotes	we
T2868	5062-5066	VBP	denotes	have
T2869	5067-5079	VBN	denotes	demonstrated
T2870	5080-5084	IN	denotes	that
T2871	5085-5100	NN	denotes	phosphorylation
T2872	5101-5104	CC	denotes	and
T2873	5105-5112	JJ	denotes	nuclear
T2874	5113-5122	NN	denotes	exclusion
T2875	5123-5125	IN	denotes	of
T2876	5126-5131	NN	denotes	class
T2877	5132-5134	NNP	denotes	II
T2878	5135-5142	NN	denotes	histone
T2879	5143-5155	NNS	denotes	deacetylases
T2880	5156-5157	-LRB-	denotes	(
T2881	5157-5162	NNS	denotes	HDACs
T2882	5162-5163	-RRB-	denotes	)
T2883	5164-5170	IN	denotes	during
T2884	5171-5174	NNP	denotes	BCR
T2885	5175-5185	NN	denotes	engagement
T2886	5186-5188	VBZ	denotes	is
T2887	5189-5198	JJ	denotes	defective
T2888	5199-5201	IN	denotes	in
T2889	5202-5208	CD	denotes	PKD1/3
T2890	5208-5209	CD	denotes	−
T2891	5209-5210	NN	denotes	/
T2892	5210-5211	NN	denotes	−
T2893	5212-5213	NNP	denotes	B
T2894	5214-5219	NNS	denotes	cells
T2895	5220-5223	CC	denotes	and
T2896	5224-5227	MD	denotes	can
T2897	5228-5236	VBD	denotes	restored
T2898	5237-5241	IN	denotes	upon
T2899	5242-5255	NN	denotes	re-expression
T2900	5256-5258	IN	denotes	of
T2901	5259-5260	DT	denotes	a
T2902	5261-5267	JJ	denotes	single
T2903	5268-5271	NNP	denotes	PKD
T2904	5272-5279	NN	denotes	isoform
T2905	5280-5281	NNP	denotes	[
T2906	5281-5282	CD	denotes	1
T2907	5282-5283	NNP	denotes	]
T2908	5283-5284	.	denotes	.
T2909	5285-5288	DT	denotes	The
T2910	5289-5294	JJ	denotes	small
T2911	5295-5299	NN	denotes	heat
T2912	5300-5305	NN	denotes	shock
T2913	5306-5313	NN	denotes	protein
T2914	5314-5319	NNP	denotes	HSP27
T2915	5320-5323	VBZ	denotes	has
T2916	5324-5332	RB	denotes	recently
T2917	5333-5337	VBN	denotes	been
T2918	5338-5346	VBN	denotes	proposed
T2919	5347-5349	IN	denotes	as
T2920	5350-5351	DT	denotes	a
T2921	5352-5356	NNP	denotes	PKD1
T2922	5357-5366	VB	denotes	substrate
T2923	5367-5368	NNP	denotes	[
T2924	5368-5370	CD	denotes	24
T2925	5370-5371	NNP	denotes	]
T2926	5372-5375	CC	denotes	and
T2927	5376-5378	PRP	denotes	we
T2928	5379-5390	RB	denotes	accordingly
T2929	5391-5399	VBD	denotes	assessed
T2930	5400-5407	IN	denotes	whether
T2931	5408-5416	NNP	denotes	PKD-null
T2932	5417-5421	NNP	denotes	DT40
T2933	5422-5427	NNS	denotes	cells
T2934	5428-5432	VBP	denotes	have
T2935	5433-5442	JJ	denotes	defective
T2936	5443-5458	NN	denotes	phosphorylation
T2937	5459-5461	IN	denotes	of
T2938	5462-5467	NNP	denotes	HSP27
T2939	5468-5470	IN	denotes	on
T2940	5471-5477	NN	denotes	serine
T2941	5478-5480	CD	denotes	82
T2942	5480-5481	,	denotes	,
T2943	5482-5485	DT	denotes	the
T2944	5486-5494	VBN	denotes	proposed
T2945	5495-5499	NNP	denotes	PKD1
T2946	5500-5509	VB	denotes	substrate
T2947	5510-5518	NN	denotes	sequence
T2948	5518-5519	.	denotes	.
T2949	5520-5522	PRP	denotes	We
T2950	5523-5532	RB	denotes	initially
T2951	5533-5545	VBD	denotes	investigated
T2952	5546-5549	DT	denotes	the
T2953	5550-5560	NN	denotes	regulation
T2954	5561-5563	IN	denotes	of
T2955	5564-5569	NNP	denotes	HSP27
T2956	5570-5585	NN	denotes	phosphorylation
T2957	5586-5588	IN	denotes	in
T2958	5589-5595	JJ	denotes	single
T2959	5596-5604	NN	denotes	knockout
T2960	5605-5609	NNP	denotes	DT40
T2961	5610-5611	NNP	denotes	B
T2962	5612-5617	NNS	denotes	cells
T2963	5618-5625	VBG	denotes	lacking
T2964	5626-5632	CC	denotes	either
T2965	5633-5637	CD	denotes	PKD1
T2966	5638-5640	CC	denotes	or
T2967	5641-5645	CD	denotes	PKD3
T2968	5645-5646	.	denotes	.
T2969	5647-5649	IN	denotes	As
T2970	5650-5655	VBN	denotes	shown
T2971	5656-5658	IN	denotes	in
T2972	5659-5663	NNP	denotes	Fig.
T2973	5664-5666	NNP	denotes	1B
T2974	5666-5667	,	denotes	,
T2975	5668-5678	NN	denotes	activation
T2976	5679-5681	IN	denotes	of
T2977	5682-5685	DT	denotes	the
T2978	5686-5689	NNP	denotes	BCR
T2979	5690-5692	CC	denotes	or
T2980	5693-5702	NN	denotes	treatment
T2981	5703-5707	IN	denotes	with
T2982	5708-5711	DT	denotes	the
T2983	5712-5723	JJ	denotes	DAG-mimetic
T2984	5724-5728	NNP	denotes	PdBu
T2985	5729-5738	VBD	denotes	increased
T2986	5739-5742	DT	denotes	the
T2987	5743-5749	NNS	denotes	levels
T2988	5750-5752	IN	denotes	of
T2989	5753-5758	NNP	denotes	HSP27
T2990	5759-5774	NN	denotes	phosphorylation
T2991	5775-5777	IN	denotes	at
T2992	5778-5781	CD	denotes	S82
T2993	5782-5784	IN	denotes	in
T2994	5785-5794	JJ	denotes	wild-type
T2995	5795-5799	NNP	denotes	DT40
T2996	5800-5801	NNP	denotes	B
T2997	5802-5807	NNS	denotes	cells
T2998	5807-5808	.	denotes	.
T2999	5809-5812	NNP	denotes	BCR
T3000	5813-5816	CC	denotes	and
T3001	5817-5824	JJ	denotes	phorbol
T3002	5825-5830	NN	denotes	ester
T3003	5831-5838	NNS	denotes	signals
T3004	5839-5843	VBD	denotes	were
T3005	5844-5848	RB	denotes	also
T3006	5849-5853	JJ	denotes	able
T3007	5854-5856	TO	denotes	to
T3008	5857-5865	VB	denotes	increase
T3009	5866-5871	NNP	denotes	HSP27
T3010	5872-5887	NN	denotes	phosphorylation
T3011	5888-5890	IN	denotes	in
T3012	5891-5895	CD	denotes	PKD1
T3013	5896-5898	CC	denotes	or
T3014	5899-5903	CD	denotes	PKD3
T3015	5904-5910	JJ	denotes	single
T3016	5911-5919	NN	denotes	knockout
T3017	5920-5924	NNP	denotes	DT40
T3018	5925-5926	NNP	denotes	B
T3019	5927-5932	NNS	denotes	cells
T3020	5933-5934	-LRB-	denotes	(
T3021	5934-5938	NNP	denotes	Fig.
T3022	5939-5941	NNP	denotes	1B
T3023	5941-5942	-RRB-	denotes	)
T3024	5942-5943	.	denotes	.
T3025	5944-5951	RB	denotes	However
T3026	5951-5952	,	denotes	,
T3027	5953-5956	NNP	denotes	BCR
T3028	5956-5957	:	denotes	-
T3029	5958-5961	CC	denotes	and
T3030	5962-5969	VB	denotes	phorbol
T3031	5970-5983	JJ	denotes	ester-induced
T3032	5984-5999	NN	denotes	phosphorylation
T3033	6000-6002	IN	denotes	of
T3034	6003-6008	NNP	denotes	HSP27
T3035	6009-6011	IN	denotes	on
T3036	6012-6015	NNP	denotes	S82
T3037	6016-6019	VBD	denotes	was
T3038	6020-6029	VBN	denotes	abolished
T3039	6030-6032	IN	denotes	in
T3040	6033-6034	NNP	denotes	B
T3041	6035-6040	NNS	denotes	cells
T3042	6041-6045	WDT	denotes	that
T3043	6046-6052	VBD	denotes	lacked
T3044	6053-6057	DT	denotes	both
T3045	6058-6062	NNP	denotes	PKD1
T3046	6063-6066	CC	denotes	and
T3047	6067-6071	NNP	denotes	PKD3
T3048	6072-6073	-LRB-	denotes	(
T3049	6073-6077	NNP	denotes	Fig.
T3050	6078-6080	NNP	denotes	1C
T3051	6080-6081	-RRB-	denotes	)
T3052	6081-6082	.	denotes	.
T3053	6083-6096	RB	denotes	Significantly
T3054	6096-6097	,	denotes	,
T3055	6098-6117	JJ	denotes	doxycycline-induced
T3056	6118-6128	NN	denotes	expression
T3057	6129-6131	IN	denotes	of
T3058	6132-6135	DT	denotes	the
T3059	6136-6145	NN	denotes	Flag-PKD3
T3060	6146-6155	NN	denotes	transgene
T3061	6156-6158	IN	denotes	in
T3062	6159-6162	DT	denotes	the
T3063	6163-6169	JJ	denotes	double
T3064	6170-6178	NN	denotes	knockout
T3065	6179-6184	NNS	denotes	cells
T3066	6185-6188	VBD	denotes	was
T3067	6189-6199	JJ	denotes	sufficient
T3068	6200-6202	TO	denotes	to
T3069	6203-6210	VB	denotes	restore
T3070	6211-6217	JJ	denotes	normal
T3071	6218-6228	NN	denotes	regulation
T3072	6229-6231	IN	denotes	of
T3073	6232-6237	NNP	denotes	HSP27
T3074	6238-6253	NN	denotes	phosphorylation
T3075	6254-6255	-LRB-	denotes	(
T3076	6255-6259	NNP	denotes	Fig.
T3077	6260-6262	NNP	denotes	1C
T3078	6262-6263	-RRB-	denotes	)
T3079	6263-6264	.	denotes	.
T3080	6265-6267	IN	denotes	In
T3081	6268-6276	NN	denotes	contrast
T3082	6276-6277	,	denotes	,
T3083	6278-6288	NN	denotes	expression
T3084	6289-6291	IN	denotes	of
T3085	6292-6293	DT	denotes	a
T3086	6294-6310	JJ	denotes	kinase-deficient
T3087	6311-6315	NN	denotes	PKD3
T3088	6316-6322	JJ	denotes	mutant
T3089	6323-6330	NN	denotes	protein
T3090	6331-6333	IN	denotes	in
T3091	6334-6337	DT	denotes	the
T3092	6338-6344	JJ	denotes	double
T3093	6345-6353	NN	denotes	knockout
T3094	6354-6359	NNS	denotes	cells
T3095	6360-6363	VBD	denotes	was
T3096	6364-6367	RB	denotes	not
T3097	6368-6372	JJ	denotes	able
T3098	6373-6375	TO	denotes	to
T3099	6376-6383	VB	denotes	restore
T3100	6384-6387	NNP	denotes	BCR
T3101	6387-6388	:	denotes	-
T3102	6389-6391	CC	denotes	or
T3103	6392-6399	VB	denotes	phorbol
T3104	6400-6413	JJ	denotes	ester-induced
T3105	6414-6419	NNP	denotes	HSP27
T3106	6420-6435	NN	denotes	phosphorylation
T3107	6436-6437	-LRB-	denotes	(
T3108	6437-6441	NNP	denotes	Fig.
T3109	6442-6444	NNP	denotes	1D
T3110	6444-6445	-RRB-	denotes	)
T3111	6445-6446	.	denotes	.
T3112	6447-6452	RB	denotes	Hence
T3113	6452-6453	,	denotes	,
T3114	6454-6458	NNP	denotes	PKD3
T3115	6459-6461	RB	denotes	as
T3116	6462-6466	RB	denotes	well
T3117	6467-6469	IN	denotes	as
T3118	6470-6474	NNP	denotes	PKD1
T3119	6475-6478	MD	denotes	can
T3120	6479-6487	VB	denotes	regulate
T3121	6488-6493	NNP	denotes	HSP27
T3122	6494-6509	NN	denotes	phosphorylation
T3123	6510-6513	CC	denotes	and
T3124	6514-6516	IN	denotes	in
T3125	6517-6521	NNP	denotes	DT40
T3126	6522-6523	NNP	denotes	B
T3127	6524-6529	NNS	denotes	cells
T3128	6530-6534	PRP	denotes	they
T3129	6535-6538	VBP	denotes	are
T3130	6539-6551	RB	denotes	functionally
T3131	6552-6561	JJ	denotes	redundant
T3132	6562-6564	IN	denotes	as
T3133	6565-6570	NNP	denotes	HSP27
T3134	6571-6578	NNS	denotes	kinases
T3135	6578-6579	.	denotes	.
T4218	6586-6594	NNP	denotes	Cellular
T4219	6595-6608	NN	denotes	proliferation
T4220	6609-6612	CC	denotes	and
T4221	6613-6621	NN	denotes	survival
T4222	6622-6624	IN	denotes	in
T4223	6625-6629	NNP	denotes	DT40
T4224	6630-6631	NNP	denotes	B
T4225	6632-6637	NNS	denotes	cells
T4226	6638-6645	VBG	denotes	lacking
T4227	6646-6656	NN	denotes	expression
T4228	6657-6659	IN	denotes	of
T4229	6660-6663	NNP	denotes	PKD
T4230	6664-6670	NN	denotes	family
T4231	6671-6678	VBZ	denotes	kinases
T4232	6679-6682	NNP	denotes	PKD
T4233	6683-6690	NNS	denotes	enzymes
T4234	6691-6695	VBP	denotes	have
T4235	6696-6706	RB	denotes	previously
T4236	6707-6711	VBN	denotes	been
T4237	6712-6718	VBN	denotes	linked
T4238	6719-6721	TO	denotes	to
T4239	6722-6725	DT	denotes	the
T4240	6726-6736	NN	denotes	regulation
T4241	6737-6739	IN	denotes	of
T4242	6740-6744	NN	denotes	cell
T4243	6745-6758	NN	denotes	proliferation
T4244	6759-6762	CC	denotes	and
T4245	6763-6771	NN	denotes	survival
T4246	6772-6773	-LRB-	denotes	(
T4247	6773-6781	VBN	denotes	reviewed
T4276	6928-6930	IN	denotes	in
T4277	6931-6934	DT	denotes	the
T4278	6935-6943	NN	denotes	presence
T4279	6944-6945	-LRB-	denotes	(
T4280	6945-6951	CD	denotes	PKD1/3
T4281	6951-6952	CD	denotes	−
T4282	6952-6953	NN	denotes	/
T4283	6953-6954	NN	denotes	−
T4284	6954-6955	:	denotes	:
T4285	6956-6965	NN	denotes	Flag-PKD3
T4286	6965-6966	NN	denotes	+
T4287	6966-6968	NN	denotes	ve
T4288	6968-6969	-RRB-	denotes	)
T4289	6970-6972	CC	denotes	or
T4290	6973-6980	NN	denotes	absence
T4291	6981-6982	-LRB-	denotes	(
T4292	6982-6988	CD	denotes	PKD1/3
T4293	6988-6989	CD	denotes	−
T4294	6989-6990	NN	denotes	/
T4295	6990-6991	NN	denotes	−
T4296	6991-6992	-RRB-	denotes	)
T4297	6993-6995	IN	denotes	of
T4298	6996-7007	NN	denotes	doxycycline
T4299	7008-7011	CC	denotes	and
T4300	7012-7021	VBD	denotes	monitored
T4301	7022-7033	JJ	denotes	exponential
T4302	7034-7040	NN	denotes	growth
T4303	7040-7041	.	denotes	.
T4304	7042-7044	IN	denotes	As
T4305	7045-7050	VBN	denotes	shown
T4306	7051-7053	IN	denotes	in
T4307	7054-7058	NNP	denotes	Fig.
T4308	7059-7061	NNP	denotes	2A
T4309	7061-7062	,	denotes	,
T4310	7063-7069	NNP	denotes	PKD1/3
T4311	7069-7070	VBD	denotes	−
T4312	7070-7071	CD	denotes	/
T4313	7071-7072	NN	denotes	−
T4314	7073-7078	NNS	denotes	cells
T4315	7079-7091	VBD	denotes	proliferated
T4316	7092-7105	RB	denotes	exponentially
T4317	7106-7109	CC	denotes	and
T4318	7110-7123	NN	denotes	re-expression
T4319	7124-7126	IN	denotes	of
T4320	7127-7136	NN	denotes	Flag-PKD3
T4321	7137-7139	IN	denotes	in
T4322	7140-7145	DT	denotes	these
T4323	7146-7151	NNS	denotes	cells
T4324	7152-7155	VBD	denotes	had
T4325	7156-7158	DT	denotes	no
T4326	7159-7165	NN	denotes	impact
T4327	7166-7168	IN	denotes	on
T4328	7169-7172	DT	denotes	the
T4329	7173-7177	NN	denotes	rate
T4330	7178-7180	IN	denotes	of
T4331	7181-7194	NN	denotes	proliferation
T4332	7194-7195	.	denotes	.
T4333	7196-7207	RB	denotes	Furthermore
T4334	7207-7208	,	denotes	,
T4335	7209-7212	DT	denotes	the
T4336	7213-7222	NN	denotes	viability
T4337	7223-7225	IN	denotes	of
T4338	7226-7232	CD	denotes	PKD1/3
T4339	7232-7233	CD	denotes	−
T4340	7233-7234	NN	denotes	/
T4341	7234-7235	NN	denotes	−
T4342	7236-7237	NNP	denotes	B
T4343	7238-7243	NNS	denotes	cells
T4344	7244-7250	IN	denotes	during
T4345	7251-7258	JJ	denotes	routine
T4346	7259-7268	NN	denotes	culturing
T4347	7269-7272	VBD	denotes	was
T4348	7273-7276	RB	denotes	not
T4349	7277-7290	RB	denotes	significantly
T4350	7291-7300	JJ	denotes	different
T4351	7301-7305	IN	denotes	from
T4352	7306-7310	DT	denotes	that
T4353	7311-7313	IN	denotes	of
T4354	7314-7323	JJ	denotes	wild-type
T4355	7324-7325	NNP	denotes	B
T4356	7326-7331	NNS	denotes	cells
T4357	7332-7333	-LRB-	denotes	(
T4358	7333-7337	NNS	denotes	data
T4359	7338-7341	RB	denotes	not
T4360	7342-7347	VBN	denotes	shown
T4361	7347-7348	-RRB-	denotes	)
T4362	7348-7349	.	denotes	.
T4363	7350-7352	PRP	denotes	It
T4364	7353-7356	VBD	denotes	was
T4365	7357-7362	VBN	denotes	noted
T4366	7363-7367	IN	denotes	that
T4367	7368-7371	DT	denotes	the
T4368	7372-7382	NN	denotes	population
T4369	7383-7391	VBG	denotes	doubling
T4370	7392-7396	NN	denotes	time
T4371	7397-7399	IN	denotes	of
T4372	7400-7406	CD	denotes	PKD1/3
T4373	7406-7407	CD	denotes	−
T4374	7407-7408	NN	denotes	/
T4375	7408-7409	NN	denotes	−
T4376	7410-7415	NNS	denotes	cells
T4377	7416-7419	VBD	denotes	was
T4378	7420-7428	RB	denotes	slightly
T4379	7429-7435	JJR	denotes	slower
T4380	7436-7440	IN	denotes	than
T4381	7441-7445	DT	denotes	that
T4382	7446-7448	IN	denotes	of
T4383	7449-7453	JJ	denotes	wild
T4384	7454-7458	NN	denotes	type
T4385	7459-7463	CD	denotes	DT40
T4386	7464-7469	NNS	denotes	cells
T4387	7470-7471	-LRB-	denotes	(
T4388	7471-7475	CD	denotes	12.7
T4389	7476-7477	CD	denotes	±
T4390	7478-7481	CD	denotes	2.8
T4391	7482-7483	NN	denotes	h
T4392	7484-7490	IN	denotes	versus
T4393	7491-7495	CD	denotes	10.2
T4394	7496-7497	CD	denotes	±
T4395	7498-7501	CD	denotes	0.4
T4396	7502-7503	NN	denotes	h
T4397	7503-7504	-RRB-	denotes	)
T4398	7505-7508	CC	denotes	but
T4399	7509-7512	DT	denotes	the
T4400	7513-7520	NN	denotes	failure
T4401	7521-7523	IN	denotes	of
T4402	7524-7528	CD	denotes	PKD3
T4403	7529-7542	NN	denotes	re-expression
T4404	7543-7545	TO	denotes	to
T4405	7546-7552	VB	denotes	modify
T4406	7553-7556	DT	denotes	the
T4407	7557-7570	NN	denotes	proliferation
T4408	7571-7575	NN	denotes	rate
T4409	7576-7578	IN	denotes	of
T4410	7579-7585	CD	denotes	PKD1/3
T4411	7585-7586	CD	denotes	−
T4412	7586-7587	NN	denotes	/
T4413	7587-7588	NN	denotes	−
T4414	7589-7594	NNS	denotes	cells
T4415	7595-7603	VBZ	denotes	suggests
T4416	7604-7608	IN	denotes	that
T4417	7609-7614	DT	denotes	these
T4418	7615-7620	JJ	denotes	small
T4419	7621-7632	NNS	denotes	differences
T4420	7633-7637	VBD	denotes	were
T4421	7638-7642	RBS	denotes	most
T4422	7643-7649	JJ	denotes	likely
T4423	7650-7653	DT	denotes	the
T4424	7654-7660	NN	denotes	result
T4425	7661-7663	IN	denotes	of
T4426	7664-7670	JJ	denotes	clonal
T4427	7671-7680	NN	denotes	variation
T4428	7681-7684	CC	denotes	and
T4429	7685-7689	VBD	denotes	were
T4430	7690-7693	RB	denotes	not
T4431	7694-7700	VBN	denotes	caused
T4432	7701-7713	RB	denotes	specifically
T4433	7714-7716	IN	denotes	by
T4434	7717-7721	NN	denotes	loss
T4435	7722-7724	IN	denotes	of
T4436	7725-7728	NNP	denotes	PKD
T4437	7729-7736	VBZ	denotes	enzymes
T4438	7736-7737	.	denotes	.
T4439	7738-7742	RB	denotes	Thus
T4440	7742-7743	,	denotes	,
T4441	7744-7747	NNP	denotes	PKD
T4442	7748-7754	NN	denotes	family
T4443	7755-7762	NNS	denotes	enzymes
T4444	7763-7766	VBP	denotes	are
T4445	7767-7770	RB	denotes	not
T4446	7771-7780	JJ	denotes	essential
T4447	7781-7784	IN	denotes	for
T4448	7785-7795	VBG	denotes	regulating
T4449	7796-7801	JJ	denotes	basal
T4450	7802-7810	NN	denotes	survival
T4451	7811-7814	CC	denotes	and
T4452	7815-7828	NN	denotes	proliferation
T4453	7829-7831	IN	denotes	of
T4454	7832-7836	NNP	denotes	DT40
T4455	7837-7838	NNP	denotes	B
T4456	7839-7844	NNS	denotes	cells
T4457	7844-7845	.	denotes	.
T4458	7846-7849	NNP	denotes	PKD
T4459	7850-7857	VBZ	denotes	enzymes
T4460	7857-7858	,	denotes	,
T4461	7859-7871	RB	denotes	specifically
T4462	7872-7876	CD	denotes	PKD1
T4463	7877-7880	CC	denotes	and
T4464	7881-7885	NNP	denotes	PKD2
T4465	7885-7886	,	denotes	,
T4466	7887-7891	VBP	denotes	have
T4467	7892-7902	RB	denotes	previously
T4468	7903-7907	VBN	denotes	been
T4469	7908-7914	VBN	denotes	linked
T4470	7915-7917	TO	denotes	to
T4471	7918-7919	DT	denotes	a
T4472	7920-7930	JJ	denotes	protective
T4473	7931-7935	NN	denotes	role
T4474	7936-7943	IN	denotes	against
T4475	7944-7953	JJ	denotes	oxidative
T4476	7954-7968	JJ	denotes	stress-induced
T4477	7969-7975	NN	denotes	injury
T4478	7976-7978	IN	denotes	in
T4479	7979-7982	NNP	denotes	3T3
T4480	7983-7993	NN	denotes	fibroblast
T4481	7993-7994	,	denotes	,
T4482	7995-7999	NNP	denotes	HeLa
T4483	8000-8003	CC	denotes	and
T4484	8004-8014	JJ	denotes	epithelial
T4485	8015-8019	NN	denotes	cell
T4486	8020-8025	NNS	denotes	lines
T4487	8026-8027	NNP	denotes	[
T4488	8027-8032	CD	denotes	17,30
T4489	8033-8035	CD	denotes	32
T4490	8035-8036	NN	denotes	]
T4491	8036-8037	.	denotes	.
T4492	8038-8040	PRP	denotes	We
T4493	8041-8050	RB	denotes	therefore
T4494	8051-8060	VBD	denotes	addressed
T4495	8061-8064	DT	denotes	the
T4496	8065-8069	NN	denotes	role
T4497	8070-8072	IN	denotes	of
T4498	8073-8076	NNP	denotes	PKD
T4499	8077-8083	NN	denotes	family
T4500	8084-8091	NNS	denotes	kinases
T4501	8092-8094	IN	denotes	in
T4502	8095-8105	VBG	denotes	regulating
T4503	8106-8107	NNP	denotes	B
T4504	8108-8112	NN	denotes	cell
T4505	8113-8121	NN	denotes	survival
T4506	8122-8124	IN	denotes	in
T4507	8125-8133	NN	denotes	response
T4508	8134-8136	TO	denotes	to
T4509	8137-8146	JJ	denotes	oxidative
T4510	8147-8153	NN	denotes	stress
T4511	8154-8157	CC	denotes	and
T4512	8158-8163	JJ	denotes	other
T4513	8164-8170	NN	denotes	stress
T4514	8171-8178	NNS	denotes	stimuli
T4515	8178-8179	.	denotes	.
T4516	8180-8182	IN	denotes	As
T4517	8183-8188	VBN	denotes	shown
T4518	8189-8191	IN	denotes	in
T4519	8192-8196	NNP	denotes	Fig.
T4520	8197-8199	NNP	denotes	2B
T4521	8199-8200	,	denotes	,
T4522	8201-8205	NN	denotes	loss
T4523	8206-8208	IN	denotes	of
T4524	8209-8215	CD	denotes	PKD1/3
T4525	8216-8226	NN	denotes	expression
T4526	8227-8230	VBD	denotes	had
T4527	8231-8233	DT	denotes	no
T4528	8234-8245	JJ	denotes	significant
T4529	8246-8252	NN	denotes	impact
T4530	8253-8255	IN	denotes	on
T4531	8256-8259	DT	denotes	the
T4532	8260-8268	NN	denotes	survival
T4533	8269-8271	IN	denotes	of
T4534	8272-8276	NNP	denotes	DT40
T4535	8277-8278	NNP	denotes	B
T4536	8279-8284	NNS	denotes	cells
T4537	8285-8287	IN	denotes	in
T4538	8288-8296	NN	denotes	response
T4539	8297-8299	TO	denotes	to
T4540	8300-8313	JJ	denotes	mitochondrial
T4541	8314-8320	NN	denotes	stress
T4542	8321-8328	NNS	denotes	stimuli
T4543	8329-8330	-LRB-	denotes	(
T4544	8330-8334	CD	denotes	H2O2
T4545	8335-8337	CC	denotes	or
T4546	8338-8343	NN	denotes	serum
T4547	8344-8355	NN	denotes	deprivation
T4548	8355-8356	-RRB-	denotes	)
T4549	8356-8357	:	denotes	;
T4550	8358-8361	NNP	denotes	DNA
T4551	8362-8370	VBG	denotes	damaging
T4552	8371-8377	NNS	denotes	agents
T4553	8378-8379	-LRB-	denotes	(
T4554	8379-8388	NN	denotes	etoposide
T4555	8389-8391	CC	denotes	or
T4556	8392-8403	NN	denotes	doxorubicin
T4557	8403-8404	-RRB-	denotes	)
T4558	8404-8405	:	denotes	;
T4559	8406-8408	NNP	denotes	ER
T4560	8409-8416	NN	denotes	pathway
T4561	8417-8423	NN	denotes	stress
T4562	8424-8427	JJ	denotes	due
T4563	8428-8430	TO	denotes	to
T4564	8431-8438	NN	denotes	calcium
T4565	8439-8447	NN	denotes	overload
T4566	8448-8449	-LRB-	denotes	(
T4567	8449-8461	NN	denotes	thapsigargin
T4568	8461-8462	-RRB-	denotes	)
T4569	8463-8465	CC	denotes	or
T4570	8466-8475	VBG	denotes	following
T4571	8476-8485	JJ	denotes	prolonged
T4572	8486-8495	NN	denotes	treatment
T4573	8496-8500	IN	denotes	with
T4574	8501-8508	NN	denotes	phorbol
T4575	8509-8515	NNS	denotes	esters
T4576	8516-8518	CC	denotes	or
T4577	8519-8531	NNP	denotes	Trichostatin
T4578	8532-8533	NNP	denotes	A
T4579	8533-8534	,	denotes	,
T4580	8535-8537	DT	denotes	an
T4581	8538-8547	NN	denotes	inhibitor
T4582	8548-8550	IN	denotes	of
T4583	8551-8556	NN	denotes	class
T4584	8557-8561	NNP	denotes	I/II
T4585	8562-8567	NNP	denotes	HDACs
T4586	8567-8568	.	denotes	.
T4587	8569-8573	RB	denotes	Thus
T4588	8573-8574	,	denotes	,
T4589	8575-8578	NNP	denotes	PKD
T4590	8579-8586	NNS	denotes	kinases
T4591	8587-8589	VBP	denotes	do
T4592	8590-8593	RB	denotes	not
T4593	8594-8598	VB	denotes	play
T4594	8599-8601	DT	denotes	an
T4595	8602-8611	JJ	denotes	essential
T4596	8612-8616	NN	denotes	role
T4597	8617-8619	IN	denotes	in
T4598	8620-8630	VBG	denotes	regulating
T4599	8631-8632	NNP	denotes	B
T4600	8633-8637	NN	denotes	cell
T4601	8638-8646	NN	denotes	survival
T4602	8647-8649	IN	denotes	in
T4603	8650-8658	NN	denotes	response
T4604	8659-8661	TO	denotes	to
T4605	8662-8663	DT	denotes	a
T4606	8664-8669	NN	denotes	range
T4607	8670-8672	IN	denotes	of
T4608	8673-8682	JJ	denotes	different
T4609	8683-8689	NN	denotes	stress
T4610	8690-8697	NNS	denotes	stimuli
T4611	8697-8698	.	denotes	.
T5769	8705-8712	NN	denotes	Antigen
T5770	8713-8721	NN	denotes	receptor
T5771	8722-8731	VBN	denotes	regulated
T5772	8732-8742	JJ	denotes	signalling
T5773	8743-8751	NNS	denotes	pathways
T5774	8752-8754	IN	denotes	in
T5775	8755-8763	NNP	denotes	PKD-null
T5776	8764-8768	NNP	denotes	DT40
T5777	8769-8770	NNP	denotes	B
T5778	8771-8776	NNS	denotes	cells
T5779	8777-8779	TO	denotes	To
T5780	8780-8787	RBR	denotes	further
T5781	8788-8795	VB	denotes	explore
T5782	8796-8799	DT	denotes	the
T5783	8800-8812	NN	denotes	contribution
T5784	8813-8815	IN	denotes	of
T5785	8816-8819	NNP	denotes	PKD
T5786	8820-8827	VBZ	denotes	kinases
T5787	8828-8830	TO	denotes	to
T5788	8831-8835	NNP	denotes	DT40
T5789	8836-8837	NNP	denotes	B
T5790	8838-8842	NN	denotes	cell
T5791	8843-8850	NN	denotes	biology
T5792	8851-8853	PRP	denotes	we
T5793	8854-8866	VBD	denotes	investigated
T5794	8867-8874	IN	denotes	whether
T5795	8875-8883	JJ	denotes	specific
T5796	8884-8897	JJ	denotes	BCR-regulated
T5797	8898-8908	JJ	denotes	signalling
T5798	8909-8915	NNS	denotes	events
T5799	8916-8920	VBD	denotes	were
T5800	8921-8930	JJ	denotes	defective
T5801	8931-8933	IN	denotes	in
T5802	8934-8937	DT	denotes	the
T5803	8938-8946	NNP	denotes	PKD-null
T5804	8947-8948	NNP	denotes	B
T5805	8949-8954	NNS	denotes	cells
T5806	8954-8955	.	denotes	.
T5807	8956-8963	JJ	denotes	Initial
T5808	8964-8975	NNS	denotes	experiments
T5809	8976-8984	VBD	denotes	revealed
T5810	8985-8989	IN	denotes	that
T5811	8990-8997	NN	denotes	surface
T5812	8998-9008	NN	denotes	expression
T5813	9009-9011	IN	denotes	of
T5814	9012-9015	DT	denotes	the
T5815	9016-9019	NNP	denotes	BCR
T5816	9020-9023	VBD	denotes	was
T5817	9024-9031	VBN	denotes	reduced
T5818	9032-9034	IN	denotes	in
T5819	9035-9041	CD	denotes	PKD1/3
T5820	9041-9042	CD	denotes	−
T5821	9042-9043	NN	denotes	/
T5822	9043-9044	NN	denotes	−
T5823	9045-9046	-LRB-	denotes	(
T5824	9046-9049	CC	denotes	and
T5825	9050-9052	IN	denotes	in
T5826	9053-9059	CD	denotes	PKD1/3
T5827	9059-9060	CD	denotes	−
T5828	9060-9061	NN	denotes	/
T5829	9061-9062	NN	denotes	−
T5830	9062-9063	:	denotes	:
T5831	9063-9072	NN	denotes	Flag-PKD3
T5832	9072-9073	NN	denotes	+
T5833	9073-9075	NN	denotes	ve
T5834	9075-9076	-RRB-	denotes	)
T5835	9077-9082	NNS	denotes	cells
T5836	9083-9091	VBN	denotes	compared
T5837	9092-9094	TO	denotes	to
T5838	9095-9104	JJ	denotes	wild-type
T5839	9105-9109	NNP	denotes	DT40
T5840	9110-9111	NNP	denotes	B
T5841	9112-9117	NNS	denotes	cells
T5842	9118-9119	-LRB-	denotes	(
T5843	9119-9123	NNP	denotes	Fig.
T5844	9124-9126	NNP	denotes	3A
T5845	9127-9130	CC	denotes	and
T5846	9131-9135	NNS	denotes	data
T5847	9136-9139	RB	denotes	not
T5848	9140-9145	VBN	denotes	shown
T5849	9145-9146	-RRB-	denotes	)
T5850	9146-9147	.	denotes	.
T5851	9148-9160	RB	denotes	Nevertheless
T5852	9160-9161	,	denotes	,
T5853	9162-9178	JJ	denotes	BCR-crosslinking
T5854	9179-9181	IN	denotes	of
T5855	9182-9188	CD	denotes	PKD1/3
T5856	9188-9189	CD	denotes	−
T5857	9189-9190	NN	denotes	/
T5858	9190-9191	NN	denotes	−
T5859	9192-9197	NNS	denotes	cells
T5860	9198-9201	VBD	denotes	was
T5861	9202-9212	JJ	denotes	sufficient
T5862	9213-9215	TO	denotes	to
T5863	9216-9222	VB	denotes	induce
T5864	9223-9226	DT	denotes	the
T5865	9227-9237	NN	denotes	activation
T5866	9238-9240	IN	denotes	of
T5867	9241-9242	DT	denotes	a
T5868	9243-9249	NN	denotes	number
T5869	9250-9252	IN	denotes	of
T5870	9253-9263	VBG	denotes	signalling
T5871	9264-9272	NNS	denotes	cascades
T5872	9272-9273	,	denotes	,
T5873	9274-9281	JJ	denotes	similar
T5874	9282-9284	TO	denotes	to
T5875	9285-9289	DT	denotes	that
T5876	9290-9298	VBN	denotes	observed
T5877	9299-9301	IN	denotes	in
T5878	9302-9311	JJ	denotes	wild-type
T5879	9312-9317	NNS	denotes	cells
T5880	9318-9319	-LRB-	denotes	(
T5881	9319-9323	NNP	denotes	Fig.
T5882	9324-9326	NNP	denotes	3B
T5883	9326-9327	-RRB-	denotes	)
T5884	9327-9328	.	denotes	.
T5885	9329-9334	RB	denotes	Hence
T5886	9334-9335	,	denotes	,
T5887	9336-9347	JJ	denotes	BCR-induced
T5888	9348-9358	NN	denotes	activation
T5889	9359-9361	IN	denotes	of
T5890	9362-9365	DT	denotes	the
T5891	9366-9369	NNP	denotes	Akt
T5892	9369-9370	,	denotes	,
T5893	9371-9379	NNP	denotes	mTOR/p70
T5894	9380-9382	NNP	denotes	S6
T5895	9383-9389	NN	denotes	kinase
T5896	9390-9391	-LRB-	denotes	(
T5897	9391-9393	IN	denotes	as
T5898	9394-9399	VBN	denotes	shown
T5899	9400-9402	IN	denotes	by
T5900	9403-9405	CD	denotes	S6
T5901	9406-9415	JJ	denotes	ribosomal
T5902	9416-9423	NN	denotes	protein
T5903	9424-9439	NN	denotes	phosphorylation
T5904	9439-9440	-RRB-	denotes	)
T5905	9441-9444	CC	denotes	and
T5906	9445-9449	NNP	denotes	MAPK
T5907	9450-9460	VBG	denotes	signalling
T5908	9461-9469	NNS	denotes	pathways
T5909	9470-9473	VBD	denotes	was
T5910	9474-9481	RB	denotes	clearly
T5911	9482-9492	JJ	denotes	detectable
T5912	9493-9495	IN	denotes	in
T5913	9496-9507	NNP	denotes	PKD1/3-null
T5914	9508-9509	NNP	denotes	B
T5915	9510-9515	NNS	denotes	cells
T5916	9516-9517	-LRB-	denotes	(
T5917	9517-9521	NNP	denotes	Fig.
T5918	9522-9524	NNP	denotes	3B
T5919	9524-9525	-RRB-	denotes	)
T5920	9525-9526	.	denotes	.
T5921	9527-9538	RB	denotes	Furthermore
T5922	9538-9539	,	denotes	,
T5923	9540-9548	JJ	denotes	enhanced
T5924	9549-9557	NN	denotes	tyrosine
T5925	9558-9573	NN	denotes	phosphorylation
T5926	9574-9576	IN	denotes	of
T5927	9577-9585	JJ	denotes	multiple
T5928	9586-9594	JJ	denotes	cellular
T5929	9595-9603	NNS	denotes	proteins
T5930	9604-9606	RB	denotes	as
T5931	9607-9611	RB	denotes	well
T5932	9612-9614	IN	denotes	as
T5933	9615-9617	DT	denotes	an
T5934	9618-9626	NN	denotes	increase
T5935	9627-9629	IN	denotes	in
T5936	9630-9643	JJ	denotes	intracellular
T5937	9644-9651	NN	denotes	calcium
T5938	9652-9658	NNS	denotes	levels
T5939	9659-9662	VBD	denotes	was
T5940	9663-9667	RB	denotes	also
T5941	9668-9676	VBN	denotes	observed
T5942	9677-9686	VBG	denotes	following
T5943	9687-9690	NNP	denotes	BCR
T5944	9691-9702	NN	denotes	stimulation
T5945	9703-9705	IN	denotes	of
T5946	9706-9717	NNP	denotes	PKD1/3-null
T5947	9718-9719	NNP	denotes	B
T5948	9720-9725	NNS	denotes	cells
T5949	9726-9727	-LRB-	denotes	(
T5950	9727-9731	NNS	denotes	data
T5951	9732-9735	RB	denotes	not
T5952	9736-9741	VBN	denotes	shown
T5953	9741-9742	-RRB-	denotes	)
T5954	9742-9743	.	denotes	.
T5955	9744-9746	PRP	denotes	We
T5956	9747-9750	VBD	denotes	did
T5957	9751-9758	VB	denotes	observe
T5958	9759-9763	IN	denotes	that
T5959	9764-9767	DT	denotes	the
T5960	9768-9776	NN	denotes	strength
T5961	9777-9779	IN	denotes	of
T5962	9780-9783	NNP	denotes	BCR
T5963	9784-9785	-LRB-	denotes	(
T5964	9785-9788	CC	denotes	but
T5965	9789-9792	RB	denotes	not
T5966	9793-9800	VB	denotes	phorbol
T5967	9801-9806	NN	denotes	ester
T5968	9806-9807	-RRB-	denotes	)
T5969	9807-9808	:	denotes	-
T5970	9808-9815	VBD	denotes	induced
T5971	9816-9826	NN	denotes	regulation
T5972	9827-9829	IN	denotes	of
T5973	9830-9833	DT	denotes	the
T5974	9834-9843	JJ	denotes	Erk1-RSK1
T5975	9844-9854	NN	denotes	signalling
T5976	9855-9862	NN	denotes	pathway
T5977	9863-9866	VBD	denotes	was
T5978	9867-9874	VBN	denotes	reduced
T5979	9875-9877	IN	denotes	in
T5980	9878-9884	CD	denotes	PKD1/3
T5981	9884-9885	CD	denotes	−
T5982	9885-9886	NN	denotes	/
T5983	9886-9887	NN	denotes	−
T5984	9888-9889	NNP	denotes	B
T5985	9890-9895	NNS	denotes	cells
T5986	9896-9904	VBN	denotes	compared
T5987	9905-9907	TO	denotes	to
T5988	9908-9917	JJ	denotes	wild-type
T5989	9918-9919	NNP	denotes	B
T5990	9920-9925	NNS	denotes	cells
T5991	9926-9927	-LRB-	denotes	(
T5992	9927-9931	NNP	denotes	Fig.
T5993	9932-9934	NNP	denotes	3B
T5994	9934-9935	-RRB-	denotes	)
T5995	9935-9936	.	denotes	.
T5996	9937-9940	CD	denotes	One
T5997	9941-9955	NN	denotes	interpretation
T5998	9956-9958	IN	denotes	of
T5999	9959-9963	DT	denotes	this
T6000	9964-9968	NN	denotes	data
T6001	9969-9971	VBZ	denotes	is
T6002	9972-9976	IN	denotes	that
T6003	9977-9980	NNP	denotes	PKD
T6004	9981-9988	VBZ	denotes	enzymes
T6005	9989-9992	MD	denotes	may
T6006	9993-10001	VB	denotes	modulate
T6007	10002-10005	NNP	denotes	Erk
T6008	10006-10016	NN	denotes	activation
T6009	10016-10017	.	denotes	.
T6010	10018-10024	RB	denotes	Indeed
T6011	10024-10025	,	denotes	,
T6012	10026-10029	NNP	denotes	PKD
T6013	10030-10037	NNS	denotes	enzymes
T6014	10038-10042	VBP	denotes	have
T6015	10043-10053	RB	denotes	previously
T6016	10054-10058	VBN	denotes	been
T6017	10059-10065	VBN	denotes	linked
T6018	10066-10068	TO	denotes	to
T6019	10069-10072	DT	denotes	the
T6020	10073-10079	NN	denotes	growth
T6021	10080-10096	JJ	denotes	factor-regulated
T6022	10097-10100	NNP	denotes	Erk
T6023	10101-10111	NN	denotes	signalling
T6024	10112-10114	IN	denotes	in
T6025	10115-10125	NN	denotes	fibroblast
T6026	10126-10129	CC	denotes	and
T6027	10130-10141	JJ	denotes	endothelial
T6028	10142-10146	NN	denotes	cell
T6029	10147-10152	NNS	denotes	lines
T6030	10153-10154	NNP	denotes	[
T6031	10154-10156	CD	denotes	33
T6032	10157-10159	CD	denotes	35
T6033	10159-10160	NN	denotes	]
T6034	10160-10161	.	denotes	.
T6035	10162-10169	RB	denotes	However
T6036	10169-10170	,	denotes	,
T6037	10171-10182	JJ	denotes	BCR-induced
T6038	10183-10186	NNP	denotes	Erk
T6039	10187-10202	NN	denotes	phosphorylation
T6040	10203-10206	VBD	denotes	was
T6041	10207-10211	RB	denotes	also
T6042	10212-10219	VBN	denotes	reduced
T6043	10220-10222	IN	denotes	in
T6044	10223-10229	CD	denotes	PKD1/3
T6045	10229-10230	CD	denotes	−
T6046	10230-10231	NN	denotes	/
T6047	10231-10232	SYM	denotes	−
T6048	10232-10233	:	denotes	-
T6049	10233-10242	NN	denotes	Flag-PKD3
T6050	10242-10243	NN	denotes	+
T6051	10244-10245	NNP	denotes	B
T6052	10246-10251	NNS	denotes	cells
T6053	10252-10253	-LRB-	denotes	(
T6054	10253-10257	NNS	denotes	data
T6055	10258-10261	RB	denotes	not
T6056	10262-10267	VBN	denotes	shown
T6057	10267-10268	-RRB-	denotes	)
T6058	10269-10279	VBG	denotes	suggesting
T6059	10280-10284	IN	denotes	that
T6060	10285-10292	VBN	denotes	reduced
T6061	10293-10296	NNP	denotes	BCR
T6062	10297-10303	NNS	denotes	levels
T6063	10304-10306	IN	denotes	on
T6064	10307-10310	DT	denotes	the
T6065	10311-10318	NN	denotes	surface
T6066	10319-10321	IN	denotes	of
T6067	10322-10328	CD	denotes	PKD1/3
T6068	10328-10329	CD	denotes	−
T6069	10329-10330	NN	denotes	/
T6070	10330-10331	NN	denotes	−
T6071	10332-10333	-LRB-	denotes	(
T6072	10333-10336	CC	denotes	and
T6073	10337-10343	NNP	denotes	PKD1/3
T6074	10343-10344	VBD	denotes	−
T6075	10344-10345	CD	denotes	/
T6076	10345-10346	SYM	denotes	−
T6077	10346-10347	:	denotes	-
T6078	10347-10356	NN	denotes	Flag-PKD3
T6079	10356-10357	NN	denotes	+
T6080	10357-10358	-RRB-	denotes	)
T6081	10359-10360	NNP	denotes	B
T6082	10361-10366	NNS	denotes	cells
T6083	10367-10370	MD	denotes	may
T6084	10371-10377	PRP	denotes	itself
T6085	10378-10384	VB	denotes	impact
T6086	10385-10387	IN	denotes	on
T6087	10388-10391	DT	denotes	the
T6088	10392-10400	NN	denotes	strength
T6089	10401-10403	IN	denotes	of
T6090	10404-10414	NN	denotes	activation
T6091	10415-10417	IN	denotes	of
T6092	10418-10422	DT	denotes	this
T6093	10423-10431	JJ	denotes	specific
T6094	10432-10445	JJ	denotes	intracellular
T6095	10446-10456	NN	denotes	signalling
T6096	10457-10464	NN	denotes	pathway
T6097	10464-10465	.	denotes	.
T6098	10466-10468	TO	denotes	To
T6099	10469-10475	VB	denotes	search
T6100	10476-10479	IN	denotes	for
T6101	10480-10485	JJ	denotes	other
T6102	10486-10495	JJ	denotes	potential
T6103	10496-10499	NNP	denotes	PKD
T6104	10500-10507	NNS	denotes	targets
T6105	10508-10512	WDT	denotes	that
T6106	10513-10516	MD	denotes	may
T6107	10517-10521	VB	denotes	show
T6108	10522-10531	JJ	denotes	defective
T6109	10532-10542	NN	denotes	regulation
T6110	10543-10545	IN	denotes	in
T6111	10546-10552	NNP	denotes	PKD1/3
T6112	10552-10553	NNP	denotes	−
T6113	10553-10554	NNP	denotes	/
T6114	10554-10555	NNP	denotes	−
T6115	10556-10560	NNP	denotes	DT40
T6116	10561-10562	NNP	denotes	B
T6117	10563-10568	NNS	denotes	cells
T6118	10568-10569	,	denotes	,
T6119	10570-10572	PRP	denotes	we
T6120	10573-10577	VBD	denotes	used
T6121	10578-10579	DT	denotes	a
T6122	10580-10583	NNP	denotes	PKD
T6123	10584-10593	VB	denotes	substrate
T6124	10594-10610	JJ	denotes	phospho-antibody
T6125	10611-10615	IN	denotes	that
T6126	10616-10626	VBZ	denotes	recognises
T6127	10627-10636	NN	denotes	consensus
T6128	10637-10652	NN	denotes	phosphorylation
T6129	10653-10662	NNS	denotes	sequences
T6130	10663-10671	VBN	denotes	targeted
T6131	10672-10674	IN	denotes	by
T6132	10675-10678	NNP	denotes	PKD
T6133	10679-10686	VBZ	denotes	enzymes
T6134	10687-10688	-LRB-	denotes	(
T6135	10688-10697	NNP	denotes	LxRxxpS/T
T6136	10697-10698	-RRB-	denotes	)
T6137	10699-10700	NNP	denotes	[
T6138	10700-10702	CD	denotes	36
T6139	10702-10703	NNP	denotes	]
T6140	10703-10704	.	denotes	.
T6141	10705-10707	IN	denotes	As
T6142	10708-10713	VBN	denotes	shown
T6143	10714-10716	IN	denotes	in
T6144	10717-10721	NNP	denotes	Fig.
T6145	10722-10724	NNP	denotes	3C
T6146	10724-10725	,	denotes	,
T6147	10726-10733	NN	denotes	phorbol
T6148	10734-10739	NN	denotes	ester
T6149	10739-10740	:	denotes	-
T6150	10741-10744	CC	denotes	and
T6151	10745-10756	JJ	denotes	BCR-induced
T6152	10757-10772	NN	denotes	phosphorylation
T6153	10773-10775	IN	denotes	of
T6154	10776-10784	JJ	denotes	cellular
T6155	10785-10795	NNS	denotes	substrates
T6156	10796-10804	VBN	denotes	detected
T6157	10805-10807	IN	denotes	by
T6158	10808-10812	DT	denotes	this
T6159	10813-10829	NN	denotes	phospho-antibody
T6160	10830-10833	VBD	denotes	was
T6161	10834-10841	JJ	denotes	similar
T6162	10842-10844	IN	denotes	in
T6163	10845-10854	JJ	denotes	wild-type
T6164	10855-10858	CC	denotes	and
T6165	10859-10865	JJ	denotes	PKD1/3
T6166	10865-10866	NN	denotes	−
T6167	10866-10867	NN	denotes	/
T6168	10867-10868	NN	denotes	−
T6169	10869-10874	NNS	denotes	cells
T6170	10875-10878	CC	denotes	and
T6171	10879-10881	VBZ	denotes	is
T6172	10882-10891	RB	denotes	therefore
T6173	10892-10903	JJ	denotes	independent
T6174	10904-10906	IN	denotes	of
T6175	10907-10910	NNP	denotes	PKD
T6176	10911-10918	VBZ	denotes	enzymes
T6177	10918-10919	.	denotes	.
T6178	10920-10927	RB	denotes	However
T6179	10927-10928	,	denotes	,
T6180	10929-10941	NN	denotes	pretreatment
T6181	10942-10944	IN	denotes	of
T6182	10945-10949	DT	denotes	both
T6183	10950-10959	JJ	denotes	wild-type
T6184	10960-10963	CC	denotes	and
T6185	10964-10970	JJ	denotes	PKD1/3
T6186	10970-10971	NN	denotes	−
T6187	10971-10972	NN	denotes	/
T6188	10972-10973	NN	denotes	−
T6189	10974-10978	NNP	denotes	DT40
T6190	10979-10980	NNP	denotes	B
T6191	10981-10986	NNS	denotes	cells
T6192	10987-10991	IN	denotes	with
T6193	10992-11001	NNP	denotes	GF109203X
T6194	11001-11002	,	denotes	,
T6195	11003-11004	DT	denotes	a
T6196	11005-11023	NN	denotes	bisindoylmaleimide
T6197	11024-11034	NN	denotes	derivative
T6198	11035-11039	WDT	denotes	that
T6199	11040-11048	VBZ	denotes	inhibits
T6200	11049-11053	NNS	denotes	PKCs
T6201	11054-11063	VBD	denotes	prevented
T6202	11064-11067	DT	denotes	the
T6203	11068-11077	NN	denotes	induction
T6204	11078-11080	IN	denotes	of
T6205	11081-11089	NNS	denotes	proteins
T6206	11090-11094	WDT	denotes	that
T6207	11095-11102	VBP	denotes	contain
T6208	11103-11117	VBN	denotes	phosphorylated
T6209	11118-11126	NNP	denotes	LxRxxS/T
T6210	11127-11133	NNS	denotes	motifs
T6211	11133-11134	.	denotes	.
T6212	11135-11139	RB	denotes	Thus
T6213	11140-11144	NN	denotes	loss
T6214	11145-11147	IN	denotes	of
T6215	11148-11154	NNP	denotes	PKD1/3
T6216	11155-11162	VBZ	denotes	enzymes
T6217	11163-11167	VBZ	denotes	does
T6218	11168-11171	RB	denotes	not
T6219	11172-11180	RB	denotes	globally
T6220	11181-11188	VB	denotes	disrupt
T6221	11189-11192	DT	denotes	the
T6222	11193-11208	NN	denotes	phosphorylation
T6223	11209-11211	IN	denotes	of
T6224	11212-11220	JJ	denotes	cellular
T6225	11221-11229	NNS	denotes	proteins
T6226	11230-11234	WDT	denotes	that
T6227	11235-11242	VBP	denotes	contain
T6228	11243-11252	NNP	denotes	LxRxxpS/T
T6229	11253-11259	NNS	denotes	motifs
T6230	11259-11260	.	denotes	.
T6231	11261-11265	DT	denotes	This
T6232	11266-11272	NN	denotes	result
T6233	11273-11275	VBZ	denotes	is
T6234	11276-11283	RB	denotes	perhaps
T6235	11284-11287	RB	denotes	not
T6236	11288-11298	JJ	denotes	surprising
T6237	11299-11301	IN	denotes	as
T6238	11302-11310	NNP	denotes	LxRxxS/T
T6239	11311-11317	NNS	denotes	motifs
T6240	11318-11322	RB	denotes	also
T6241	11323-11326	VBP	denotes	act
T6242	11327-11329	RB	denotes	as
T6243	11330-11334	JJ	denotes	good
T6244	11335-11345	NNS	denotes	substrates
T6245	11346-11349	IN	denotes	for
T6246	11350-11355	JJ	denotes	other
T6247	11356-11372	JJ	denotes	serine/threonine
T6248	11373-11380	NNS	denotes	kinases
T6249	11381-11385	JJ	denotes	such
T6250	11386-11388	IN	denotes	as
T6251	11389-11397	NNP	denotes	MAPKAPK2
T6252	11397-11398	.	denotes	.
T6253	11399-11406	RB	denotes	However
T6254	11407-11412	DT	denotes	these
T6255	11413-11424	NNS	denotes	experiments
T6256	11425-11427	VBP	denotes	do
T6257	11428-11435	VB	denotes	provide
T6258	11436-11443	JJ	denotes	further
T6259	11444-11452	NN	denotes	evidence
T6260	11453-11457	IN	denotes	that
T6261	11458-11473	JJ	denotes	phosphospecific
T6262	11474-11482	NN	denotes	antisera
T6263	11483-11486	VBP	denotes	are
T6264	11487-11490	RB	denotes	not
T6265	11491-11503	RB	denotes	sufficiently
T6266	11504-11513	JJ	denotes	selective
T6267	11514-11516	TO	denotes	to
T6268	11517-11519	VB	denotes	be
T6269	11520-11530	VBN	denotes	designated
T6270	11531-11537	NN	denotes	kinase
T6271	11538-11546	JJ	denotes	specific
T6272	11547-11556	JJ	denotes	substrate
T6273	11557-11565	NN	denotes	antisera
T6274	11565-11566	.	denotes	.
T6275	11567-11578	JJ	denotes	BCR-induced
T6276	11579-11589	JJ	denotes	signalling
T6277	11590-11598	NNS	denotes	pathways
T6278	11599-11608	VBP	denotes	culminate
T6279	11609-11611	IN	denotes	in
T6280	11612-11615	DT	denotes	the
T6281	11616-11626	NN	denotes	activation
T6282	11627-11629	IN	denotes	of
T6283	11630-11634	NN	denotes	gene
T6284	11635-11648	NN	denotes	transcription
T6285	11649-11655	NNS	denotes	events
T6286	11656-11660	WDT	denotes	that
T6287	11661-11668	VBP	denotes	control
T6288	11669-11670	NNP	denotes	B
T6289	11671-11675	NN	denotes	cell
T6290	11676-11684	NN	denotes	survival
T6291	11684-11685	,	denotes	,
T6292	11686-11699	NN	denotes	proliferation
T6293	11700-11703	CC	denotes	and
T6294	11704-11712	NN	denotes	function
T6295	11712-11713	.	denotes	.
T6296	11714-11716	IN	denotes	In
T6297	11717-11721	DT	denotes	this
T6298	11722-11729	NN	denotes	context
T6299	11729-11730	,	denotes	,
T6300	11731-11733	PRP	denotes	it
T6301	11734-11737	VBZ	denotes	has
T6302	11738-11742	VBN	denotes	been
T6303	11743-11751	VBN	denotes	proposed
T6304	11752-11756	IN	denotes	that
T6305	11757-11760	NNP	denotes	PKD
T6306	11761-11767	NN	denotes	family
T6307	11768-11775	NNS	denotes	members
T6308	11776-11783	NN	denotes	control
T6309	11784-11786	IN	denotes	of
T6310	11787-11791	NN	denotes	gene
T6311	11792-11805	NN	denotes	transcription
T6312	11806-11813	IN	denotes	through
T6313	11814-11824	NN	denotes	activation
T6314	11825-11827	IN	denotes	of
T6315	11828-11831	DT	denotes	the
T6316	11832-11836	NNP	denotes	NFκB
T6317	11837-11850	NN	denotes	transcription
T6318	11851-11857	NN	denotes	factor
T6319	11857-11858	.	denotes	.
T6320	11859-11863	RB	denotes	Thus
T6321	11863-11864	,	denotes	,
T6322	11865-11877	JJ	denotes	PKD-mediated
T6323	11878-11888	NN	denotes	activation
T6324	11889-11891	IN	denotes	of
T6325	11892-11896	NNP	denotes	NFκB
T6326	11897-11903	VBZ	denotes	occurs
T6327	11904-11914	JJ	denotes	downstream
T6328	11915-11917	IN	denotes	of
T6329	11918-11919	DT	denotes	a
T6330	11920-11927	NN	denotes	variety
T6331	11928-11930	IN	denotes	of
T6332	11931-11940	JJ	denotes	different
T6333	11941-11948	NNS	denotes	signals
T6334	11948-11949	,	denotes	,
T6335	11950-11959	VBG	denotes	including
T6336	11960-11974	JJ	denotes	mROS/oxidative
T6337	11975-11981	NN	denotes	stress
T6338	11981-11982	,	denotes	,
T6339	11983-11999	JJ	denotes	lysophosphatidic
T6340	12000-12004	NN	denotes	acid
T6341	12005-12008	CC	denotes	and
T6342	12009-12012	DT	denotes	the
T6343	12013-12020	NNP	denotes	Bcr-Abl
T6344	12021-12029	NN	denotes	oncogene
T6345	12030-12031	NNP	denotes	[
T6346	12031-12045	CD	denotes	17,21,23,30,37
T6347	12045-12046	NNP	denotes	]
T6348	12046-12047	.	denotes	.
T6349	12048-12059	RB	denotes	Furthermore
T6350	12059-12060	,	denotes	,
T6351	12061-12071	NN	denotes	expression
T6352	12072-12074	IN	denotes	of
T6353	12075-12077	DT	denotes	an
T6354	12078-12087	VBN	denotes	activated
T6355	12088-12092	NNP	denotes	PKD1
T6356	12093-12099	JJ	denotes	mutant
T6357	12100-12108	VBZ	denotes	enhances
T6358	12109-12122	JJ	denotes	HPK1-mediated
T6359	12123-12127	NNP	denotes	NFκB
T6360	12128-12138	NN	denotes	activation
T6361	12139-12140	NNP	denotes	[
T6362	12140-12142	CD	denotes	38
T6363	12142-12143	NNP	denotes	]
T6364	12143-12144	.	denotes	.
T6365	12145-12147	IN	denotes	In
T6366	12148-12149	NNP	denotes	B
T6367	12150-12155	NNS	denotes	cells
T6368	12155-12156	,	denotes	,
T6369	12157-12161	NNP	denotes	NFκB
T6370	12162-12164	VBZ	denotes	is
T6371	12165-12170	VBN	denotes	known
T6372	12171-12173	TO	denotes	to
T6373	12174-12176	VB	denotes	be
T6374	12177-12186	VBN	denotes	regulated
T6375	12187-12190	IN	denotes	via
T6376	12191-12194	NNP	denotes	DAG
T6377	12195-12198	CC	denotes	and
T6378	12199-12203	NNP	denotes	PKCβ
T6379	12204-12205	NNP	denotes	[
T6380	12205-12210	CD	denotes	39,40
T6381	12210-12211	NNP	denotes	]
T6382	12212-12215	CC	denotes	but
T6383	12216-12223	IN	denotes	whether
T6384	12224-12228	NNS	denotes	PKDs
T6385	12229-12232	VBP	denotes	are
T6386	12233-12236	JJ	denotes	key
T6387	12237-12251	NNS	denotes	intermediaries
T6388	12252-12255	IN	denotes	for
T6389	12256-12260	NNP	denotes	NFκB
T6390	12261-12271	NN	denotes	regulation
T6391	12272-12275	VBZ	denotes	has
T6392	12276-12279	RB	denotes	not
T6393	12280-12284	VBN	denotes	been
T6394	12285-12293	VBN	denotes	explored
T6395	12293-12294	.	denotes	.
T6396	12295-12298	DT	denotes	The
T6397	12299-12303	NNS	denotes	data
T6398	12304-12305	-LRB-	denotes	(
T6399	12305-12309	NNP	denotes	Fig.
T6400	12310-12312	NNP	denotes	4A
T6401	12312-12313	-RRB-	denotes	)
T6402	12314-12318	VBP	denotes	show
T6403	12319-12323	IN	denotes	that
T6404	12324-12328	NNP	denotes	NFκB
T6405	12329-12344	JJ	denotes	transcriptional
T6406	12345-12353	NN	denotes	activity
T6407	12354-12357	VBD	denotes	was
T6408	12358-12366	RB	denotes	strongly
T6409	12367-12374	VBN	denotes	induced
T6410	12375-12377	IN	denotes	in
T6411	12378-12382	DT	denotes	both
T6412	12383-12392	JJ	denotes	wild-type
T6413	12393-12396	CC	denotes	and
T6414	12397-12403	JJ	denotes	PKD1/3
T6415	12403-12404	NN	denotes	−
T6416	12404-12405	NN	denotes	/
T6417	12405-12406	NN	denotes	−
T6418	12407-12411	NNP	denotes	DT40
T6419	12412-12413	NNP	denotes	B
T6420	12414-12419	NNS	denotes	cells
T6421	12420-12422	IN	denotes	in
T6422	12423-12431	NN	denotes	response
T6423	12432-12434	TO	denotes	to
T6424	12435-12441	DT	denotes	either
T6425	12442-12449	NN	denotes	phorbol
T6426	12450-12455	NN	denotes	ester
T6427	12456-12458	CC	denotes	or
T6428	12459-12462	NNP	denotes	BCR
T6429	12463-12474	NN	denotes	stimulation
T6430	12474-12475	.	denotes	.
T6431	12476-12478	IN	denotes	In
T6432	12479-12487	NN	denotes	contrast
T6433	12487-12488	,	denotes	,
T6434	12489-12492	NNP	denotes	BCR
T6435	12493-12496	CC	denotes	and
T6436	12497-12504	JJ	denotes	phorbol
T6437	12505-12518	JJ	denotes	ester-induced
T6438	12519-12523	NNP	denotes	NFκB
T6439	12524-12539	JJ	denotes	transcriptional
T6440	12540-12548	NN	denotes	activity
T6441	12549-12552	VBD	denotes	was
T6442	12553-12562	VBN	denotes	abolished
T6443	12563-12565	IN	denotes	in
T6444	12566-12570	NNP	denotes	PKCβ
T6445	12570-12571	NNP	denotes	−
T6446	12571-12572	NNP	denotes	/
T6447	12572-12573	NNP	denotes	−
T6448	12574-12578	NNP	denotes	DT40
T6449	12579-12580	NNP	denotes	B
T6450	12581-12586	NNS	denotes	cells
T6451	12587-12588	-LRB-	denotes	(
T6452	12588-12592	NNP	denotes	Fig.
T6453	12593-12595	NNP	denotes	4A
T6454	12595-12596	-RRB-	denotes	)
T6455	12596-12597	,	denotes	,
T6456	12598-12606	IN	denotes	although
T6457	12607-12613	JJ	denotes	strong
T6458	12614-12624	NN	denotes	activation
T6459	12625-12627	IN	denotes	of
T6460	12628-12631	NNP	denotes	PKD
T6461	12632-12639	NNS	denotes	kinases
T6462	12640-12641	-LRB-	denotes	(
T6463	12641-12643	IN	denotes	as
T6464	12644-12652	VBN	denotes	assessed
T6465	12653-12655	IN	denotes	by
T6466	12656-12675	NN	denotes	autophosphorylation
T6467	12676-12678	IN	denotes	of
T6468	12679-12683	NNP	denotes	PKD1
T6469	12684-12686	IN	denotes	at
T6470	12687-12691	NNP	denotes	S916
T6471	12691-12692	-RRB-	denotes	)
T6472	12693-12696	VBD	denotes	was
T6473	12697-12705	VBN	denotes	observed
T6474	12706-12708	IN	denotes	in
T6475	12709-12712	DT	denotes	the
T6476	12713-12717	NNP	denotes	PKCβ
T6477	12717-12718	NNP	denotes	−
T6478	12718-12719	VBD	denotes	/
T6479	12719-12720	CD	denotes	−
T6480	12721-12726	NNS	denotes	cells
T6481	12727-12728	-LRB-	denotes	(
T6482	12728-12732	NNP	denotes	Fig.
T6483	12733-12735	NNP	denotes	4B
T6484	12735-12736	-RRB-	denotes	)
T6485	12736-12737	.	denotes	.
T6486	12738-12742	RB	denotes	Thus
T6487	12742-12743	,	denotes	,
T6488	12744-12747	NNP	denotes	PKD
T6489	12748-12755	NNS	denotes	kinases
T6490	12756-12759	VBP	denotes	are
T6491	12760-12767	DT	denotes	neither
T6492	12768-12777	JJ	denotes	essential
T6493	12778-12781	CC	denotes	nor
T6494	12782-12792	JJ	denotes	sufficient
T6495	12793-12795	TO	denotes	to
T6496	12796-12803	VB	denotes	mediate
T6497	12804-12815	JJ	denotes	BCR-induced
T6498	12816-12820	NN	denotes	NFκB
T6499	12821-12831	NN	denotes	activation
T6500	12832-12834	IN	denotes	in
T6501	12835-12839	NNP	denotes	DT40
T6502	12840-12841	NNP	denotes	B
T6503	12842-12847	NNS	denotes	cells
T6504	12848-12851	CC	denotes	and
T6505	12852-12857	RB	denotes	hence
T6506	12858-12860	VBP	denotes	do
T6507	12861-12864	RB	denotes	not
T6508	12865-12876	VB	denotes	participate
T6509	12877-12879	IN	denotes	in
T6510	12880-12887	NNP	denotes	DAG/PKC
T6511	12888-12896	VBD	denotes	mediated
T6512	12897-12904	NN	denotes	control
T6513	12905-12907	IN	denotes	of
T6514	12908-12912	NNP	denotes	NFκB
T6515	12912-12913	.	denotes	.
T7377	0-12936	JJ	denotes	40 B-lymphocyte cell line. Previously we have shown that PKDs have an essential role in regulating class II histone deacetylases in DT40 B-cells [Matthews, S.A., Liu, P., Spitaler, M., Olson, E.N., McKinsey, T.A., Cantrell, D.A. and Scharenberg, A.M. (2006) Essential role for protein kinase D family kinases in the regulation of class II histone deacetylases in B lymphocytes. Mol. Cell Biol. 26, 1569–1577]. We now show that PKDs are also required to regulate HSP27 phosphorylation in DT40 B-cells. However, in contrast to previous observations in other cell types, PKD enzymes do not regulate basic cellular processes such as proliferation or survival responses, nor NFκB transcriptional activity downstream of the B cell antigen receptor. Thus, PKDs have a selective role in DT40 B-cell biology. 1 Introduction The protein kinase D (PKD) serine/threonine kinase family has three members: PKD1, PKD2 and PKD3. Most cell types express at least two PKD isoforms but PKD enzymes are especially highly expressed in haematopoietic cells, where they are activated in response to antigen receptors stimulation [2,3]. A conserved signalling pathway linking antigen receptors to PKDs involves the activation of PLCγ and the subsequent production of diacylglycerol (DAG) which stimulates classical and/or novel protein kinase Cs (PKC) that phosphorylate two key regulatory serine residues in the activation loop of PKD kinases [3–6]. The N-terminal regulatory region of PKD enzymes contains a DAG binding domain and direct binding of DAG also contributes to PKD1 activation [7] as well as regulating the spatial location of PKD enzymes within cells [8–12]. PKD enzymes have been proposed to regulate numerous cellular functions, including cell proliferation [13–16], anti-apoptotic signals [17,18] and thymocyte development [19]. Expression of mutant catalytically inactive and constitutively activated PKDs can also modify Golgi function, cell adhesion and cell motility (reviewed in [20]). In particular, PKDs have been widely linked to the activation of the NFκB transcription factor and in regulating cell survival during oxidative stress [17,21–23]. Another recently proposed PKD1 substrate is HSP27 [24], a small heat shock protein involved in regulating cell migration and cell survival [25]. An essential role for PKD enzymes in regulating class II histone deacetylases (HDACs), enzymes that repress MEF2-dependent gene transcription, has also been demonstrated [1,26–28]. To investigate the biological role of PKDs we have generated DT40 B cell lines that lack expression of one or more members of the PKD family [1], allowing us to investigate the function(s) of PKD isoforms following B cell antigen receptor (BCR) stimulation, as well addressing the issue of functional redundancy between the different PKD family members. Previous studies have shown that PKDs are indispensable for HDAC regulation in B cells [1]. Herein we show that PKDs are also indispensable for HSP27 phosphorylation in B cells. However, PKD-null DT40 B cells are viable and proliferate normally. Moreover, loss of the entire cellular pool of PKD does not critically affect oxidative stress responses in B cells nor do PKD kinases play an essential role in regulating NFκB transcriptional activity. Together, these findings reveal that in B lymphocytes, PKD kinases are not critical regulators of many of the cellular processes previously ascribed to them in other cellular systems. 2 Materials and methods 2.1 Cell culture, transient transfections and cell stimulation The generation, culture and activation of PKD1−/−, PKD3−/− and PKD1/3−/− knockout DT40 B cell lines have been described previously [1]. Cells were lysed and protein extracts were analysed in Western blotting experiments as previously described [1]. Chloramphenicol acetyl transferase assays have been described previously [29]. 2.2 sIgM staining DT40 B cells (2 × 106 cells per point) were resuspended in 200 μl buffer (RPMI 1640 media, 1% foetal calf serum) containing anti-chicken M1 monoclonal antibody conjugated to FITC for 20 min on ice. The cells were washed twice and fluorescent intensity was analysed by flow cytometry. All results shown are representative of at two to four independent experiments unless otherwise indicated. 3 Results 3.1 Loss of HSP27 phosphorylation in DT40 B cells lacking expression of PKD family kinases DT40 B cells express two PKD isoforms, PKD1 and PKD3, and as previously described we have recently generated DT40 B cell lines that lack expression of either PKD1 or PKD3 or both enzymes [1]. In generating the double knockout cell lines we targeted the PKD1 loci in a PKD3−/− cell line that expressed a Flag-PKD3 transgene under the control of a doxycycline-inducible promoter. Hence, in the presence of doxycycline, Flag-PKD3 expression in PKD1/3 double knockout cells is comparable to endogenous PKD3 present in wild-type DT40 cells and removal of doxycycline from the culture media for 5 days results in a completely null PKD phenotype (Fig. 1A). Previously, we have demonstrated that phosphorylation and nuclear exclusion of class II histone deacetylases (HDACs) during BCR engagement is defective in PKD1/3−/− B cells and can restored upon re-expression of a single PKD isoform [1]. The small heat shock protein HSP27 has recently been proposed as a PKD1 substrate [24] and we accordingly assessed whether PKD-null DT40 cells have defective phosphorylation of HSP27 on serine 82, the proposed PKD1 substrate sequence. We initially investigated the regulation of HSP27 phosphorylation in single knockout DT40 B cells lacking either PKD1 or PKD3. As shown in Fig. 1B, activation of the BCR or treatment with the DAG-mimetic PdBu increased the levels of HSP27 phosphorylation at S82 in wild-type DT40 B cells. BCR and phorbol ester signals were also able to increase HSP27 phosphorylation in PKD1 or PKD3 single knockout DT40 B cells (Fig. 1B). However, BCR- and phorbol ester-induced phosphorylation of HSP27 on S82 was abolished in B cells that lacked both PKD1 and PKD3 (Fig. 1C). Significantly, doxycycline-induced expression of the Flag-PKD3 transgene in the double knockout cells was sufficient to restore normal regulation of HSP27 phosphorylation (Fig. 1C). In contrast, expression of a kinase-deficient PKD3 mutant protein in the double knockout cells was not able to restore BCR- or phorbol ester-induced HSP27 phosphorylation (Fig. 1D). Hence, PKD3 as well as PKD1 can regulate HSP27 phosphorylation and in DT40 B cells they are functionally redundant as HSP27 kinases. 3.2 Cellular proliferation and survival in DT40 B cells lacking expression of PKD family kinases PKD enzymes have previously been linked to the regulation of cell proliferation and survival (reviewed in [20]). To investigate the effect that loss of PKD kinases had on B cell survival and/or proliferation we cultured wild-type and PKD-null cells in the presence (PKD1/3−/−: Flag-PKD3+ve) or absence (PKD1/3−/−) of doxycycline and monitored exponential growth. As shown in Fig. 2A, PKD1/3−/− cells proliferated exponentially and re-expression of Flag-PKD3 in these cells had no impact on the rate of proliferation. Furthermore, the viability of PKD1/3−/− B cells during routine culturing was not significantly different from that of wild-type B cells (data not shown). It was noted that the population doubling time of PKD1/3−/− cells was slightly slower than that of wild type DT40 cells (12.7 ± 2.8 h versus 10.2 ± 0.4 h) but the failure of PKD3 re-expression to modify the proliferation rate of PKD1/3−/− cells suggests that these small differences were most likely the result of clonal variation and were not caused specifically by loss of PKD enzymes. Thus, PKD family enzymes are not essential for regulating basal survival and proliferation of DT40 B cells. PKD enzymes, specifically PKD1 and PKD2, have previously been linked to a protective role against oxidative stress-induced injury in 3T3 fibroblast, HeLa and epithelial cell lines [17,30–32]. We therefore addressed the role of PKD family kinases in regulating B cell survival in response to oxidative stress and other stress stimuli. As shown in Fig. 2B, loss of PKD1/3 expression had no significant impact on the survival of DT40 B cells in response to mitochondrial stress stimuli (H2O2 or serum deprivation); DNA damaging agents (etoposide or doxorubicin); ER pathway stress due to calcium overload (thapsigargin) or following prolonged treatment with phorbol esters or Trichostatin A, an inhibitor of class I/II HDACs. Thus, PKD kinases do not play an essential role in regulating B cell survival in response to a range of different stress stimuli. 3.3 Antigen receptor regulated signalling pathways in PKD-null DT40 B cells To further explore the contribution of PKD kinases to DT40 B cell biology we investigated whether specific BCR-regulated signalling events were defective in the PKD-null B cells. Initial experiments revealed that surface expression of the BCR was reduced in PKD1/3−/− (and in PKD1/3−/−:Flag-PKD3+ve) cells compared to wild-type DT40 B cells (Fig. 3A and data not shown). Nevertheless, BCR-crosslinking of PKD1/3−/− cells was sufficient to induce the activation of a number of signalling cascades, similar to that observed in wild-type cells (Fig. 3B). Hence, BCR-induced activation of the Akt, mTOR/p70 S6 kinase (as shown by S6 ribosomal protein phosphorylation) and MAPK signalling pathways was clearly detectable in PKD1/3-null B cells (Fig. 3B). Furthermore, enhanced tyrosine phosphorylation of multiple cellular proteins as well as an increase in intracellular calcium levels was also observed following BCR stimulation of PKD1/3-null B cells (data not shown). We did observe that the strength of BCR (but not phorbol ester)-induced regulation of the Erk1-RSK1 signalling pathway was reduced in PKD1/3−/− B cells compared to wild-type B cells (Fig. 3B). One interpretation of this data is that PKD enzymes may modulate Erk activation. Indeed, PKD enzymes have previously been linked to the growth factor-regulated Erk signalling in fibroblast and endothelial cell lines [33–35]. However, BCR-induced Erk phosphorylation was also reduced in PKD1/3−/−-Flag-PKD3+ B cells (data not shown) suggesting that reduced BCR levels on the surface of PKD1/3−/− (and PKD1/3−/−-Flag-PKD3+) B cells may itself impact on the strength of activation of this specific intracellular signalling pathway. To search for other potential PKD targets that may show defective regulation in PKD1/3−/− DT40 B cells, we used a PKD substrate phospho-antibody that recognises consensus phosphorylation sequences targeted by PKD enzymes (LxRxxpS/T) [36]. As shown in Fig. 3C, phorbol ester- and BCR-induced phosphorylation of cellular substrates detected by this phospho-antibody was similar in wild-type and PKD1/3−/− cells and is therefore independent of PKD enzymes. However, pretreatment of both wild-type and PKD1/3−/− DT40 B cells with GF109203X, a bisindoylmaleimide derivative that inhibits PKCs prevented the induction of proteins that contain phosphorylated LxRxxS/T motifs. Thus loss of PKD1/3 enzymes does not globally disrupt the phosphorylation of cellular proteins that contain LxRxxpS/T motifs. This result is perhaps not surprising as LxRxxS/T motifs also act as good substrates for other serine/threonine kinases such as MAPKAPK2. However these experiments do provide further evidence that phosphospecific antisera are not sufficiently selective to be designated kinase specific substrate antisera. BCR-induced signalling pathways culminate in the activation of gene transcription events that control B cell survival, proliferation and function. In this context, it has been proposed that PKD family members control of gene transcription through activation of the NFκB transcription factor. Thus, PKD-mediated activation of NFκB occurs downstream of a variety of different signals, including mROS/oxidative stress, lysophosphatidic acid and the Bcr-Abl oncogene [17,21,23,30,37]. Furthermore, expression of an activated PKD1 mutant enhances HPK1-mediated NFκB activation [38]. In B cells, NFκB is known to be regulated via DAG and PKCβ [39,40] but whether PKDs are key intermediaries for NFκB regulation has not been explored. The data (Fig. 4A) show that NFκB transcriptional activity was strongly induced in both wild-type and PKD1/3−/− DT40 B cells in response to either phorbol ester or BCR stimulation. In contrast, BCR and phorbol ester-induced NFκB transcriptional activity was abolished in PKCβ−/− DT40 B cells (Fig. 4A), although strong activation of PKD kinases (as assessed by autophosphorylation of PKD1 at S916) was observed in the PKCβ−/− cells (Fig. 4B). Thus, PKD kinases are neither essential nor sufficient to mediate BCR-induced NFκB activation in DT40 B cells and hence do not participate in DAG/PKC mediated control of NFκB. 4 Discussion Protein
T7378	12937-12943	NN	denotes	kinase
T7379	12944-12945	NNP	denotes	D
T7380	12946-12952	NN	denotes	serine
T7381	12953-12960	NNS	denotes	kinases
T4248	6782-6784	IN	denotes	in
T4249	6785-6786	NNP	denotes	[
T4250	6786-6788	CD	denotes	20
T4251	6788-6789	NNP	denotes	]
T4252	6789-6790	-RRB-	denotes	)
T4253	6790-6791	.	denotes	.
T4254	6792-6794	TO	denotes	To
T4255	6795-6806	VB	denotes	investigate
T4256	6807-6810	DT	denotes	the
T4257	6811-6817	NN	denotes	effect
T4258	6818-6822	WDT	denotes	that
T4259	6823-6827	NN	denotes	loss
T4260	6828-6830	IN	denotes	of
T4261	6831-6834	NNP	denotes	PKD
T4262	6835-6842	NNS	denotes	kinases
T4263	6843-6846	VBD	denotes	had
T4264	6847-6849	IN	denotes	on
T4265	6850-6851	NNP	denotes	B
T4266	6852-6856	NN	denotes	cell
T4267	6857-6865	NN	denotes	survival
T4268	6866-6872	CC	denotes	and/or
T4269	6873-6886	NN	denotes	proliferation
T4270	6887-6889	PRP	denotes	we
T4271	6890-6898	VBD	denotes	cultured
T4272	6899-6908	JJ	denotes	wild-type
T4273	6909-6912	CC	denotes	and
T4274	6913-6921	JJ	denotes	PKD-null
T4275	6922-6927	NNS	denotes	cells
R210	T247	T249	compound	B-lymphocyte,line
R211	T248	T249	compound	cell,line
R214	T251	T254	advmod	Previously,shown
R215	T252	T254	nsubj	we,shown
R216	T253	T254	aux	have,shown
R217	T254	T254	ROOT	shown,shown
R218	T255	T257	mark	that,have
R219	T256	T257	nsubj	PKDs,have
R220	T257	T254	ccomp	have,shown
R221	T258	T260	det	an,role
R222	T259	T260	amod	essential,role
R223	T260	T257	dobj	role,have
R224	T261	T260	prep	in,role
R225	T262	T261	pcomp	regulating,in
R226	T263	T266	compound	class,deacetylases
R227	T264	T266	compound	II,deacetylases
R228	T265	T266	compound	histone,deacetylases
R229	T266	T262	dobj	deacetylases,regulating
R230	T267	T262	prep	in,regulating
R231	T268	T271	compound	DT40,Matthews
R232	T269	T271	compound	B-cells,Matthews
R233	T270	T271	compound	[,Matthews
R234	T271	T267	pobj	Matthews,in
R235	T272	T271	punct	",",Matthews
R236	T273	T271	conj	S.A.,Matthews
R237	T274	T271	punct	",",Matthews
R238	T275	T271	conj	Liu,Matthews
R239	T276	T275	punct	",",Liu
R240	T277	T275	conj	P.,Liu
R241	T278	T277	punct	",",P.
R242	T279	T277	conj	Spitaler,P.
R243	T280	T279	punct	",",Spitaler
R244	T281	T279	conj	M.,Spitaler
R245	T282	T281	punct	",",M.
R246	T283	T281	conj	Olson,M.
R247	T284	T283	punct	",",Olson
R248	T285	T283	conj	E.N.,Olson
R249	T286	T285	punct	",",E.N.
R250	T287	T285	conj	McKinsey,E.N.
R251	T288	T287	punct	",",McKinsey
R252	T289	T287	conj	T.A.,McKinsey
R253	T290	T287	punct	",",McKinsey
R254	T291	T287	conj	Cantrell,McKinsey
R255	T292	T291	punct	",",Cantrell
R256	T293	T291	conj	D.A.,Cantrell
R257	T294	T293	cc	and,D.A.
R258	T295	T293	conj	Scharenberg,D.A.
R259	T296	T295	punct	",",Scharenberg
R260	T297	T295	conj	A.M.,Scharenberg
R261	T298	T297	punct	(,A.M.
R262	T299	T297	appos	2006,A.M.
R263	T300	T297	punct	),A.M.
R264	T301	T302	amod	Essential,role
R265	T302	T260	appos	role,role
R266	T303	T302	prep	for,role
R267	T304	T303	pobj	protein,for
R268	T305	T308	compound	kinase,kinases
R269	T306	T307	compound	D,family
R270	T307	T308	compound	family,kinases
R271	T308	T302	conj	kinases,role
R272	T309	T308	prep	in,kinases
R273	T310	T311	det	the,regulation
R274	T311	T309	pobj	regulation,in
R275	T312	T311	prep	of,regulation
R276	T313	T316	compound	class,deacetylases
R277	T314	T316	compound	II,deacetylases
R278	T315	T316	compound	histone,deacetylases
R279	T316	T312	pobj	deacetylases,of
R280	T317	T316	prep	in,deacetylases
R281	T318	T319	compound	B,lymphocytes
R282	T319	T317	pobj	lymphocytes,in
R283	T320	T254	punct	.,shown
R284	T321	T321	ROOT	Mol,Mol
R285	T322	T321	punct	.,Mol
R286	T323	T324	compound	Cell,Biol
R287	T324	T324	ROOT	Biol,Biol
R288	T325	T326	punct	.,26
R289	T326	T324	nummod	26,Biol
R290	T327	T324	punct	",",Biol
R291	T328	T324	appos	1569,Biol
R292	T329	T324	appos	1577,Biol
R293	T330	T330	ROOT	],]
R294	T331	T324	punct	.,Biol
R295	T332	T334	nsubj	We,show
R296	T333	T334	advmod	now,show
R297	T334	T334	ROOT	show,show
R298	T335	T339	mark	that,required
R299	T336	T339	nsubjpass	PKDs,required
R300	T337	T339	auxpass	are,required
R301	T338	T339	advmod	also,required
R302	T339	T334	ccomp	required,show
R303	T340	T341	aux	to,regulate
R304	T341	T339	xcomp	regulate,required
R305	T342	T343	compound	HSP27,phosphorylation
R306	T343	T341	dobj	phosphorylation,regulate
R307	T344	T343	prep	in,phosphorylation
R308	T345	T346	compound	DT40,B-cells
R309	T346	T344	pobj	B-cells,in
R310	T347	T334	punct	.,show
R311	T348	T364	advmod	However,regulate
R312	T349	T364	punct	",",regulate
R313	T350	T364	prep	in,regulate
R314	T351	T350	pobj	contrast,in
R315	T352	T351	prep	to,contrast
R316	T353	T354	amod	previous,observations
R317	T354	T352	pobj	observations,to
R318	T355	T354	prep	in,observations
R319	T356	T358	amod	other,types
R320	T357	T358	compound	cell,types
R321	T358	T355	pobj	types,in
R322	T359	T364	punct	",",regulate
R323	T360	T364	nsubj	PKD,regulate
R324	T361	T364	nsubj	enzymes,regulate
R325	T362	T364	aux	do,regulate
R326	T363	T364	neg	not,regulate
R327	T364	T364	ROOT	regulate,regulate
R328	T365	T367	amod	basic,processes
R329	T366	T367	amod	cellular,processes
R330	T367	T364	dobj	processes,regulate
R331	T368	T369	amod	such,as
R332	T369	T367	prep	as,processes
R333	T370	T369	pobj	proliferation,as
R334	T371	T370	cc	or,proliferation
R335	T372	T370	conj	survival,proliferation
R336	T373	T370	conj	responses,proliferation
R337	T374	T373	punct	",",responses
R338	T375	T364	cc	nor,regulate
R339	T376	T378	nmod	NFκB,activity
R340	T377	T378	amod	transcriptional,activity
R341	T378	T364	conj	activity,regulate
R342	T379	T378	amod	downstream,activity
R343	T380	T379	prep	of,downstream
R344	T381	T385	det	the,receptor
R345	T382	T384	compound	B,antigen
R346	T383	T384	compound	cell,antigen
R347	T384	T385	compound	antigen,receptor
R348	T385	T380	pobj	receptor,of
R349	T386	T364	punct	.,regulate
R350	T387	T390	advmod	Thus,have
R351	T388	T390	punct	",",have
R352	T389	T390	nsubj	PKDs,have
R353	T390	T390	ROOT	have,have
R354	T391	T393	det	a,role
R355	T392	T393	amod	selective,role
R356	T393	T390	dobj	role,have
R357	T394	T393	prep	in,role
R358	T395	T396	compound	DT40,B-cell
R359	T396	T397	compound	B-cell,biology
R360	T397	T394	pobj	biology,in
R361	T398	T390	punct	.,have
R894	T1008	T1011	amod	"1569–1577]. We now show that PKDs are also required to regulate HSP27 phosphorylation in DT40 B-cells. However, in contrast to previous observations in other cell types, PKD enzymes do not regulate basic cellular processes such as proliferation or survival responses, nor NFκB transcriptional activity downstream of the B cell antigen receptor. Thus, PKDs have a selective role in DT40 B-cell biology. 1 Introduction The",D
R895	T1009	T1011	nmod	protein,D
R896	T1010	T1011	compound	kinase,D
R897	T1011	T1011	ROOT	D,D
R898	T1012	T1011	punct	(,D
R899	T1013	T1011	appos	PKD,D
R900	T1014	T1011	punct	),D
R901	T1015	T1017	amod	serine/threonine,family
R902	T1016	T1017	compound	kinase,family
R903	T1017	T1018	nsubj	family,has
R904	T1018	T1018	ROOT	has,has
R905	T1019	T1020	nummod	three,members
R906	T1020	T1018	dobj	members,has
R907	T1021	T1018	punct	:,has
R908	T1022	T1022	ROOT	PKD1,PKD1
R909	T1023	T1022	punct	",",PKD1
R910	T1024	T1022	conj	PKD2,PKD1
R911	T1025	T1024	cc	and,PKD2
R912	T1026	T1024	conj	PKD3,PKD2
R913	T1027	T1018	punct	.,has
R914	T1028	T1030	amod	Most,types
R915	T1029	T1030	compound	cell,types
R916	T1030	T1031	nsubj	types,express
R917	T1031	T1031	ROOT	express,express
R918	T1032	T1033	advmod	at,least
R919	T1033	T1034	advmod	least,two
R920	T1034	T1036	nummod	two,isoforms
R921	T1035	T1036	compound	PKD,isoforms
R922	T1036	T1031	dobj	isoforms,express
R923	T1037	T1031	cc	but,express
R924	T1038	T1039	compound	PKD,enzymes
R925	T1039	T1040	nsubj	enzymes,are
R926	T1040	T1043	auxpass	are,expressed
R927	T1041	T1042	advmod	especially,highly
R928	T1042	T1043	advmod	highly,expressed
R929	T1043	T1031	conj	expressed,express
R930	T1044	T1043	prep	in,expressed
R931	T1045	T1046	amod	haematopoietic,cells
R932	T1046	T1044	pobj	cells,in
R933	T1047	T1043	punct	",",expressed
R934	T1048	T1051	advmod	where,activated
R935	T1049	T1051	nsubjpass	they,activated
R936	T1050	T1051	auxpass	are,activated
R937	T1051	T1043	advcl	activated,expressed
R938	T1052	T1051	prep	in,activated
R939	T1053	T1052	pobj	response,in
R940	T1054	T1053	prep	to,response
R941	T1055	T1056	compound	antigen,receptors
R942	T1056	T1057	compound	receptors,stimulation
R943	T1057	T1054	pobj	stimulation,to
R944	T1058	T1060	compound	[,]
R945	T1059	T1060	compound	"2,3",]
R946	T1060	T1057	appos	],stimulation
R947	T1061	T1043	punct	.,expressed
R948	T1062	T1065	det	A,pathway
R949	T1063	T1065	amod	conserved,pathway
R950	T1064	T1065	amod	signalling,pathway
R951	T1065	T1071	nsubj	pathway,involves
R952	T1066	T1065	acl	linking,pathway
R953	T1067	T1068	compound	antigen,receptors
R954	T1068	T1066	dobj	receptors,linking
R955	T1069	T1066	prep	to,linking
R956	T1070	T1069	pobj	PKDs,to
R957	T1071	T1071	ROOT	involves,involves
R958	T1072	T1073	det	the,activation
R959	T1073	T1071	dobj	activation,involves
R960	T1074	T1073	prep	of,activation
R961	T1075	T1074	pobj	PLCγ,of
R962	T1076	T1073	cc	and,activation
R963	T1077	T1079	det	the,production
R964	T1078	T1079	amod	subsequent,production
R965	T1079	T1073	conj	production,activation
R966	T1080	T1079	prep	of,production
R967	T1081	T1080	pobj	diacylglycerol,of
R968	T1082	T1083	punct	(,DAG
R969	T1083	T1081	appos	DAG,diacylglycerol
R970	T1084	T1081	punct	),diacylglycerol
R971	T1085	T1086	nsubj	which,stimulates
R972	T1086	T1079	relcl	stimulates,production
R973	T1087	T1090	amod	classical,protein
R974	T1088	T1087	cc	and/or,classical
R975	T1089	T1087	conj	novel,classical
R976	T1090	T1092	compound	protein,Cs
R977	T1091	T1092	compound	kinase,Cs
R978	T1092	T1086	dobj	Cs,stimulates
R979	T1093	T1092	punct	(,Cs
R980	T1094	T1092	appos	PKC,Cs
R981	T1095	T1092	punct	),Cs
R982	T1096	T1109	nsubj	that,kinases
R983	T1097	T1096	aux	phosphorylate,that
R984	T1098	T1102	nummod	two,residues
R985	T1099	T1102	amod	key,residues
R986	T1100	T1102	amod	regulatory,residues
R987	T1101	T1102	compound	serine,residues
R988	T1102	T1097	dobj	residues,phosphorylate
R989	T1103	T1102	prep	in,residues
R990	T1104	T1106	det	the,loop
R991	T1105	T1106	compound	activation,loop
R992	T1106	T1103	pobj	loop,in
R993	T1107	T1106	prep	of,loop
R994	T1108	T1107	pobj	PKD,of
R995	T1109	T1079	relcl	kinases,production
R996	T1110	T1109	dobj	[,kinases
R997	T1111	T1110	nummod	3,[
R998	T1112	T1113	nummod	6,]
R999	T1113	T1079	appos	],production
R1000	T1114	T1071	punct	.,involves
R1001	T1115	T1118	det	The,region
R1002	T1116	T1118	amod	N-terminal,region
R1003	T1117	T1118	amod	regulatory,region
R1004	T1118	T1121	nsubj	region,enzymes
R1005	T1119	T1118	prep	of,region
R1006	T1120	T1119	pobj	PKD,of
R1007	T1121	T1121	ROOT	enzymes,enzymes
R1008	T1122	T1121	conj	contains,enzymes
R1009	T1123	T1124	det	a,DAG
R1010	T1124	T1126	nmod	DAG,domain
R1011	T1125	T1126	amod	binding,domain
R1012	T1126	T1122	dobj	domain,contains
R1013	T1127	T1126	cc	and,domain
R1014	T1128	T1129	amod	direct,binding
R1015	T1129	T1126	conj	binding,domain
R1016	T1130	T1129	prep	of,binding
R1017	T1131	T1130	pobj	DAG,of
R1018	T1132	T1133	advmod	also,contributes
R1019	T1133	T1121	conj	contributes,enzymes
R1020	T1134	T1133	prep	to,contributes
R1021	T1135	T1139	nummod	PKD1,]
R1022	T1136	T1137	compound	activation,[
R1023	T1137	T1139	nmod	[,]
R1024	T1138	T1137	nummod	7,[
R1025	T1139	T1134	pobj	],to
R1026	T1140	T1142	advmod	as,as
R1027	T1141	T1142	advmod	well,as
R1028	T1142	T1133	prep	as,contributes
R1029	T1143	T1142	pcomp	regulating,as
R1030	T1144	T1146	det	the,location
R1031	T1145	T1146	amod	spatial,location
R1032	T1146	T1143	dobj	location,regulating
R1033	T1147	T1146	prep	of,location
R1034	T1148	T1149	compound	PKD,enzymes
R1035	T1149	T1147	pobj	enzymes,of
R1036	T1150	T1143	prep	within,regulating
R1037	T1151	T1150	pobj	cells,within
R1038	T1152	T1153	nmod	[,8
R1039	T1153	T1143	npadvmod	8,regulating
R1040	T1154	T1155	nummod	12,]
R1041	T1155	T1153	appos	],8
R1042	T1156	T1121	punct	.,enzymes
R1043	T1157	T1158	compound	PKD,enzymes
R1044	T1158	T1161	nsubjpass	enzymes,proposed
R1045	T1159	T1161	aux	have,proposed
R1062	T1176	T1177	amod	anti-apoptotic,signals
R1063	T1177	T1171	appos	signals,[
R1064	T1178	T1180	compound	[,]
R1065	T1179	T1180	compound	"17,18",]
R1066	T1180	T1177	dobj	],signals
R1067	T1181	T1180	cc	and,]
R1068	T1182	T1183	amod	thymocyte,development
R1069	T1183	T1186	nmod	development,]
R1070	T1184	T1186	nmod	[,]
R1071	T1185	T1186	nummod	19,]
R1072	T1186	T1180	conj	],]
R1073	T1187	T1177	punct	.,signals
R1074	T1188	T1199	nsubj	Expression,modify
R1075	T1189	T1188	prep	of,Expression
R1076	T1190	T1192	amod	mutant,inactive
R1077	T1191	T1192	advmod	catalytically,inactive
R1078	T1192	T1196	amod	inactive,PKDs
R1079	T1193	T1192	cc	and,inactive
R1080	T1194	T1195	advmod	constitutively,activated
R1081	T1195	T1192	conj	activated,inactive
R1082	T1196	T1188	appos	PKDs,Expression
R1083	T1197	T1199	aux	can,modify
R1084	T1198	T1199	advmod	also,modify
R1085	T1199	T1199	ROOT	modify,modify
R1086	T1200	T1201	compound	Golgi,function
R1087	T1201	T1199	dobj	function,modify
R1088	T1202	T1201	punct	",",function
R1089	T1203	T1204	compound	cell,adhesion
R1090	T1204	T1201	conj	adhesion,function
R1091	T1205	T1204	cc	and,adhesion
R1092	T1206	T1207	compound	cell,motility
R1093	T1207	T1204	conj	motility,adhesion
R1094	T1208	T1209	punct	(,reviewed
R1095	T1209	T1199	advcl	reviewed,modify
R1096	T1210	T1209	prep	in,reviewed
R1097	T1211	T1210	pobj	[,in
R1098	T1212	T1213	nummod	20,]
R1099	T1213	T1211	appos	],[
R1100	T1214	T1211	punct	),[
R1101	T1215	T1199	punct	.,modify
R1102	T1216	T1223	prep	In,linked
R1103	T1217	T1216	amod	particular,In
R1104	T1218	T1223	punct	",",linked
R1105	T1219	T1223	nsubjpass	PKDs,linked
R1106	T1220	T1223	aux	have,linked
R1107	T1221	T1223	auxpass	been,linked
R1108	T1222	T1223	advmod	widely,linked
R1109	T1223	T1223	ROOT	linked,linked
R1110	T1224	T1223	prep	to,linked
R1111	T1225	T1226	det	the,activation
R1112	T1226	T1224	pobj	activation,to
R1113	T1227	T1226	prep	of,activation
R1114	T1228	T1231	det	the,factor
R1115	T1229	T1231	compound	NFκB,factor
R1116	T1230	T1231	compound	transcription,factor
R1117	T1231	T1227	pobj	factor,of
R1118	T1232	T1224	cc	and,to
R1119	T1233	T1223	prep	in,linked
R1120	T1234	T1233	pcomp	regulating,in
R1121	T1235	T1236	compound	cell,survival
R1122	T1236	T1234	dobj	survival,regulating
R1123	T1237	T1234	prep	during,regulating
R1124	T1238	T1239	amod	oxidative,stress
R1125	T1239	T1241	compound	stress,"17,21"
R1126	T1240	T1241	compound	[,"17,21"
R1127	T1241	T1237	pobj	"17,21",during
R1175	T1289	T1289	ROOT	enzymes,enzymes
R1176	T1290	T1291	mark	that,repress
R1196	T1310	T1309	prep	of,role
R1197	T1311	T1310	pobj	PKDs,of
R1198	T1312	T1314	nsubj	we,generated
R1199	T1313	T1314	aux	have,generated
R1200	T1314	T1314	ROOT	generated,generated
R1201	T1315	T1318	compound	DT40,lines
R1202	T1316	T1318	compound	B,lines
R1203	T1317	T1318	compound	cell,lines
R1204	T1318	T1314	dobj	lines,generated
R1205	T1319	T1320	nsubj	that,lack
R1206	T1320	T1318	relcl	lack,lines
R1207	T1321	T1320	dobj	expression,lack
R1208	T1322	T1321	prep	of,expression
R1209	T1323	T1326	nummod	one,members
R1210	T1324	T1323	cc	or,one
R1211	T1325	T1323	conj	more,one
R1212	T1326	T1322	pobj	members,of
R1213	T1327	T1326	prep	of,members
R1214	T1328	T1330	det	the,family
R1215	T1329	T1330	compound	PKD,family
R1216	T1330	T1327	pobj	family,of
R1217	T1331	T1333	nmod	[,]
R1218	T1332	T1333	nummod	1,]
R1219	T1333	T1326	appos	],members
R1220	T1334	T1314	punct	",",generated
R1221	T1335	T1314	advcl	allowing,generated
R1222	T1336	T1338	nsubj	us,investigate
R1223	T1337	T1338	aux	to,investigate
R1224	T1338	T1335	ccomp	investigate,allowing
R1225	T1339	T1340	det	the,function
R1226	T1340	T1338	dobj	function,investigate
R1227	T1341	T1340	punct	(,function
R1228	T1342	T1340	appos	s,function
R1229	T1343	T1340	punct	),function
R1230	T1344	T1340	prep	of,function
R1231	T1345	T1344	pobj	PKD,of
R1232	T1346	T1344	pobj	isoforms,of
R1233	T1347	T1346	acl	following,isoforms
R1234	T1348	T1350	compound	B,antigen
R1235	T1349	T1350	compound	cell,antigen
R1236	T1350	T1351	compound	antigen,receptor
R1237	T1351	T1347	dobj	receptor,following
R1238	T1352	T1353	punct	(,BCR
R1239	T1353	T1351	appos	BCR,receptor
R1240	T1354	T1353	punct	),BCR
R1241	T1355	T1351	conj	stimulation,receptor
R1242	T1356	T1347	punct	",",following
R1243	T1357	T1359	advmod	as,addressing
R1244	T1358	T1359	advmod	well,addressing
R1245	T1359	T1338	advcl	addressing,investigate
R1246	T1360	T1361	det	the,issue
R1247	T1361	T1359	dobj	issue,addressing
R1248	T1362	T1361	prep	of,issue
R1249	T1363	T1364	amod	functional,redundancy
R1250	T1364	T1362	pobj	redundancy,of
R1251	T1365	T1364	prep	between,redundancy
R1252	T1366	T1370	det	the,members
R1253	T1367	T1370	amod	different,members
R1254	T1368	T1370	compound	PKD,members
R1255	T1369	T1370	compound	family,members
R1256	T1370	T1365	pobj	members,between
R1257	T1371	T1314	punct	.,generated
R1258	T1372	T1373	amod	Previous,studies
R1259	T1373	T1375	nsubj	studies,shown
R1261	T1374	T1375	aux	have,shown
R1264	T1375	T1375	ROOT	shown,shown
R1267	T1376	T1378	mark	that,are
R1275	T1377	T1378	nsubj	PKDs,are
R1279	T1378	T1375	ccomp	are,shown
R1284	T1379	T1378	acomp	indispensable,are
R1288	T1380	T1378	prep	for,are
R1292	T1381	T1382	compound	HDAC,regulation
R1296	T1382	T1380	pobj	regulation,for
R1298	T1383	T1382	prep	in,regulation
R1299	T1477	T1474	prep	in,ascribed
R1300	T1478	T1480	amod	other,systems
R1301	T1479	T1480	amod	cellular,systems
R1302	T1480	T1477	pobj	systems,in
R1303	T1384	T1385	compound	B,cells
R1304	T1481	T1455	punct	.,reveal
R1305	T1385	T1383	pobj	cells,in
R1306	T1386	T1388	nmod	[,]
R1307	T1387	T1388	nummod	1,]
R1308	T1388	T1382	appos	],regulation
R1309	T1389	T1375	punct	.,shown
R1310	T1390	T1392	npadvmod	Herein,show
R1311	T1391	T1392	nsubj	we,show
R1312	T1392	T1392	ROOT	show,show
R1313	T1393	T1395	mark	that,are
R1314	T1394	T1395	nsubj	PKDs,are
R1315	T1395	T1392	ccomp	are,show
R1316	T1396	T1395	advmod	also,are
R1317	T1397	T1395	acomp	indispensable,are
R1318	T1398	T1395	prep	for,are
R1319	T1399	T1400	compound	HSP27,phosphorylation
R1320	T1400	T1398	pobj	phosphorylation,for
R1321	T1401	T1400	prep	in,phosphorylation
R1322	T1402	T1403	compound	B,cells
R1323	T1403	T1401	pobj	cells,in
R1324	T1404	T1392	punct	.,show
R1325	T1405	T1411	advmod	However,are
R1326	T1406	T1411	punct	",",are
R1327	T1407	T1409	compound	PKD-null,B
R1328	T1408	T1409	compound	DT40,B
R1329	T1409	T1410	compound	B,cells
R1331	T1410	T1411	nsubj	cells,are
R1335	T1411	T1411	ROOT	are,are
R1336	T1412	T1411	acomp	viable,are
R1338	T1413	T1411	cc	and,are
R1340	T1414	T1411	conj	proliferate,are
R1341	T1415	T1414	advmod	normally,proliferate
R1342	T1416	T1411	punct	.,are
R1343	T1417	T1430	advmod	Moreover,affect
R1344	T1418	T1430	punct	",",affect
R1345	T1419	T1430	nsubj	loss,affect
R1347	T1420	T1419	prep	of,loss
R1351	T1421	T1424	det	the,pool
R1352	T1422	T1424	amod	entire,pool
R1355	T1423	T1424	amod	cellular,pool
R1356	T1424	T1420	pobj	pool,of
R1357	T1425	T1424	prep	of,pool
R1358	T1426	T1425	pobj	PKD,of
R1359	T1427	T1430	aux	does,affect
R1360	T1428	T1430	neg	not,affect
R1361	T1429	T1430	advmod	critically,affect
R1362	T1430	T1430	ROOT	affect,affect
R1365	T1431	T1433	amod	oxidative,responses
R1367	T1432	T1433	compound	stress,responses
R1369	T1433	T1430	dobj	responses,affect
R1371	T1434	T1433	prep	in,responses
R1373	T1435	T1436	compound	B,cells
R1374	T1436	T1434	pobj	cells,in
R1376	T1437	T1430	cc	nor,affect
R1378	T1438	T1441	aux	do,play
R1379	T1439	T1440	compound	PKD,kinases
R1380	T1440	T1441	nsubj	kinases,play
R1381	T1441	T1430	conj	play,affect
R1382	T1442	T1444	det	an,role
R1383	T1443	T1444	amod	essential,role
R1384	T1444	T1441	dobj	role,play
R1385	T1445	T1444	prep	in,role
R1387	T1446	T1445	pcomp	regulating,in
R1391	T1447	T1449	nmod	NFκB,activity
R1519	T1759	T1761	nummod	−,−
R1520	T1760	T1761	compound	/,−
R1521	T1761	T1757	pobj	−,of
R1522	T1762	T1765	punct	",",/
R1523	T1763	T1764	compound	PKD3,−
R1524	T1764	T1765	nsubj	−,/
R1525	T1765	T1765	ROOT	/,/
R1526	T1766	T1776	nummod	−,lines
R1527	T1767	T1766	cc	and,−
R1528	T1768	T1776	nummod	PKD1/3,lines
R1529	T1769	T1776	nummod	−,lines
R1530	T1770	T1772	nmod	/,knockout
R1531	T1771	T1772	compound	−,knockout
R1532	T1772	T1776	compound	knockout,lines
R1533	T1773	T1774	compound	DT40,B
R1534	T1774	T1775	compound	B,cell
R1535	T1775	T1776	compound	cell,lines
R1536	T1776	T1779	nsubjpass	lines,described
R1537	T1777	T1779	aux	have,described
R1538	T1778	T1779	auxpass	been,described
R1539	T1779	T1765	ccomp	described,/
R1540	T1780	T1783	advmod	previously,]
R1541	T1781	T1783	nmod	[,]
R1542	T1782	T1781	nummod	1,[
R1543	T1783	T1779	dobj	],described
R1544	T1784	T1765	punct	.,/
R1545	T1785	T1787	nsubjpass	Cells,lysed
R1546	T1786	T1787	auxpass	were,lysed
R1547	T1787	T1787	ROOT	lysed,lysed
R1548	T1788	T1787	cc	and,lysed
R1549	T1789	T1790	compound	protein,extracts
R1550	T1790	T1792	nsubjpass	extracts,analysed
R1551	T1791	T1792	auxpass	were,analysed
R1552	T1792	T1787	conj	analysed,lysed
R1553	T1793	T1792	prep	in,analysed
R1554	T1794	T1796	amod	Western,experiments
R1555	T1795	T1796	amod	blotting,experiments
R1556	T1796	T1793	pobj	experiments,in
R1557	T1797	T1799	mark	as,described
R1558	T1798	T1799	advmod	previously,described
R1559	T1799	T1792	advcl	described,analysed
R1560	T1800	T1802	nmod	[,]
R1561	T1801	T1802	nummod	1,]
R1562	T1802	T1799	dobj	],described
R1563	T1803	T1792	punct	.,analysed
R1564	T1804	T1807	nmod	Chloramphenicol,assays
R1565	T1805	T1807	nmod	acetyl,assays
R1566	T1806	T1807	compound	transferase,assays
R1567	T1807	T1810	nsubjpass	assays,described
R1568	T1808	T1810	aux	have,described
R1569	T1809	T1810	auxpass	been,described
R1570	T1810	T1810	ROOT	described,described
R1571	T1811	T1814	advmod	previously,]
R1572	T1812	T1814	nmod	[,]
R1573	T1813	T1814	nummod	29,]
R1574	T1814	T1810	dobj	],described
R1575	T1815	T1810	punct	.,described
R1664	T1940	T1944	amod	sIgM,cells
R1665	T1941	T1944	amod	staining,cells
R1666	T1942	T1943	compound	DT40,B
R1667	T1943	T1944	compound	B,cells
R1668	T1944	T1954	nsubjpass	cells,resuspended
R1669	T1945	T1944	punct	(,cells
R1670	T1946	T1949	nummod	2,cells
R1671	T1947	T1949	nummod	×,cells
R1677	T1953	T1954	auxpass	were,resuspended
R1678	T1954	T1954	ROOT	resuspended,resuspended
R1679	T1955	T1954	prep	in,resuspended
R1680	T1956	T1958	nummod	200,buffer
R1681	T1957	T1958	compound	μl,buffer
R1682	T1958	T1955	pobj	buffer,in
R1683	T1959	T1958	punct	(,buffer
R1684	T1960	T1962	compound	RPMI,media
R1685	T1961	T1962	compound	1640,media
R1686	T1962	T1958	appos	media,buffer
R1687	T1963	T1962	punct	",",media
R1688	T1964	T1965	nummod	1,%
R1689	T1965	T1968	nmod	%,serum
R1690	T1966	T1968	amod	foetal,serum
R1691	T1967	T1968	compound	calf,serum
R1692	T1968	T1962	appos	serum,media
R1693	T1969	T1962	punct	),media
R1694	T1970	T1958	acl	containing,buffer
R1695	T1971	T1975	amod	anti-chicken,conjugated
R1696	T1972	T1974	nummod	M1,antibody
R1697	T1973	T1974	amod	monoclonal,antibody
R1698	T1974	T1975	compound	antibody,conjugated
R1699	T1975	T1954	conj	conjugated,resuspended
R1700	T1976	T1975	prep	to,conjugated
R1701	T1977	T1976	pobj	FITC,to
R1702	T1978	T1975	prep	for,conjugated
R1703	T1979	T1980	nummod	20,min
R1704	T1980	T1978	pobj	min,for
R1705	T1981	T1980	prep	on,min
R1706	T1982	T1981	pobj	ice,on
R1707	T1983	T1954	punct	.,resuspended
R1708	T1984	T1985	det	The,cells
R1709	T1985	T1987	nsubjpass	cells,washed
R1710	T1986	T1987	auxpass	were,washed
R1711	T1987	T1987	ROOT	washed,washed
R1712	T1988	T1987	advmod	twice,washed
R1713	T1989	T1988	cc	and,twice
R1714	T1990	T1991	amod	fluorescent,intensity
R1715	T1991	T1993	nsubjpass	intensity,analysed
R1716	T1992	T1993	auxpass	was,analysed
R1717	T1993	T1987	conj	analysed,washed
R1718	T1994	T1993	agent	by,analysed
R1719	T1995	T1996	compound	flow,cytometry
R1720	T1996	T1994	pobj	cytometry,by
R1721	T1997	T1993	punct	.,analysed
R1722	T1998	T1999	det	All,results
R1723	T1999	T2001	nsubj	results,are
R1724	T2000	T1999	acl	shown,results
R1725	T2001	T2001	ROOT	are,are
R1726	T2002	T2001	attr	representative,are
R1727	T2003	T2002	prep	of,representative
R1728	T2004	T2001	prep	at,are
R1729	T2005	T2007	quantmod	two,four
R1730	T2006	T2007	quantmod	to,four
R1731	T2007	T2009	nummod	four,experiments
R1732	T2008	T2009	amod	independent,experiments
R1733	T2009	T2004	pobj	experiments,at
R1734	T2010	T2012	mark	unless,indicated
R1735	T2011	T2012	advmod	otherwise,indicated
R1736	T2012	T2001	advcl	indicated,are
R1737	T2013	T2001	punct	.,are
R2280	T2731	T2744	nsubj	Loss,kinases
R2281	T2732	T2731	prep	of,Loss
R2282	T2733	T2734	compound	HSP27,phosphorylation
R2283	T2734	T2732	pobj	phosphorylation,of
R2284	T2735	T2731	prep	in,Loss
R2285	T2736	T2737	compound	DT40,B
R2286	T2737	T2738	compound	B,cells
R2287	T2738	T2735	pobj	cells,in
R2288	T2739	T2744	advcl	lacking,kinases
R2289	T2740	T2739	dobj	expression,lacking
R2290	T2741	T2740	prep	of,expression
R2291	T2742	T2743	compound	PKD,family
R2292	T2743	T2741	pobj	family,of
R2293	T2744	T2744	ROOT	kinases,kinases
R2294	T2745	T2746	compound	DT40,B
R2295	T2746	T2747	compound	B,cells
R2296	T2747	T2748	nsubj	cells,express
R2297	T2748	T2744	ccomp	express,kinases
R2298	T2749	T2751	nummod	two,isoforms
R2299	T2750	T2751	compound	PKD,isoforms
R2300	T2751	T2748	dobj	isoforms,express
R2301	T2752	T2751	punct	",",isoforms
R2302	T2753	T2751	conj	PKD1,isoforms
R2303	T2754	T2753	cc	and,PKD1
R2304	T2755	T2753	conj	PKD3,PKD1
R2305	T2756	T2755	punct	",",PKD3
R2306	T2757	T2748	cc	and,express
R2307	T2758	T2760	mark	as,described
R2308	T2759	T2760	advmod	previously,described
R2309	T2760	T2764	advcl	described,generated
R2310	T2761	T2764	nsubj	we,generated
R2311	T2762	T2764	aux	have,generated
R2312	T2763	T2764	advmod	recently,generated
R2313	T2764	T2748	conj	generated,express
R2314	T2765	T2768	compound	DT40,lines
R2315	T2766	T2768	compound	B,lines
R2316	T2767	T2768	compound	cell,lines
R2317	T2768	T2764	dobj	lines,generated
R2318	T2769	T2770	nsubj	that,lack
R2319	T2770	T2768	relcl	lack,lines
R2320	T2771	T2770	dobj	expression,lack
R2321	T2772	T2771	prep	of,expression
R2322	T2773	T2774	det	either,PKD1
R2323	T2774	T2772	pobj	PKD1,of
R2324	T2775	T2774	cc	or,PKD1
R2325	T2776	T2774	conj	PKD3,PKD1
R2326	T2777	T2776	cc	or,PKD3
R2327	T2778	T2779	det	both,enzymes
R2328	T2779	T2772	pobj	enzymes,of
R2329	T2780	T2782	nmod	[,]
R2330	T2781	T2782	nummod	1,]
R2331	T2782	T2764	npadvmod	],generated
R2332	T2783	T2744	punct	.,kinases
R2333	T2784	T2800	prep	In,/
R2334	T2785	T2784	pcomp	generating,In
R2335	T2786	T2790	det	the,lines
R2336	T2787	T2789	amod	double,cell
R2337	T2788	T2789	compound	knockout,cell
R2338	T2789	T2790	compound	cell,lines
R2339	T2790	T2785	dobj	lines,generating
R2340	T2791	T2792	nsubj	we,targeted
R2341	T2792	T2790	relcl	targeted,lines
R2342	T2793	T2795	det	the,loci
R2343	T2794	T2795	compound	PKD1,loci
R2344	T2795	T2792	dobj	loci,targeted
R2345	T2796	T2792	prep	in,targeted
R2346	T2797	T2799	det	a,−
R2347	T2798	T2799	compound	PKD3,−
R2348	T2799	T2796	pobj	−,in
R2349	T2800	T2800	ROOT	/,/
R2350	T2801	T2803	nummod	−,line
R2351	T2802	T2803	compound	cell,line
R2352	T2803	T2800	dobj	line,/
R2353	T2804	T2805	nsubj	that,expressed
R2354	T2805	T2803	relcl	expressed,line
R2355	T2806	T2808	det	a,transgene
R2356	T2807	T2808	amod	Flag-PKD3,transgene
R2357	T2808	T2805	dobj	transgene,expressed
R2358	T2809	T2808	prep	under,transgene
R2359	T2810	T2811	det	the,control
R2360	T2811	T2809	pobj	control,under
R2361	T2812	T2811	prep	of,control
R2362	T2813	T2815	det	a,promoter
R2363	T2814	T2815	amod	doxycycline-inducible,promoter
R2364	T2815	T2812	pobj	promoter,of
R2365	T2816	T2800	punct	.,/
R2366	T2817	T2832	advmod	Hence,is
R2367	T2818	T2832	punct	",",is
R2368	T2819	T2826	nmod	in,expression
R2369	T2820	T2821	det	the,presence
R2370	T2821	T2819	pobj	presence,in
R2371	T2822	T2821	prep	of,presence
R2372	T2823	T2822	pobj	doxycycline,of
R2373	T2824	T2821	punct	",",presence
R2374	T2825	T2826	compound	Flag-PKD3,expression
R2375	T2826	T2832	nsubj	expression,is
R2376	T2827	T2826	prep	in,expression
R2377	T2828	T2831	nummod	PKD1/3,cells
R2378	T2829	T2831	amod	double,cells
R2379	T2830	T2831	compound	knockout,cells
R2380	T2831	T2827	pobj	cells,in
R2381	T2832	T2832	ROOT	is,is
R2382	T2833	T2832	acomp	comparable,is
R2383	T2834	T2833	prep	to,comparable
R2384	T2835	T2837	amod	endogenous,present
R2385	T2836	T2837	amod	PKD3,present
R2386	T2837	T2834	pobj	present,to
R2387	T2838	T2837	prep	in,present
R2388	T2839	T2841	amod	wild-type,cells
R2389	T2840	T2841	compound	DT40,cells
R2390	T2841	T2838	pobj	cells,in
R2391	T2842	T2837	cc	and,present
R2392	T2843	T2837	conj	removal,present
R2393	T2844	T2843	prep	of,removal
R2394	T2845	T2844	pobj	doxycycline,of
R2395	T2846	T2843	prep	from,removal
R2396	T2847	T2849	det	the,media
R2397	T2848	T2849	compound	culture,media
R2398	T2849	T2846	pobj	media,from
R2399	T2850	T2832	prep	for,is
R2400	T2851	T2852	nummod	5,days
R2401	T2852	T2853	compound	days,results
R2402	T2853	T2850	pobj	results,for
R2403	T2854	T2853	prep	in,results
R2404	T2855	T2859	det	a,phenotype
R2405	T2856	T2857	advmod	completely,null
R2406	T2857	T2859	amod	null,phenotype
R2407	T2858	T2859	compound	PKD,phenotype
R2408	T2859	T2854	pobj	phenotype,in
R2409	T2860	T2862	punct	(,1A
R2410	T2861	T2862	compound	Fig.,1A
R2411	T2862	T2859	appos	1A,phenotype
R2412	T2863	T2862	punct	),1A
R2413	T2864	T2832	punct	.,is
R2414	T2865	T2869	advmod	Previously,demonstrated
R2415	T2866	T2869	punct	",",demonstrated
R2416	T2867	T2869	nsubj	we,demonstrated
R2417	T2868	T2869	aux	have,demonstrated
R2418	T2869	T2869	ROOT	demonstrated,demonstrated
R2419	T2870	T2886	mark	that,is
R2420	T2871	T2886	nsubj	phosphorylation,is
R2421	T2872	T2871	cc	and,phosphorylation
R2422	T2873	T2874	amod	nuclear,exclusion
R2423	T2874	T2871	conj	exclusion,phosphorylation
R2424	T2875	T2874	prep	of,exclusion
R2425	T2876	T2879	nmod	class,deacetylases
R2426	T2877	T2879	nmod	II,deacetylases
R2427	T2878	T2879	compound	histone,deacetylases
R2428	T2879	T2875	pobj	deacetylases,of
R2429	T2880	T2879	punct	(,deacetylases
R2430	T2881	T2879	appos	HDACs,deacetylases
R2431	T2882	T2879	punct	),deacetylases
R2432	T2883	T2871	prep	during,phosphorylation
R2433	T2884	T2885	compound	BCR,engagement
R2434	T2885	T2883	pobj	engagement,during
R2435	T2886	T2869	ccomp	is,demonstrated
R2436	T2887	T2886	acomp	defective,is
R2437	T2888	T2886	prep	in,is
R2438	T2889	T2894	nummod	PKD1/3,cells
R2439	T2890	T2894	nummod	−,cells
R2440	T2891	T2894	nmod	/,cells
R2441	T2892	T2894	compound	−,cells
R2442	T2893	T2894	compound	B,cells
R2443	T2894	T2888	pobj	cells,in
R2444	T2895	T2886	cc	and,is
R2445	T2896	T2897	aux	can,restored
R2446	T2897	T2886	conj	restored,is
R2451	T2902	T2904	amod	single,isoform
R2488	T2939	T2936	prep	on,phosphorylation
R2489	T2940	T2939	pobj	serine,on
R2490	T2941	T2940	nummod	82,serine
R2491	T2942	T2936	punct	",",phosphorylation
R2492	T2943	T2947	det	the,sequence
R2493	T2944	T2947	amod	proposed,sequence
R2494	T2945	T2946	compound	PKD1,substrate
R2495	T2946	T2947	compound	substrate,sequence
R2496	T2947	T2936	appos	sequence,phosphorylation
R2497	T2948	T2929	punct	.,assessed
R2498	T2949	T2951	nsubj	We,investigated
R2499	T2950	T2951	advmod	initially,investigated
R2500	T2951	T2951	ROOT	investigated,investigated
R2501	T2952	T2953	det	the,regulation
R2502	T2953	T2951	dobj	regulation,investigated
R2503	T2954	T2953	prep	of,regulation
R2504	T2955	T2956	compound	HSP27,phosphorylation
R2505	T2956	T2954	pobj	phosphorylation,of
R2506	T2957	T2956	prep	in,phosphorylation
R2507	T2958	T2959	amod	single,knockout
R2508	T2959	T2962	compound	knockout,cells
R2509	T2960	T2961	compound	DT40,B
R2510	T2961	T2962	compound	B,cells
R2511	T2962	T2957	pobj	cells,in
R2512	T2963	T2951	advcl	lacking,investigated
R2513	T2964	T2965	preconj	either,PKD1
R2514	T2965	T2963	dobj	PKD1,lacking
R2515	T2966	T2965	cc	or,PKD1
R2516	T2967	T2965	conj	PKD3,PKD1
R2517	T2968	T2951	punct	.,investigated
R2518	T2969	T2970	mark	As,shown
R2519	T2970	T2985	advcl	shown,increased
R2520	T2971	T2970	prep	in,shown
R2521	T2972	T2973	compound	Fig.,1B
R2522	T2973	T2971	pobj	1B,in
R2523	T2974	T2973	punct	",",1B
R2524	T2975	T2973	appos	activation,1B
R2525	T2976	T2975	prep	of,activation
R2526	T2977	T2978	det	the,BCR
R2527	T2978	T2976	pobj	BCR,of
R2528	T2979	T2975	cc	or,activation
R2529	T2980	T2975	conj	treatment,activation
R2530	T2981	T2975	prep	with,activation
R2531	T2982	T2984	det	the,PdBu
R2532	T2983	T2984	compound	DAG-mimetic,PdBu
R2533	T2984	T2981	pobj	PdBu,with
R2534	T2985	T2985	ROOT	increased,increased
R2535	T2986	T2987	det	the,levels
R2536	T2987	T2985	dobj	levels,increased
R2537	T2988	T2987	prep	of,levels
R2538	T2989	T2990	compound	HSP27,phosphorylation
R2539	T2990	T2988	pobj	phosphorylation,of
R2540	T2991	T2987	prep	at,levels
R2541	T2992	T2991	pobj	S82,at
R2542	T2993	T2992	prep	in,S82
R2543	T2994	T2997	amod	wild-type,cells
R2544	T2995	T2996	compound	DT40,B
R2545	T2996	T2997	compound	B,cells
R2546	T2997	T2993	pobj	cells,in
R2547	T2998	T2985	punct	.,increased
R2548	T2999	T3004	nsubj	BCR,were
R2549	T3000	T2999	cc	and,BCR
R2550	T3001	T3003	amod	phorbol,signals
R2551	T3002	T3003	compound	ester,signals
R2552	T3003	T2999	conj	signals,BCR
R2553	T3004	T3004	ROOT	were,were
R2554	T3005	T3004	advmod	also,were
R2555	T3006	T3004	acomp	able,were
R2556	T3007	T3008	aux	to,increase
R2557	T3008	T3006	xcomp	increase,able
R2558	T3009	T3010	compound	HSP27,phosphorylation
R2559	T3010	T3008	dobj	phosphorylation,increase
R2560	T3011	T3008	prep	in,increase
R2561	T3012	T3016	nummod	PKD1,knockout
R2562	T3013	T3012	cc	or,PKD1
R2563	T3014	T3012	conj	PKD3,PKD1
R2564	T3015	T3016	amod	single,knockout
R2565	T3016	T3019	compound	knockout,cells
R2566	T3017	T3018	compound	DT40,B
R2567	T3018	T3019	compound	B,cells
R2568	T3019	T3011	pobj	cells,in
R2569	T3020	T3004	punct	(,were
R2570	T3021	T3022	compound	Fig.,1B
R2571	T3022	T3004	npadvmod	1B,were
R2572	T3023	T3004	punct	),were
R2573	T3024	T3004	punct	.,were
R2574	T3025	T3038	advmod	However,abolished
R2575	T3026	T3038	punct	",",abolished
R2576	T3027	T3038	nsubjpass	BCR,abolished
R2577	T3028	T3027	punct	-,BCR
R2578	T3029	T3027	cc	and,BCR
R2579	T3030	T3032	nmod	phorbol,phosphorylation
R2580	T3031	T3032	amod	ester-induced,phosphorylation
R2581	T3032	T3027	conj	phosphorylation,BCR
R2582	T3033	T3032	prep	of,phosphorylation
R2583	T3034	T3033	pobj	HSP27,of
R2584	T3035	T3032	prep	on,phosphorylation
R2585	T3036	T3035	pobj	S82,on
R2586	T3037	T3038	auxpass	was,abolished
R2587	T3038	T3038	ROOT	abolished,abolished
R2588	T3039	T3038	prep	in,abolished
R2589	T3040	T3041	compound	B,cells
R2590	T3041	T3039	pobj	cells,in
R2591	T3042	T3043	nsubj	that,lacked
R2592	T3043	T3041	relcl	lacked,cells
R2593	T3044	T3045	preconj	both,PKD1
R2594	T3045	T3043	dobj	PKD1,lacked
R2595	T3046	T3045	cc	and,PKD1
R2596	T3047	T3045	conj	PKD3,PKD1
R2597	T3048	T3047	punct	(,PKD3
R2598	T3049	T3050	compound	Fig.,1C
R2599	T3050	T3047	appos	1C,PKD3
R2600	T3051	T3047	punct	),PKD3
R2601	T3052	T3038	punct	.,abolished
R2602	T3053	T3066	advmod	Significantly,was
R2603	T3054	T3056	punct	",",expression
R2604	T3055	T3056	amod	doxycycline-induced,expression
R2605	T3056	T3066	nsubj	expression,was
R2606	T3057	T3056	prep	of,expression
R2607	T3058	T3060	det	the,transgene
R2608	T3059	T3060	compound	Flag-PKD3,transgene
R2609	T3060	T3057	pobj	transgene,of
R2610	T3061	T3060	prep	in,transgene
R2611	T3062	T3065	det	the,cells
R2612	T3063	T3065	amod	double,cells
R2613	T3064	T3065	compound	knockout,cells
R2614	T3065	T3061	pobj	cells,in
R2615	T3066	T3066	ROOT	was,was
R2616	T3067	T3066	acomp	sufficient,was
R2617	T3068	T3069	aux	to,restore
R2618	T3069	T3067	xcomp	restore,sufficient
R2619	T3070	T3071	amod	normal,regulation
R2620	T3071	T3069	dobj	regulation,restore
R2621	T3072	T3071	prep	of,regulation
R2622	T3073	T3074	compound	HSP27,phosphorylation
R2623	T3074	T3072	pobj	phosphorylation,of
R2624	T3075	T3077	punct	(,1C
R2625	T3076	T3077	compound	Fig.,1C
R2626	T3077	T3074	appos	1C,phosphorylation
R2627	T3078	T3077	punct	),1C
R2628	T3079	T3066	punct	.,was
R2629	T3080	T3095	prep	In,was
R2630	T3081	T3080	pobj	contrast,In
R2631	T3082	T3095	punct	",",was
R2632	T3083	T3095	nsubj	expression,was
R2633	T3084	T3083	prep	of,expression
R2634	T3085	T3089	det	a,protein
R2635	T3086	T3089	amod	kinase-deficient,protein
R2636	T3087	T3089	amod	PKD3,protein
R2637	T3088	T3089	amod	mutant,protein
R2638	T3089	T3084	pobj	protein,of
R2639	T3090	T3089	prep	in,protein
R2640	T3091	T3094	det	the,cells
R2641	T3092	T3094	amod	double,cells
R2642	T3093	T3094	compound	knockout,cells
R2643	T3094	T3090	pobj	cells,in
R2644	T3095	T3095	ROOT	was,was
R2645	T3096	T3095	neg	not,was
R2646	T3097	T3095	acomp	able,was
R2647	T3098	T3099	aux	to,restore
R2648	T3099	T3097	xcomp	restore,able
R2649	T3100	T3099	dobj	BCR,restore
R2650	T3101	T3100	punct	-,BCR
R2651	T3102	T3099	cc	or,restore
R2652	T3103	T3099	conj	phorbol,restore
R2653	T3104	T3106	amod	ester-induced,phosphorylation
R2654	T3105	T3106	compound	HSP27,phosphorylation
R2655	T3106	T3103	dobj	phosphorylation,phorbol
R2656	T3107	T3106	punct	(,phosphorylation
R2657	T3108	T3109	compound	Fig.,1D
R2658	T3109	T3106	appos	1D,phosphorylation
R2659	T3110	T3106	punct	),phosphorylation
R2660	T3111	T3095	punct	.,was
R2661	T3112	T3120	advmod	Hence,regulate
R2662	T3113	T3120	punct	",",regulate
R2663	T3114	T3120	nsubj	PKD3,regulate
R2664	T3115	T3117	advmod	as,as
R2665	T3116	T3117	advmod	well,as
R2666	T3117	T3114	cc	as,PKD3
R2667	T3118	T3114	conj	PKD1,PKD3
R2668	T3119	T3120	aux	can,regulate
R2669	T3120	T3120	ROOT	regulate,regulate
R2670	T3121	T3122	compound	HSP27,phosphorylation
R2671	T3122	T3120	dobj	phosphorylation,regulate
R2672	T3123	T3120	cc	and,regulate
R2673	T3124	T3120	prep	in,regulate
R2674	T3125	T3126	compound	DT40,B
R2675	T3126	T3127	compound	B,cells
R2676	T3127	T3124	pobj	cells,in
R2677	T3128	T3129	nsubj	they,are
R2678	T3129	T3120	conj	are,regulate
R2679	T3130	T3131	advmod	functionally,redundant
R2680	T3131	T3129	acomp	redundant,are
R2681	T3132	T3131	prep	as,redundant
R2682	T3133	T3134	compound	HSP27,kinases
R2683	T3134	T3132	pobj	kinases,as
R2684	T3135	T3129	punct	.,are
R3417	T4218	T4219	compound	Cellular,proliferation
R3418	T4219	T4231	nsubj	proliferation,kinases
R3419	T4220	T4219	cc	and,proliferation
R3420	T4221	T4219	conj	survival,proliferation
R3421	T4222	T4219	prep	in,proliferation
R3422	T4223	T4224	compound	DT40,B
R3423	T4224	T4225	compound	B,cells
R3424	T4225	T4222	pobj	cells,in
R3425	T4226	T4231	advcl	lacking,kinases
R3426	T4227	T4226	dobj	expression,lacking
R3427	T4228	T4227	prep	of,expression
R3428	T4229	T4230	compound	PKD,family
R3429	T4230	T4228	pobj	family,of
R3430	T4231	T4231	ROOT	kinases,kinases
R3431	T4232	T4233	compound	PKD,enzymes
R3432	T4233	T4237	nsubjpass	enzymes,linked
R3433	T4234	T4237	aux	have,linked
R3434	T4235	T4237	advmod	previously,linked
R3435	T4236	T4237	auxpass	been,linked
R3436	T4237	T4231	ccomp	linked,kinases
R3437	T4238	T4237	prep	to,linked
R3438	T4239	T4240	det	the,regulation
R3439	T4240	T4238	pobj	regulation,to
R3440	T4241	T4240	prep	of,regulation
R3441	T4242	T4243	compound	cell,proliferation
R3442	T4243	T4241	pobj	proliferation,of
R3443	T4244	T4243	cc	and,proliferation
R3444	T4245	T4243	conj	survival,proliferation
R3445	T4246	T4243	punct	(,proliferation
R3446	T4247	T4240	acl	reviewed,regulation
R3447	T4248	T4247	prep	in,reviewed
R3448	T4249	T4248	pobj	[,in
R3449	T4250	T4251	nummod	20,]
R3450	T4251	T4249	appos	],[
R3451	T4252	T4249	punct	),[
R3452	T4253	T4231	punct	.,kinases
R3453	T4254	T4255	aux	To,investigate
R3454	T4255	T4271	advcl	investigate,cultured
R3455	T4256	T4257	det	the,effect
R3456	T4257	T4255	dobj	effect,investigate
R3457	T4258	T4263	dobj	that,had
R3458	T4259	T4263	nsubj	loss,had
R3459	T4260	T4259	prep	of,loss
R3460	T4261	T4262	compound	PKD,kinases
R3461	T4262	T4260	pobj	kinases,of
R3462	T4263	T4257	relcl	had,effect
R3463	T4264	T4263	prep	on,had
R3464	T4265	T4267	compound	B,survival
R3465	T4266	T4267	compound	cell,survival
R3466	T4267	T4264	pobj	survival,on
R3467	T4268	T4263	cc	and/or,had
R3468	T4269	T4271	dobj	proliferation,cultured
R3469	T4270	T4271	nsubj	we,cultured
R3470	T4271	T4271	ROOT	cultured,cultured
R3471	T4272	T4275	amod	wild-type,cells
R3472	T4273	T4272	cc	and,wild-type
R3473	T4274	T4272	conj	PKD-null,wild-type
R3474	T4275	T4271	dobj	cells,cultured
R3475	T4276	T4271	prep	in,cultured
R3476	T4277	T4278	det	the,presence
R3477	T4278	T4276	pobj	presence,in
R3478	T4279	T4278	punct	(,presence
R3479	T4280	T4300	nsubj	PKD1/3,monitored
R3480	T4281	T4283	nummod	−,−
R3481	T4282	T4283	compound	/,−
R3482	T4283	T4300	dep	−,monitored
R3483	T4284	T4283	punct	:,−
R3484	T4285	T4287	nmod	Flag-PKD3,ve
R3485	T4286	T4287	compound	+,ve
R3486	T4287	T4283	appos	ve,−
R3487	T4288	T4287	punct	),ve
R3488	T4289	T4287	cc	or,ve
R3489	T4290	T4287	conj	absence,ve
R3490	T4291	T4290	punct	(,absence
R3491	T4292	T4295	nummod	PKD1/3,−
R3492	T4293	T4295	nummod	−,−
R3493	T4294	T4295	compound	/,−
R3494	T4295	T4290	appos	−,absence
R3495	T4296	T4295	punct	),−
R3496	T4297	T4290	prep	of,absence
R3497	T4298	T4297	pobj	doxycycline,of
R3498	T4299	T4290	cc	and,absence
R3499	T4300	T4271	advcl	monitored,cultured
R3500	T4301	T4302	amod	exponential,growth
R3501	T4302	T4300	dobj	growth,monitored
R3502	T4303	T4271	punct	.,cultured
R3503	T4304	T4305	mark	As,shown
R3504	T4305	T4311	advcl	shown,−
R3505	T4306	T4305	prep	in,shown
R3506	T4307	T4308	compound	Fig.,2A
R3507	T4308	T4306	pobj	2A,in
R3508	T4309	T4311	punct	",",−
R3509	T4310	T4311	nsubj	PKD1/3,−
R3510	T4311	T4311	ROOT	−,−
R3511	T4312	T4314	nummod	/,cells
R3512	T4313	T4314	compound	−,cells
R3513	T4314	T4315	nsubj	cells,proliferated
R3514	T4315	T4311	ccomp	proliferated,−
R3515	T4316	T4315	advmod	exponentially,proliferated
R3516	T4317	T4315	cc	and,proliferated
R3517	T4318	T4324	nsubj	re-expression,had
R3518	T4319	T4318	prep	of,re-expression
R3519	T4320	T4319	pobj	Flag-PKD3,of
R3520	T4321	T4318	prep	in,re-expression
R3521	T4322	T4323	det	these,cells
R3522	T4323	T4321	pobj	cells,in
R3523	T4324	T4315	conj	had,proliferated
R3524	T4325	T4326	det	no,impact
R3525	T4326	T4324	dobj	impact,had
R3526	T4327	T4326	prep	on,impact
R3527	T4328	T4329	det	the,rate
R3528	T4329	T4327	pobj	rate,on
R3529	T4330	T4329	prep	of,rate
R3530	T4331	T4330	pobj	proliferation,of
R3531	T4332	T4311	punct	.,−
R3532	T4333	T4347	advmod	Furthermore,was
R3533	T4334	T4347	punct	",",was
R3534	T4335	T4336	det	the,viability
R3535	T4336	T4347	nsubj	viability,was
R3536	T4337	T4336	prep	of,viability
R3537	T4338	T4343	nummod	PKD1/3,cells
R3538	T4339	T4343	nummod	−,cells
R3539	T4340	T4343	compound	/,cells
R3540	T4341	T4343	compound	−,cells
R3541	T4342	T4343	compound	B,cells
R3542	T4343	T4337	pobj	cells,of
R3543	T4344	T4336	prep	during,viability
R3544	T4345	T4346	amod	routine,culturing
R3545	T4346	T4344	pobj	culturing,during
R3546	T4347	T4347	ROOT	was,was
R3547	T4348	T4347	neg	not,was
R3548	T4349	T4350	advmod	significantly,different
R3549	T4350	T4347	acomp	different,was
R3550	T4351	T4350	prep	from,different
R3551	T4352	T4351	pobj	that,from
R3552	T4353	T4352	prep	of,that
R3553	T4354	T4356	amod	wild-type,cells
R3554	T4355	T4356	compound	B,cells
R3555	T4356	T4353	pobj	cells,of
R3556	T4357	T4360	punct	(,shown
R3557	T4358	T4360	nsubjpass	data,shown
R3558	T4359	T4360	neg	not,shown
R3559	T4360	T4347	conj	shown,was
R3560	T4361	T4360	punct	),shown
R3561	T4362	T4347	punct	.,was
R3562	T4363	T4365	nsubjpass	It,noted
R3563	T4364	T4365	auxpass	was,noted
R3564	T4365	T4365	ROOT	noted,noted
R3565	T4366	T4377	mark	that,was
R3566	T4367	T4370	det	the,time
R3567	T4368	T4369	compound	population,doubling
R3568	T4369	T4370	amod	doubling,time
R3569	T4370	T4377	nsubj	time,was
R3570	T4371	T4370	prep	of,time
R3571	T4372	T4376	nummod	PKD1/3,cells
R3572	T4373	T4376	nummod	−,cells
R3573	T4374	T4376	compound	/,cells
R3574	T4375	T4376	compound	−,cells
R3575	T4376	T4371	pobj	cells,of
R3576	T4377	T4365	ccomp	was,noted
R3577	T4378	T4379	advmod	slightly,slower
R3578	T4379	T4377	acomp	slower,was
R3579	T4380	T4379	prep	than,slower
R3580	T4381	T4380	pobj	that,than
R3581	T4382	T4381	prep	of,that
R3582	T4383	T4384	amod	wild,type
R3583	T4384	T4382	pobj	type,of
R3584	T4385	T4386	nummod	DT40,cells
R3585	T4386	T4384	appos	cells,type
R3586	T4387	T4386	punct	(,cells
R3587	T4388	T4391	nummod	12.7,h
R3588	T4389	T4391	nmod	±,h
R3589	T4390	T4391	nummod	2.8,h
R3590	T4391	T4386	appos	h,cells
R3591	T4392	T4391	prep	versus,h
R3592	T4393	T4396	nummod	10.2,h
R3593	T4394	T4396	nmod	±,h
R3594	T4395	T4396	nummod	0.4,h
R3595	T4396	T4392	pobj	h,versus
R3596	T4397	T4386	punct	),cells
R3597	T4398	T4365	cc	but,noted
R3598	T4399	T4400	det	the,failure
R3599	T4400	T4415	nsubj	failure,suggests
R3600	T4401	T4400	prep	of,failure
R3601	T4402	T4403	nummod	PKD3,re-expression
R3602	T4403	T4401	pobj	re-expression,of
R3603	T4404	T4405	aux	to,modify
R3604	T4405	T4400	acl	modify,failure
R3605	T4406	T4408	det	the,rate
R3606	T4407	T4408	compound	proliferation,rate
R3607	T4408	T4405	dobj	rate,modify
R3608	T4409	T4408	prep	of,rate
R3609	T4410	T4414	nummod	PKD1/3,cells
R3610	T4411	T4414	nummod	−,cells
R3611	T4412	T4414	compound	/,cells
R3612	T4413	T4414	compound	−,cells
R3613	T4414	T4409	pobj	cells,of
R3614	T4415	T4365	conj	suggests,noted
R3615	T4416	T4420	mark	that,were
R3616	T4417	T4419	det	these,differences
R3617	T4418	T4419	amod	small,differences
R3618	T4419	T4420	nsubj	differences,were
R3619	T4420	T4415	ccomp	were,suggests
R3620	T4421	T4422	advmod	most,likely
R3621	T4422	T4420	acomp	likely,were
R3622	T4423	T4424	det	the,result
R3623	T4424	T4420	attr	result,were
R3624	T4425	T4424	prep	of,result
R3625	T4426	T4427	amod	clonal,variation
R3626	T4427	T4425	pobj	variation,of
R3627	T4428	T4420	cc	and,were
R3628	T4429	T4431	auxpass	were,caused
R3629	T4430	T4431	neg	not,caused
R3630	T4431	T4420	conj	caused,were
R3631	T4432	T4431	advmod	specifically,caused
R3632	T4433	T4431	agent	by,caused
R3633	T4434	T4433	pobj	loss,by
R3634	T4435	T4434	prep	of,loss
R3635	T4436	T4437	compound	PKD,enzymes
R3636	T4437	T4435	pobj	enzymes,of
R3637	T4438	T4415	punct	.,suggests
R3638	T4439	T4444	advmod	Thus,are
R3639	T4440	T4444	punct	",",are
R3640	T4441	T4443	compound	PKD,enzymes
R3641	T4442	T4443	compound	family,enzymes
R3642	T4443	T4444	nsubj	enzymes,are
R3643	T4444	T4444	ROOT	are,are
R3644	T4445	T4444	neg	not,are
R3645	T4446	T4444	acomp	essential,are
R3646	T4447	T4446	prep	for,essential
R3647	T4448	T4447	pcomp	regulating,for
R3648	T4449	T4450	amod	basal,survival
R3649	T4450	T4448	dobj	survival,regulating
R3650	T4451	T4450	cc	and,survival
R3658	T4459	T4469	nsubj	enzymes,linked
R3659	T4460	T4459	punct	",",enzymes
R3660	T4461	T4462	advmod	specifically,PKD1
R3661	T4462	T4459	appos	PKD1,enzymes
R3662	T4463	T4462	cc	and,PKD1
R3663	T4464	T4462	conj	PKD2,PKD1
R3664	T4465	T4469	punct	",",linked
R3665	T4466	T4469	aux	have,linked
R3666	T4467	T4469	advmod	previously,linked
R3667	T4468	T4469	auxpass	been,linked
R3668	T4469	T4469	ROOT	linked,linked
R3669	T4470	T4469	prep	to,linked
R3670	T4471	T4473	det	a,role
R3671	T4472	T4473	amod	protective,role
R3672	T4473	T4470	pobj	role,to
R3673	T4474	T4473	prep	against,role
R3674	T4475	T4477	amod	oxidative,injury
R3675	T4476	T4477	amod	stress-induced,injury
R3676	T4477	T4486	nmod	injury,lines
R3677	T4478	T4477	prep	in,injury
R3678	T4479	T4480	compound	3T3,fibroblast
R3679	T4480	T4478	pobj	fibroblast,in
R3680	T4481	T4480	punct	",",fibroblast
R3681	T4482	T4480	conj	HeLa,fibroblast
R3682	T4483	T4482	cc	and,HeLa
R3683	T4484	T4486	amod	epithelial,lines
R3684	T4485	T4486	compound	cell,lines
R3685	T4486	T4474	pobj	lines,against
R3686	T4487	T4488	compound	[,"17,30"
R3687	T4488	T4486	appos	"17,30",lines
R3688	T4489	T4490	nummod	32,]
R3689	T4490	T4486	appos	],lines
R3690	T4491	T4469	punct	.,linked
R3691	T4492	T4494	nsubj	We,addressed
R3692	T4493	T4494	advmod	therefore,addressed
R3693	T4494	T4494	ROOT	addressed,addressed
R3694	T4495	T4496	det	the,role
R3695	T4496	T4494	dobj	role,addressed
R3696	T4497	T4496	prep	of,role
R3697	T4498	T4499	compound	PKD,family
R3698	T4499	T4500	compound	family,kinases
R3699	T4500	T4497	pobj	kinases,of
R3700	T4501	T4496	prep	in,role
R3701	T4502	T4501	pcomp	regulating,in
R3702	T4503	T4504	compound	B,cell
R3703	T4504	T4505	compound	cell,survival
R3704	T4505	T4502	dobj	survival,regulating
R3705	T4506	T4502	prep	in,regulating
R3706	T4507	T4506	pobj	response,in
R3707	T4508	T4507	prep	to,response
R3708	T4509	T4510	amod	oxidative,stress
R3709	T4510	T4508	pobj	stress,to
R3710	T4511	T4510	cc	and,stress
R3711	T4512	T4514	amod	other,stimuli
R3712	T4513	T4514	compound	stress,stimuli
R3713	T4514	T4510	conj	stimuli,stress
R3714	T4515	T4494	punct	.,addressed
R3715	T4516	T4517	mark	As,shown
R3716	T4517	T4526	advcl	shown,had
R3717	T4518	T4517	prep	in,shown
R3718	T4519	T4520	compound	Fig.,2B
R3719	T4520	T4518	pobj	2B,in
R3720	T4521	T4520	punct	",",2B
R3721	T4522	T4520	appos	loss,2B
R3722	T4523	T4522	prep	of,loss
R3723	T4524	T4525	nummod	PKD1/3,expression
R3724	T4525	T4523	pobj	expression,of
R3725	T4526	T4526	ROOT	had,had
R3726	T4527	T4529	det	no,impact
R3727	T4528	T4529	amod	significant,impact
R3728	T4529	T4526	dobj	impact,had
R3729	T4530	T4529	prep	on,impact
R3730	T4531	T4532	det	the,survival
R3731	T4532	T4530	pobj	survival,on
R3732	T4533	T4532	prep	of,survival
R3733	T4534	T4535	compound	DT40,B
R3734	T4535	T4536	compound	B,cells
R3735	T4536	T4533	pobj	cells,of
R3736	T4537	T4526	prep	in,had
R3737	T4538	T4537	pobj	response,in
R3738	T4539	T4538	prep	to,response
R3739	T4540	T4542	amod	mitochondrial,stimuli
R3740	T4541	T4542	compound	stress,stimuli
R3741	T4542	T4539	pobj	stimuli,to
R3742	T4543	T4542	punct	(,stimuli
R3743	T4544	T4542	appos	H2O2,stimuli
R3744	T4545	T4544	cc	or,H2O2
R3745	T4546	T4547	compound	serum,deprivation
R3746	T4547	T4544	conj	deprivation,H2O2
R3747	T4548	T4542	punct	),stimuli
R3748	T4549	T4542	punct	;,stimuli
R3749	T4550	T4552	amod	DNA,agents
R3750	T4551	T4552	amod	damaging,agents
R3751	T4552	T4542	conj	agents,stimuli
R3752	T4553	T4552	punct	(,agents
R3753	T4554	T4552	appos	etoposide,agents
R3754	T4555	T4554	cc	or,etoposide
R3755	T4556	T4554	conj	doxorubicin,etoposide
R3756	T4557	T4552	punct	),agents
R3757	T4558	T4526	punct	;,had
R3758	T4559	T4561	compound	ER,stress
R3759	T4560	T4561	compound	pathway,stress
R3760	T4561	T4570	nsubj	stress,following
R3761	T4562	T4561	amod	due,stress
R3762	T4563	T4562	pcomp	to,due
R3763	T4564	T4565	compound	calcium,overload
R3764	T4565	T4562	pobj	overload,due
R3765	T4566	T4567	punct	(,thapsigargin
R3766	T4567	T4565	appos	thapsigargin,overload
R3767	T4568	T4567	punct	),thapsigargin
R3768	T4569	T4565	cc	or,overload
R3769	T4570	T4526	advcl	following,had
R3770	T4571	T4572	amod	prolonged,treatment
R3771	T4572	T4570	dobj	treatment,following
R3772	T4573	T4572	prep	with,treatment
R3773	T4574	T4575	compound	phorbol,esters
R3774	T4575	T4573	pobj	esters,with
R3775	T4576	T4575	cc	or,esters
R3776	T4577	T4578	compound	Trichostatin,A
R3777	T4578	T4575	conj	A,esters
R3778	T4579	T4578	punct	",",A
R3779	T4580	T4581	det	an,inhibitor
R3780	T4581	T4578	appos	inhibitor,A
R3781	T4582	T4581	prep	of,inhibitor
R3782	T4583	T4585	compound	class,HDACs
R3783	T4584	T4585	compound	I/II,HDACs
R3784	T4585	T4582	pobj	HDACs,of
R3785	T4586	T4526	punct	.,had
R3786	T4587	T4593	advmod	Thus,play
R3787	T4588	T4593	punct	",",play
R3788	T4589	T4590	compound	PKD,kinases
R3789	T4590	T4593	nsubj	kinases,play
R3790	T4591	T4593	aux	do,play
R3791	T4592	T4593	neg	not,play
R3792	T4593	T4593	ROOT	play,play
R3793	T4594	T4596	det	an,role
R3794	T4595	T4596	amod	essential,role
R3795	T4596	T4593	dobj	role,play
R3796	T4597	T4593	prep	in,play
R3797	T4598	T4597	pcomp	regulating,in
R3798	T4599	T4600	compound	B,cell
R3799	T4600	T4601	compound	cell,survival
R3800	T4601	T4598	dobj	survival,regulating
R3801	T4602	T4598	prep	in,regulating
R3802	T4603	T4602	pobj	response,in
R3803	T4604	T4603	prep	to,response
R3804	T4605	T4606	det	a,range
R3805	T4606	T4604	pobj	range,to
R3806	T4607	T4606	prep	of,range
R3807	T4608	T4610	amod	different,stimuli
R3808	T4609	T4610	compound	stress,stimuli
R3809	T4610	T4607	pobj	stimuli,of
R3810	T4611	T4593	punct	.,play
R4622	T5769	T5770	compound	Antigen,receptor
R4623	T5770	T5773	amod	receptor,pathways
R4624	T5771	T5773	amod	regulated,pathways
R4625	T5772	T5773	amod	signalling,pathways
R4626	T5773	T5781	nsubj	pathways,explore
R4627	T5774	T5773	prep	in,pathways
R4628	T5775	T5777	compound	PKD-null,B
R4629	T5776	T5777	compound	DT40,B
R4630	T5777	T5778	compound	B,cells
R4631	T5778	T5774	pobj	cells,in
R4632	T5779	T5781	aux	To,explore
R4633	T5780	T5781	advmod	further,explore
R4634	T5781	T5781	ROOT	explore,explore
R4635	T5782	T5783	det	the,contribution
R4636	T5783	T5781	dobj	contribution,explore
R4637	T5784	T5783	prep	of,contribution
R4638	T5785	T5786	compound	PKD,kinases
R4639	T5786	T5784	pobj	kinases,of
R4640	T5787	T5786	prep	to,kinases
R4641	T5788	T5791	compound	DT40,biology
R4642	T5789	T5791	compound	B,biology
R4643	T5790	T5791	compound	cell,biology
R4644	T5791	T5787	pobj	biology,to
R4645	T5792	T5793	nsubj	we,investigated
R4646	T5793	T5783	relcl	investigated,contribution
R4647	T5794	T5799	mark	whether,were
R4648	T5795	T5798	amod	specific,events
R4649	T5796	T5798	amod	BCR-regulated,events
R4650	T5797	T5798	amod	signalling,events
R4651	T5798	T5799	nsubj	events,were
R4652	T5799	T5793	ccomp	were,investigated
R4653	T5800	T5799	acomp	defective,were
R4654	T5801	T5800	prep	in,defective
R4655	T5802	T5805	det	the,cells
R4656	T5803	T5804	compound	PKD-null,B
R4657	T5804	T5805	compound	B,cells
R4658	T5805	T5801	pobj	cells,in
R4659	T5806	T5781	punct	.,explore
R4660	T5807	T5808	amod	Initial,experiments
R4661	T5808	T5809	nsubj	experiments,revealed
R4662	T5809	T5809	ROOT	revealed,revealed
R4663	T5810	T5817	mark	that,reduced
R4664	T5811	T5812	compound	surface,expression
R4665	T5812	T5817	nsubjpass	expression,reduced
R4666	T5813	T5812	prep	of,expression
R4667	T5814	T5815	det	the,BCR
R4668	T5815	T5813	pobj	BCR,of
R4669	T5816	T5817	auxpass	was,reduced
R4670	T5817	T5809	ccomp	reduced,revealed
R4671	T5818	T5817	prep	in,reduced
R4672	T5819	T5822	nummod	PKD1/3,−
R4673	T5820	T5822	nummod	−,−
R4674	T5821	T5822	compound	/,−
R4675	T5822	T5818	pobj	−,in
R4676	T5823	T5822	punct	(,−
R4677	T5824	T5818	cc	and,in
R4678	T5825	T5817	prep	in,reduced
R4679	T5826	T5835	nummod	PKD1/3,cells
R4680	T5827	T5829	nummod	−,−
R4681	T5828	T5829	compound	/,−
R4682	T5829	T5835	nummod	−,cells
R4683	T5830	T5829	punct	:,−
R4684	T5831	T5829	appos	Flag-PKD3,−
R4685	T5832	T5833	advmod	+,ve
R4686	T5833	T5829	appos	ve,−
R4687	T5834	T5829	punct	),−
R4688	T5835	T5825	pobj	cells,in
R4689	T5836	T5817	prep	compared,reduced
R4690	T5837	T5836	prep	to,compared
R4691	T5838	T5841	amod	wild-type,cells
R4692	T5839	T5840	compound	DT40,B
R4693	T5840	T5841	compound	B,cells
R4694	T5841	T5837	pobj	cells,to
R4695	T5842	T5841	punct	(,cells
R4696	T5843	T5844	compound	Fig.,3A
R4697	T5844	T5841	appos	3A,cells
R4698	T5845	T5844	cc	and,3A
R4699	T5846	T5848	nsubj	data,shown
R4700	T5847	T5848	neg	not,shown
R4701	T5848	T5841	relcl	shown,cells
R4702	T5849	T5817	punct	),reduced
R4703	T5850	T5809	punct	.,revealed
R4704	T5851	T5860	advmod	Nevertheless,was
R4705	T5852	T5860	punct	",",was
R4706	T5853	T5860	nsubj	BCR-crosslinking,was
R4707	T5854	T5853	prep	of,BCR-crosslinking
R4708	T5855	T5859	nummod	PKD1/3,cells
R4709	T5856	T5859	nummod	−,cells
R4710	T5857	T5859	nmod	/,cells
R4711	T5858	T5859	amod	−,cells
R4712	T5859	T5854	pobj	cells,of
R4713	T5860	T5860	ROOT	was,was
R4714	T5861	T5860	acomp	sufficient,was
R4715	T5862	T5863	aux	to,induce
R4716	T5863	T5861	xcomp	induce,sufficient
R4717	T5864	T5865	det	the,activation
R4718	T5865	T5863	dobj	activation,induce
R4719	T5866	T5865	prep	of,activation
R4720	T5867	T5868	det	a,number
R4721	T5868	T5866	pobj	number,of
R4722	T5869	T5868	prep	of,number
R4723	T5870	T5869	pcomp	signalling,of
R4724	T5871	T5870	dobj	cascades,signalling
R4725	T5872	T5871	punct	",",cascades
R4726	T5873	T5871	amod	similar,cascades
R4727	T5874	T5873	prep	to,similar
R4728	T5875	T5876	nsubj	that,observed
R4729	T5876	T5871	relcl	observed,cascades
R4730	T5877	T5876	prep	in,observed
R4731	T5878	T5879	amod	wild-type,cells
R4732	T5879	T5877	pobj	cells,in
R4733	T5880	T5871	punct	(,cascades
R4734	T5881	T5882	compound	Fig.,3B
R4735	T5882	T5871	appos	3B,cascades
R4736	T5883	T5871	punct	),cascades
R4737	T5884	T5860	punct	.,was
R4738	T5885	T5888	advmod	Hence,activation
R4739	T5886	T5888	punct	",",activation
R4740	T5887	T5888	amod	BCR-induced,activation
R4741	T5888	T5909	nsubj	activation,was
R4742	T5889	T5888	prep	of,activation
R4743	T5890	T5891	det	the,Akt
R4744	T5891	T5889	pobj	Akt,of
R4745	T5892	T5891	punct	",",Akt
R4746	T5893	T5895	compound	mTOR/p70,kinase
R4747	T5894	T5895	compound	S6,kinase
R4748	T5895	T5891	appos	kinase,Akt
R4749	T5896	T5898	punct	(,shown
R4750	T5897	T5898	mark	as,shown
R4751	T5898	T5888	advcl	shown,activation
R4752	T5899	T5898	agent	by,shown
R4753	T5900	T5908	nummod	S6,pathways
R4754	T5901	T5902	amod	ribosomal,protein
R4755	T5902	T5908	nmod	protein,pathways
R4756	T5903	T5902	appos	phosphorylation,protein
R4757	T5904	T5902	punct	),protein
R4758	T5905	T5902	cc	and,protein
R4759	T5906	T5902	conj	MAPK,protein
R4760	T5907	T5908	amod	signalling,pathways
R4761	T5908	T5899	pobj	pathways,by
R4762	T5909	T5909	ROOT	was,was
R4763	T5910	T5909	advmod	clearly,was
R4764	T5911	T5909	acomp	detectable,was
R4765	T5912	T5911	prep	in,detectable
R4766	T5913	T5914	compound	PKD1/3-null,B
R4767	T5914	T5915	compound	B,cells
R4768	T5915	T5912	pobj	cells,in
R4769	T5916	T5918	punct	(,3B
R4770	T5917	T5918	compound	Fig.,3B
R4771	T5918	T5911	appos	3B,detectable
R4772	T5919	T5918	punct	),3B
R4773	T5920	T5909	punct	.,was
R4774	T5921	T5941	advmod	Furthermore,observed
R4775	T5922	T5941	punct	",",observed
R4776	T5923	T5925	amod	enhanced,phosphorylation
R4777	T5924	T5925	compound	tyrosine,phosphorylation
R4778	T5925	T5941	nsubjpass	phosphorylation,observed
R4779	T5926	T5925	prep	of,phosphorylation
R4780	T5927	T5929	amod	multiple,proteins
R4781	T5928	T5929	amod	cellular,proteins
R4782	T5929	T5926	pobj	proteins,of
R4783	T5930	T5932	advmod	as,as
R4784	T5931	T5932	advmod	well,as
R4785	T5932	T5925	cc	as,phosphorylation
R4786	T5933	T5934	det	an,increase
R4787	T5934	T5925	conj	increase,phosphorylation
R4788	T5935	T5934	prep	in,increase
R4789	T5936	T5938	amod	intracellular,levels
R4790	T5937	T5938	compound	calcium,levels
R4791	T5938	T5935	pobj	levels,in
R4792	T5939	T5941	auxpass	was,observed
R4793	T5940	T5941	advmod	also,observed
R4794	T5941	T5941	ROOT	observed,observed
R4795	T5942	T5941	prep	following,observed
R4796	T5943	T5944	compound	BCR,stimulation
R4797	T5944	T5942	pobj	stimulation,following
R4798	T5945	T5944	prep	of,stimulation
R4799	T5946	T5948	nmod	PKD1/3-null,cells
R4800	T5947	T5948	compound	B,cells
R4801	T5948	T5945	pobj	cells,of
R4802	T5949	T5950	punct	(,data
R4803	T5950	T5948	appos	data,cells
R4804	T5951	T5952	neg	not,shown
R4805	T5952	T5950	acl	shown,data
R4806	T5953	T5950	punct	),data
R4807	T5954	T5941	punct	.,observed
R4808	T5955	T5957	nsubj	We,observe
R4809	T5956	T5957	aux	did,observe
R4810	T5957	T5957	ROOT	observe,observe
R4811	T5958	T5970	mark	that,induced
R4812	T5959	T5960	det	the,strength
R4813	T5960	T5970	nsubj	strength,induced
R4814	T5961	T5960	prep	of,strength
R4815	T5962	T5961	pobj	BCR,of
R4816	T5963	T5960	punct	(,strength
R4817	T5964	T5960	cc	but,strength
R4818	T5965	T5966	neg	not,phorbol
R4819	T5966	T5967	advmod	phorbol,ester
R4820	T5967	T5960	conj	ester,strength
R4821	T5968	T5960	punct	),strength
R4822	T5969	T5970	punct	-,induced
R4823	T5970	T5957	ccomp	induced,observe
R4824	T5971	T5970	dobj	regulation,induced
R4825	T5972	T5971	prep	of,regulation
R4826	T5973	T5976	det	the,pathway
R4827	T5974	T5976	amod	Erk1-RSK1,pathway
R4828	T5975	T5976	compound	signalling,pathway
R4829	T5976	T5972	pobj	pathway,of
R4830	T5977	T5978	auxpass	was,reduced
R4831	T5978	T5970	conj	reduced,induced
R4832	T5979	T5978	prep	in,reduced
R4833	T5980	T5985	nummod	PKD1/3,cells
R4834	T5981	T5985	nummod	−,cells
R4835	T5982	T5985	compound	/,cells
R4836	T5983	T5985	compound	−,cells
R4837	T5984	T5985	compound	B,cells
R4838	T5985	T5979	pobj	cells,in
R4839	T5986	T5978	prep	compared,reduced
R4840	T5987	T5986	prep	to,compared
R4841	T5988	T5990	amod	wild-type,cells
R4842	T5989	T5990	compound	B,cells
R4843	T5990	T5987	pobj	cells,to
R4844	T5991	T5993	punct	(,3B
R4845	T5992	T5993	compound	Fig.,3B
R4846	T5993	T5990	appos	3B,cells
R4847	T5994	T5990	punct	),cells
R4848	T5995	T5957	punct	.,observe
R4849	T5996	T5997	nummod	One,interpretation
R4854	T6001	T6001	ROOT	is,is
R4855	T6002	T6006	mark	that,modulate
R4856	T6003	T6004	compound	PKD,enzymes
R4857	T6004	T6006	nsubj	enzymes,modulate
R4858	T6005	T6006	aux	may,modulate
R4859	T6006	T6001	ccomp	modulate,is
R4860	T6007	T6008	compound	Erk,activation
R4861	T6008	T6006	dobj	activation,modulate
R4862	T6009	T6001	punct	.,is
R4863	T6010	T6017	advmod	Indeed,linked
R4864	T6011	T6017	punct	",",linked
R4865	T6012	T6013	compound	PKD,enzymes
R4866	T6013	T6017	nsubj	enzymes,linked
R4867	T6014	T6017	aux	have,linked
R4868	T6015	T6017	advmod	previously,linked
R4869	T6016	T6017	auxpass	been,linked
R4870	T6017	T6017	ROOT	linked,linked
R4871	T6018	T6017	prep	to,linked
R4872	T6019	T6020	det	the,growth
R4873	T6020	T6018	pobj	growth,to
R4874	T6021	T6023	amod	factor-regulated,signalling
R4875	T6022	T6023	compound	Erk,signalling
R4876	T6023	T6017	dobj	signalling,linked
R4877	T6024	T6023	prep	in,signalling
R4878	T6025	T6029	nmod	fibroblast,lines
R4879	T6026	T6025	cc	and,fibroblast
R4880	T6027	T6029	amod	endothelial,lines
R4881	T6028	T6029	compound	cell,lines
R4882	T6029	T6024	pobj	lines,in
R4883	T6030	T6023	dobj	[,signalling
R4884	T6031	T6030	nummod	33,[
R4885	T6032	T6033	nummod	35,]
R4886	T6033	T6030	appos	],[
R4887	T6034	T6017	punct	.,linked
R4888	T6035	T6042	advmod	However,reduced
R4889	T6036	T6042	punct	",",reduced
R4890	T6037	T6039	amod	BCR-induced,phosphorylation
R4891	T6038	T6039	compound	Erk,phosphorylation
R4892	T6039	T6042	nsubjpass	phosphorylation,reduced
R4893	T6040	T6042	auxpass	was,reduced
R4894	T6041	T6042	advmod	also,reduced
R4895	T6042	T6042	ROOT	reduced,reduced
R4896	T6043	T6042	prep	in,reduced
R4897	T6044	T6052	nummod	PKD1/3,cells
R4898	T6045	T6046	nummod	−,/
R4899	T6046	T6052	compound	/,cells
R4900	T6047	T6049	punct	−,Flag-PKD3
R4901	T6048	T6049	punct	-,Flag-PKD3
R4902	T6049	T6052	compound	Flag-PKD3,cells
R4903	T6050	T6052	compound	+,cells
R4904	T6051	T6052	compound	B,cells
R4905	T6052	T6043	pobj	cells,in
R4906	T6053	T6052	punct	(,cells
R4907	T6054	T6054	ROOT	data,data
R4908	T6055	T6056	neg	not,shown
R4909	T6056	T6054	acl	shown,data
R4910	T6057	T6054	punct	),data
R4911	T6058	T6042	advcl	suggesting,reduced
R4912	T6059	T6074	mark	that,−
R4913	T6060	T6062	amod	reduced,levels
R4914	T6061	T6062	compound	BCR,levels
R4915	T6062	T6074	nsubj	levels,−
R4916	T6063	T6062	prep	on,levels
R4917	T6064	T6065	det	the,surface
R4918	T6065	T6063	pobj	surface,on
R4919	T6066	T6065	prep	of,surface
R4920	T6067	T6070	nummod	PKD1/3,−
R4921	T6068	T6070	nummod	−,−
R4922	T6069	T6070	compound	/,−
R4923	T6070	T6066	pobj	−,of
R4924	T6071	T6070	punct	(,−
R4925	T6072	T6070	cc	and,−
R4926	T6073	T6074	nsubj	PKD1/3,−
R4927	T6074	T6058	ccomp	−,suggesting
R4928	T6075	T6079	nummod	/,+
R4929	T6076	T6078	punct	−,Flag-PKD3
R4930	T6077	T6078	punct	-,Flag-PKD3
R4939	T6086	T6085	prep	on,impact
R4940	T6087	T6088	det	the,strength
R4941	T6088	T6086	pobj	strength,on
R4942	T6089	T6088	prep	of,strength
R4943	T6090	T6089	pobj	activation,of
R4944	T6091	T6090	prep	of,activation
R4945	T6092	T6096	det	this,pathway
R4946	T6093	T6096	amod	specific,pathway
R4947	T6094	T6096	amod	intracellular,pathway
R4948	T6095	T6096	compound	signalling,pathway
R4949	T6096	T6091	pobj	pathway,of
R4950	T6097	T6085	punct	.,impact
R4951	T6098	T6099	aux	To,search
R4952	T6099	T6120	advcl	search,used
R4953	T6100	T6099	prep	for,search
R4954	T6101	T6104	amod	other,targets
R4955	T6102	T6104	amod	potential,targets
R4956	T6103	T6104	compound	PKD,targets
R4957	T6104	T6100	pobj	targets,for
R4958	T6105	T6107	nsubj	that,show
R4959	T6106	T6107	aux	may,show
R4960	T6107	T6104	relcl	show,targets
R4961	T6108	T6109	amod	defective,regulation
R4962	T6109	T6107	dobj	regulation,show
R4963	T6110	T6109	prep	in,regulation
R4964	T6111	T6116	compound	PKD1/3,B
R4965	T6112	T6116	compound	−,B
R4966	T6113	T6116	compound	/,B
R4967	T6114	T6116	compound	−,B
R4968	T6115	T6116	compound	DT40,B
R4969	T6116	T6117	compound	B,cells
R4970	T6117	T6110	pobj	cells,in
R4971	T6118	T6120	punct	",",used
R4972	T6119	T6120	nsubj	we,used
R4973	T6120	T6120	ROOT	used,used
R4974	T6121	T6123	det	a,substrate
R4975	T6122	T6123	compound	PKD,substrate
R4976	T6123	T6120	dobj	substrate,used
R4977	T6124	T6123	amod	phospho-antibody,substrate
R4978	T6125	T6126	nsubj	that,recognises
R4979	T6126	T6124	relcl	recognises,phospho-antibody
R4980	T6127	T6129	compound	consensus,sequences
R4981	T6128	T6129	compound	phosphorylation,sequences
R4982	T6129	T6126	dobj	sequences,recognises
R4983	T6130	T6129	acl	targeted,sequences
R4984	T6131	T6130	agent	by,targeted
R4985	T6132	T6133	compound	PKD,enzymes
R4986	T6133	T6131	pobj	enzymes,by
R4987	T6134	T6137	punct	(,[
R4988	T6135	T6137	nmod	LxRxxpS/T,[
R4989	T6136	T6137	punct	),[
R4990	T6137	T6133	appos	[,enzymes
R4991	T6138	T6139	nummod	36,]
R4992	T6139	T6137	appos	],[
R4993	T6140	T6120	punct	.,used
R4994	T6141	T6142	mark	As,shown
R4995	T6142	T6160	advcl	shown,was
R4996	T6143	T6142	prep	in,shown
R4997	T6144	T6145	compound	Fig.,3C
R4998	T6145	T6143	pobj	3C,in
R4999	T6146	T6145	punct	",",3C
R5000	T6147	T6160	nsubj	phorbol,was
R5001	T6148	T6160	nsubj	ester,was
R5002	T6149	T6148	punct	-,ester
R5003	T6150	T6148	cc	and,ester
R5004	T6151	T6152	amod	BCR-induced,phosphorylation
R5005	T6152	T6148	conj	phosphorylation,ester
R5006	T6153	T6152	prep	of,phosphorylation
R5007	T6154	T6155	amod	cellular,substrates
R5008	T6155	T6153	pobj	substrates,of
R5009	T6156	T6155	acl	detected,substrates
R5010	T6157	T6156	agent	by,detected
R5011	T6158	T6159	det	this,phospho-antibody
R5012	T6159	T6157	pobj	phospho-antibody,by
R5013	T6160	T6160	ROOT	was,was
R5014	T6161	T6160	acomp	similar,was
R5015	T6162	T6161	prep	in,similar
R5016	T6163	T6169	amod	wild-type,cells
R5017	T6164	T6163	cc	and,wild-type
R5018	T6165	T6163	conj	PKD1/3,wild-type
R5019	T6166	T6169	compound	−,cells
R5020	T6167	T6169	compound	/,cells
R5021	T6168	T6169	compound	−,cells
R5022	T6169	T6162	pobj	cells,in
R5023	T6170	T6160	cc	and,was
R5024	T6171	T6160	conj	is,was
R5025	T6172	T6173	advmod	therefore,independent
R5026	T6173	T6171	acomp	independent,is
R5027	T6174	T6173	prep	of,independent
R5028	T6175	T6176	compound	PKD,enzymes
R5029	T6176	T6174	pobj	enzymes,of
R5030	T6177	T6171	punct	.,is
R5031	T6178	T6201	advmod	However,prevented
R5032	T6179	T6201	punct	",",prevented
R5033	T6180	T6201	nsubj	pretreatment,prevented
R5034	T6181	T6180	prep	of,pretreatment
R5035	T6182	T6183	preconj	both,wild-type
R5036	T6183	T6181	pobj	wild-type,of
R5037	T6184	T6183	cc	and,wild-type
R5038	T6185	T6183	conj	PKD1/3,wild-type
R5039	T6186	T6188	compound	−,−
R5040	T6187	T6188	compound	/,−
R5041	T6188	T6191	compound	−,cells
R5042	T6189	T6190	compound	DT40,B
R5043	T6190	T6191	compound	B,cells
R5044	T6191	T6183	appos	cells,wild-type
R5045	T6192	T6180	prep	with,pretreatment
R5046	T6193	T6192	pobj	GF109203X,with
R5047	T6194	T6193	punct	",",GF109203X
R5048	T6195	T6197	det	a,derivative
R5049	T6196	T6197	compound	bisindoylmaleimide,derivative
R5050	T6197	T6193	appos	derivative,GF109203X
R5051	T6198	T6199	nsubj	that,inhibits
R5052	T6199	T6197	relcl	inhibits,derivative
R5053	T6200	T6199	dobj	PKCs,inhibits
R5054	T6201	T6201	ROOT	prevented,prevented
R5055	T6202	T6203	det	the,induction
R5056	T6203	T6201	dobj	induction,prevented
R5057	T6204	T6203	prep	of,induction
R5058	T6205	T6204	pobj	proteins,of
R5059	T6206	T6207	nsubj	that,contain
R5060	T6207	T6205	relcl	contain,proteins
R5061	T6208	T6209	compound	phosphorylated,LxRxxS/T
R5062	T6209	T6210	compound	LxRxxS/T,motifs
R5063	T6210	T6207	dobj	motifs,contain
R5064	T6211	T6201	punct	.,prevented
R5065	T6212	T6216	advmod	Thus,enzymes
R5066	T6213	T6216	nsubj	loss,enzymes
R5067	T6214	T6213	prep	of,loss
R5068	T6215	T6214	pobj	PKD1/3,of
R5069	T6216	T6220	nsubj	enzymes,disrupt
R5070	T6217	T6220	aux	does,disrupt
R5071	T6218	T6220	neg	not,disrupt
R5072	T6219	T6220	advmod	globally,disrupt
R5073	T6220	T6220	ROOT	disrupt,disrupt
R5074	T6221	T6222	det	the,phosphorylation
R5075	T6222	T6220	dobj	phosphorylation,disrupt
R5076	T6223	T6222	prep	of,phosphorylation
R5077	T6224	T6225	amod	cellular,proteins
R5078	T6225	T6223	pobj	proteins,of
R5132	T6279	T6278	prep	in,culminate
R5133	T6280	T6281	det	the,activation
R5134	T6281	T6279	pobj	activation,in
R5135	T6282	T6281	prep	of,activation
R5136	T6283	T6284	compound	gene,transcription
R5137	T6284	T6285	compound	transcription,events
R5138	T6285	T6282	pobj	events,of
R5139	T6286	T6287	nsubj	that,control
R5140	T6287	T6285	relcl	control,events
R5141	T6288	T6290	compound	B,survival
R5142	T6289	T6290	compound	cell,survival
R5143	T6290	T6287	dobj	survival,control
R5144	T6291	T6290	punct	",",survival
R5145	T6292	T6290	conj	proliferation,survival
R5146	T6293	T6292	cc	and,proliferation
R5147	T6294	T6292	conj	function,proliferation
R5148	T6295	T6278	punct	.,culminate
R5149	T6296	T6303	prep	In,proposed
R5150	T6297	T6298	det	this,context
R5151	T6298	T6296	pobj	context,In
R5152	T6299	T6303	punct	",",proposed
R5153	T6300	T6303	nsubjpass	it,proposed
R5154	T6301	T6303	aux	has,proposed
R5155	T6302	T6303	auxpass	been,proposed
R5156	T6303	T6303	ROOT	proposed,proposed
R5157	T6304	T6303	dobj	that,proposed
R5158	T6305	T6307	compound	PKD,members
R5159	T6306	T6307	compound	family,members
R5160	T6307	T6304	nsubj	members,that
R5161	T6308	T6307	dobj	control,members
R5162	T6309	T6308	prep	of,control
R5163	T6310	T6311	compound	gene,transcription
R5164	T6311	T6309	pobj	transcription,of
R5165	T6312	T6307	prep	through,members
R5166	T6313	T6312	pobj	activation,through
R5167	T6314	T6313	prep	of,activation
R5168	T6315	T6318	det	the,factor
R5169	T6316	T6318	compound	NFκB,factor
R5170	T6317	T6318	compound	transcription,factor
R5171	T6318	T6314	pobj	factor,of
R5172	T6319	T6303	punct	.,proposed
R5173	T6320	T6326	advmod	Thus,occurs
R5174	T6321	T6326	punct	",",occurs
R5175	T6322	T6323	amod	PKD-mediated,activation
R5176	T6323	T6326	nsubj	activation,occurs
R5177	T6324	T6323	prep	of,activation
R5178	T6325	T6324	pobj	NFκB,of
R5179	T6326	T6326	ROOT	occurs,occurs
R5180	T6327	T6326	advmod	downstream,occurs
R5181	T6328	T6327	prep	of,downstream
R5182	T6329	T6330	det	a,variety
R5183	T6330	T6328	pobj	variety,of
R5184	T6331	T6330	prep	of,variety
R5185	T6332	T6333	amod	different,signals
R5186	T6333	T6331	pobj	signals,of
R5187	T6334	T6333	punct	",",signals
R5188	T6335	T6333	prep	including,signals
R5189	T6336	T6337	amod	mROS/oxidative,stress
R5190	T6337	T6335	pobj	stress,including
R5191	T6338	T6337	punct	",",stress
R5192	T6339	T6340	amod	lysophosphatidic,acid
R5193	T6340	T6337	conj	acid,stress
R5194	T6341	T6340	cc	and,acid
R5195	T6342	T6344	det	the,oncogene
R5196	T6343	T6344	compound	Bcr-Abl,oncogene
R5197	T6344	T6340	conj	oncogene,acid
R5198	T6345	T6347	compound	[,]
R5199	T6346	T6347	compound	"17,21,23,30,37",]
R5200	T6347	T6344	appos	],oncogene
R5201	T6348	T6326	punct	.,occurs
R5202	T6349	T6357	advmod	Furthermore,enhances
R5203	T6350	T6351	punct	",",expression
R5204	T6351	T6357	nsubj	expression,enhances
R5205	T6352	T6351	prep	of,expression
R5206	T6353	T6356	det	an,mutant
R5207	T6354	T6356	amod	activated,mutant
R5208	T6355	T6356	compound	PKD1,mutant
R5209	T6356	T6352	pobj	mutant,of
R5210	T6357	T6357	ROOT	enhances,enhances
R5211	T6358	T6360	amod	HPK1-mediated,activation
R5212	T6359	T6360	compound	NFκB,activation
R5213	T6360	T6357	dobj	activation,enhances
R5214	T6361	T6363	nmod	[,]
R5215	T6362	T6363	nummod	38,]
R5216	T6363	T6357	npadvmod	],enhances
R5217	T6364	T6357	punct	.,enhances
R5218	T6365	T6371	prep	In,known
R5219	T6366	T6367	compound	B,cells
R5220	T6367	T6365	pobj	cells,In
R5221	T6368	T6371	punct	",",known
R5222	T6369	T6371	nsubjpass	NFκB,known
R5223	T6370	T6371	auxpass	is,known
R5224	T6371	T6371	ROOT	known,known
R5225	T6372	T6374	aux	to,regulated
R5226	T6373	T6374	auxpass	be,regulated
R5227	T6374	T6371	xcomp	regulated,known
R5228	T6375	T6374	prep	via,regulated
R5229	T6376	T6375	pobj	DAG,via
R5230	T6377	T6376	cc	and,DAG
R5231	T6378	T6379	compound	PKCβ,[
R5232	T6379	T6376	conj	[,DAG
R5233	T6380	T6381	compound	"39,40",]
R5234	T6381	T6376	conj	],DAG
R5235	T6382	T6371	cc	but,known
R5236	T6383	T6385	mark	whether,are
R5237	T6384	T6385	nsubj	PKDs,are
R5238	T6385	T6371	conj	are,known
R5239	T6386	T6387	amod	key,intermediaries
R5240	T6387	T6385	attr	intermediaries,are
R5241	T6388	T6385	prep	for,are
R5242	T6389	T6390	compound	NFκB,regulation
R5243	T6406	T6409	nsubjpass	activity,induced
R5244	T6390	T6388	pobj	regulation,for
R5245	T6407	T6409	auxpass	was,induced
R5246	T6408	T6409	advmod	strongly,induced
R5247	T6391	T6394	aux	has,explored
R5248	T6409	T6402	ccomp	induced,show
R5249	T6410	T6409	prep	in,induced
R5250	T6392	T6394	neg	not,explored
R5251	T6411	T6412	preconj	both,wild-type
R5252	T6393	T6394	auxpass	been,explored
R5253	T6412	T6417	nmod	wild-type,−
R5254	T6394	T6385	conj	explored,are
R5255	T6413	T6412	cc	and,wild-type
R5256	T6414	T6412	conj	PKD1/3,wild-type
R5257	T6415	T6417	compound	−,−
R5258	T6395	T6371	punct	.,known
R5259	T6416	T6417	compound	/,−
R5260	T6417	T6420	compound	−,cells
R5261	T6418	T6419	compound	DT40,B
R5262	T6396	T6397	det	The,data
R5263	T6419	T6420	compound	B,cells
R5264	T6420	T6410	pobj	cells,in
R5265	T6421	T6409	prep	in,induced
R5266	T6397	T6402	nsubj	data,show
R5267	T6422	T6421	pobj	response,in
R5268	T6423	T6422	prep	to,response
R5269	T6398	T6397	punct	(,data
R5270	T6424	T6426	preconj	either,ester
R5271	T6425	T6426	compound	phorbol,ester
R5272	T6399	T6400	compound	Fig.,4A
R5273	T6426	T6423	pobj	ester,to
R5274	T6427	T6426	cc	or,ester
R5275	T6428	T6429	compound	BCR,stimulation
R5276	T6429	T6426	conj	stimulation,ester
R5277	T6430	T6402	punct	.,show
R5278	T6431	T6442	prep	In,abolished
R5279	T6432	T6431	pobj	contrast,In
R5280	T6400	T6397	appos	4A,data
R5281	T6433	T6442	punct	",",abolished
R5282	T6434	T6440	nmod	BCR,activity
R5283	T6401	T6397	punct	),data
R5284	T6435	T6434	cc	and,BCR
R5285	T6436	T6440	amod	phorbol,activity
R5286	T6437	T6440	amod	ester-induced,activity
R5287	T6438	T6440	nmod	NFκB,activity
R5288	T6439	T6440	amod	transcriptional,activity
R5289	T6402	T6402	ROOT	show,show
R5290	T6440	T6442	nsubjpass	activity,abolished
R5291	T6441	T6442	auxpass	was,abolished
R5292	T6403	T6409	mark	that,induced
R5293	T6442	T6442	ROOT	abolished,abolished
R5294	T6443	T6442	prep	in,abolished
R5295	T6444	T6449	compound	PKCβ,B
R5296	T6404	T6406	nmod	NFκB,activity
R5297	T6445	T6449	compound	−,B
R5298	T6446	T6449	compound	/,B
R5299	T6447	T6449	compound	−,B
R5300	T6405	T6406	amod	transcriptional,activity
R5301	T6448	T6449	compound	DT40,B
R5302	T6449	T6450	compound	B,cells
R5304	T6450	T6443	pobj	cells,in
R5305	T6451	T6442	punct	(,abolished
R1050	T1164	T1166	amod	numerous,functions
R1051	T1165	T1166	amod	cellular,functions
R1052	T1166	T1163	dobj	functions,regulate
R1053	T1167	T1166	punct	",",functions
R1054	T1168	T1166	prep	including,functions
R1055	T1169	T1170	compound	cell,proliferation
R1056	T1170	T1168	pobj	proliferation,including
R1057	T1171	T1170	dobj	[,proliferation
R1058	T1172	T1171	nummod	13,[
R1059	T1173	T1174	nummod	16,]
R1060	T1174	T1171	appos	],[
R1061	T1175	T1177	punct	",",signals
R1131	T1245	T1249	det	Another,substrate
R1132	T1246	T1247	advmod	recently,proposed
R1133	T1247	T1249	amod	proposed,substrate
R1134	T1248	T1249	compound	PKD1,substrate
R1135	T1249	T1250	nsubj	substrate,is
R1136	T1250	T1250	ROOT	is,is
R1137	T1251	T1252	compound	HSP27,[
R1138	T1252	T1250	attr	[,is
R1139	T1253	T1254	nummod	24,]
R1140	T1254	T1252	appos	],[
R1141	T1255	T1254	punct	",",]
R1142	T1256	T1260	det	a,protein
R1143	T1257	T1260	amod	small,protein
R1144	T1258	T1259	compound	heat,shock
R1145	T1259	T1260	compound	shock,protein
R1146	T1260	T1254	appos	protein,]
R1147	T1261	T1260	amod	involved,protein
R1148	T1262	T1261	prep	in,involved
R1149	T1263	T1262	pcomp	regulating,in
R1150	T1264	T1265	compound	cell,migration
R1151	T1265	T1263	dobj	migration,regulating
R1152	T1266	T1265	cc	and,migration
R1153	T1267	T1268	compound	cell,survival
R1154	T1268	T1265	conj	survival,migration
R1155	T1269	T1271	nmod	[,]
R1156	T1270	T1271	nummod	25,]
R1157	T1271	T1265	appos	],migration
R1158	T1272	T1250	punct	.,is
R1159	T1273	T1275	det	An,role
R1160	T1274	T1275	amod	essential,role
R1161	T1275	T1289	nsubj	role,enzymes
R1162	T1276	T1275	prep	for,role
R1163	T1277	T1278	compound	PKD,enzymes
R1164	T1278	T1276	pobj	enzymes,for
R1165	T1279	T1278	prep	in,enzymes
R1166	T1280	T1279	pcomp	regulating,in
R1167	T1281	T1284	nmod	class,deacetylases
R1168	T1282	T1281	nummod	II,class
R1169	T1283	T1284	compound	histone,deacetylases
R1170	T1284	T1280	dobj	deacetylases,regulating
R1171	T1285	T1284	punct	(,deacetylases
R1172	T1286	T1284	appos	HDACs,deacetylases
R1173	T1287	T1284	punct	),deacetylases
R1174	T1288	T1278	punct	",",enzymes
R1177	T1291	T1289	ccomp	repress,enzymes
R1178	T1292	T1294	amod	MEF2-dependent,transcription
R1179	T1293	T1294	compound	gene,transcription
R1180	T1294	T1291	dobj	transcription,repress
R1181	T1295	T1299	punct	",",demonstrated
R1182	T1296	T1299	aux	has,demonstrated
R1183	T1297	T1299	advmod	also,demonstrated
R1184	T1298	T1299	auxpass	been,demonstrated
R1185	T1299	T1289	conj	demonstrated,enzymes
R1186	T1300	T1301	compound	[,"1,26"
R1187	T1301	T1299	dobj	"1,26",demonstrated
R1188	T1302	T1303	nummod	28,]
R1189	T1303	T1299	npadvmod	],demonstrated
R1190	T1304	T1299	punct	.,demonstrated
R1191	T1305	T1306	aux	To,investigate
R1192	T1306	T1314	advcl	investigate,generated
R1193	T1307	T1309	det	the,role
R1194	T1308	T1309	amod	biological,role
R1195	T1309	T1306	dobj	role,investigate
R1260	T1448	T1449	amod	transcriptional,activity
R1262	T1449	T1446	dobj	activity,regulating
R1263	T1450	T1441	punct	.,play
R1265	T1451	T1455	advmod	Together,reveal
R1266	T1452	T1455	punct	",",reveal
R1268	T1453	T1454	det	these,findings
R1269	T1454	T1455	nsubj	findings,reveal
R1270	T1455	T1455	ROOT	reveal,reveal
R1271	T1456	T1463	mark	that,are
R1272	T1457	T1463	prep	in,are
R1273	T1458	T1459	compound	B,lymphocytes
R1274	T1459	T1457	pobj	lymphocytes,in
R1276	T1460	T1463	punct	",",are
R1277	T1461	T1462	compound	PKD,kinases
R1278	T1462	T1463	nsubj	kinases,are
R1280	T1463	T1455	ccomp	are,reveal
R1281	T1464	T1463	neg	not,are
R1282	T1465	T1466	amod	critical,regulators
R1283	T1466	T1463	attr	regulators,are
R1285	T1467	T1466	prep	of,regulators
R1286	T1468	T1467	pobj	many,of
R1287	T1469	T1468	prep	of,many
R1289	T1470	T1472	det	the,processes
R1290	T1471	T1472	amod	cellular,processes
R1291	T1472	T1469	pobj	processes,of
R1293	T1473	T1474	advmod	previously,ascribed
R1294	T1474	T1463	conj	ascribed,are
R1295	T1475	T1474	prep	to,ascribed
R1297	T1476	T1475	pobj	them,to
R1503	T1743	T1744	compound	Cell,culture
R1504	T1744	T1744	ROOT	culture,culture
R1505	T1745	T1744	punct	",",culture
R1506	T1746	T1747	compound	transient,transfections
R1507	T1747	T1744	appos	transfections,culture
R1508	T1748	T1747	cc	and,transfections
R1509	T1749	T1750	compound	cell,stimulation
R1510	T1750	T1747	conj	stimulation,transfections
R1511	T1751	T1752	det	The,generation
R1512	T1752	T1765	nsubj	generation,/
R1513	T1753	T1752	punct	",",generation
R1514	T1754	T1752	conj	culture,generation
R1515	T1755	T1754	cc	and,culture
R1046	T1160	T1161	auxpass	been,proposed
R1047	T1161	T1161	ROOT	proposed,proposed
R1048	T1162	T1163	aux	to,regulate
R1049	T1163	T1161	xcomp	regulate,proposed
R1128	T1242	T1243	nummod	23,]
R1129	T1243	T1243	ROOT	],]
R1130	T1244	T1223	punct	.,linked
R1516	T1756	T1754	conj	activation,culture
R1517	T1757	T1752	prep	of,generation
R1518	T1758	T1761	nummod	PKD1,−
R1672	T1948	T1949	nummod	106,cells
R1673	T1949	T1944	appos	cells,cells
R1674	T1950	T1949	prep	per,cells
R1675	T1951	T1950	pobj	point,per
R1676	T1952	T1944	punct	),cells
R2447	T2898	T2897	prep	upon,restored
R2448	T2899	T2898	pobj	re-expression,upon
R2449	T2900	T2899	prep	of,re-expression
R2450	T2901	T2904	det	a,isoform
R2452	T2903	T2904	compound	PKD,isoform
R2453	T2904	T2900	pobj	isoform,of
R2454	T2905	T2907	nmod	[,]
R2455	T2906	T2907	nummod	1,]
R2456	T2907	T2869	dobj	],demonstrated
R2457	T2908	T2869	punct	.,demonstrated
R2458	T2909	T2913	det	The,protein
R2459	T2910	T2913	amod	small,protein
R2460	T2911	T2912	compound	heat,shock
R2461	T2912	T2913	compound	shock,protein
R2462	T2913	T2918	nsubj	protein,proposed
R2463	T2914	T2913	appos	HSP27,protein
R2464	T2915	T2918	aux	has,proposed
R2465	T2916	T2918	advmod	recently,proposed
R2466	T2917	T2918	auxpass	been,proposed
R2467	T2918	T2918	ROOT	proposed,proposed
R2468	T2919	T2918	prep	as,proposed
R2469	T2920	T2922	det	a,substrate
R2470	T2921	T2922	compound	PKD1,substrate
R2471	T2922	T2919	pobj	substrate,as
R2472	T2923	T2925	nmod	[,]
R2473	T2924	T2925	nummod	24,]
R2474	T2925	T2922	dep	],substrate
R2475	T2926	T2922	cc	and,substrate
R2476	T2927	T2929	nsubj	we,assessed
R2477	T2928	T2929	advmod	accordingly,assessed
R2478	T2929	T2922	conj	assessed,substrate
R2479	T2930	T2934	mark	whether,have
R2480	T2931	T2932	compound	PKD-null,DT40
R2481	T2932	T2933	compound	DT40,cells
R2482	T2933	T2934	nsubj	cells,have
R2483	T2934	T2929	ccomp	have,assessed
R2484	T2935	T2936	amod	defective,phosphorylation
R2485	T2936	T2934	dobj	phosphorylation,have
R2486	T2937	T2936	prep	of,phosphorylation
R2487	T2938	T2937	pobj	HSP27,of
R3651	T4452	T4450	conj	proliferation,survival
R3652	T4453	T4452	prep	of,proliferation
R3653	T4454	T4455	compound	DT40,B
R3654	T4455	T4456	compound	B,cells
R3655	T4456	T4453	pobj	cells,of
R3656	T4457	T4444	punct	.,are
R3657	T4458	T4459	compound	PKD,enzymes
R4850	T5997	T6001	nsubj	interpretation,is
R4851	T5998	T5997	prep	of,interpretation
R4852	T5999	T6000	det	this,data
R4853	T6000	T5998	pobj	data,of
R4931	T6078	T6079	compound	Flag-PKD3,+
R4932	T6079	T6074	appos	+,−
R4933	T6080	T6074	punct	),−
R4934	T6081	T6082	amod	B,cells
R4935	T6082	T6085	nsubj	cells,impact
R4936	T6083	T6085	aux	may,impact
R4937	T6084	T6085	nsubj	itself,impact
R4938	T6085	T6085	ROOT	impact,impact
R5079	T6226	T6227	nsubj	that,contain
R5080	T6227	T6225	relcl	contain,proteins
R5081	T6228	T6229	compound	LxRxxpS/T,motifs
R5082	T6229	T6227	dobj	motifs,contain
R5083	T6230	T6220	punct	.,disrupt
R5084	T6231	T6232	det	This,result
R5085	T6232	T6233	nsubj	result,is
R5086	T6233	T6233	ROOT	is,is
R5087	T6234	T6236	advmod	perhaps,surprising
R5088	T6235	T6236	neg	not,surprising
R5089	T6236	T6233	acomp	surprising,is
R5090	T6237	T6241	mark	as,act
R5091	T6238	T6239	compound	LxRxxS/T,motifs
R5092	T6239	T6241	nsubj	motifs,act
R5093	T6240	T6241	advmod	also,act
R5094	T6241	T6236	advcl	act,surprising
R5095	T6242	T6241	prep	as,act
R5096	T6243	T6244	amod	good,substrates
R5097	T6244	T6242	pobj	substrates,as
R5098	T6245	T6244	prep	for,substrates
R5099	T6246	T6248	amod	other,kinases
R5100	T6247	T6248	amod	serine/threonine,kinases
R5101	T6248	T6245	pobj	kinases,for
R5102	T6249	T6250	amod	such,as
R5103	T6250	T6248	prep	as,kinases
R5104	T6251	T6250	pobj	MAPKAPK2,as
R5105	T6252	T6233	punct	.,is
R5106	T6253	T6257	advmod	However,provide
R5107	T6254	T6255	det	these,experiments
R5108	T6255	T6257	nsubj	experiments,provide
R5109	T6256	T6257	aux	do,provide
R5110	T6257	T6257	ROOT	provide,provide
R5111	T6258	T6259	amod	further,evidence
R5112	T6259	T6257	dobj	evidence,provide
R5113	T6260	T6263	mark	that,are
R5114	T6261	T6262	amod	phosphospecific,antisera
R5115	T6262	T6263	nsubj	antisera,are
R5116	T6263	T6259	acl	are,evidence
R5117	T6264	T6263	neg	not,are
R5118	T6265	T6266	advmod	sufficiently,selective
R5119	T6266	T6263	acomp	selective,are
R5120	T6267	T6269	aux	to,designated
R5121	T6268	T6269	auxpass	be,designated
R5122	T6269	T6266	xcomp	designated,selective
R5123	T6270	T6269	oprd	kinase,designated
R5124	T6271	T6273	amod	specific,antisera
R5125	T6272	T6273	compound	substrate,antisera
R5126	T6273	T6270	appos	antisera,kinase
R5127	T6274	T6257	punct	.,provide
R5128	T6275	T6277	amod	BCR-induced,pathways
R5129	T6276	T6277	amod	signalling,pathways
R5130	T6277	T6278	nsubj	pathways,culminate
R5131	T6278	T6278	ROOT	culminate,culminate
R5308	T6452	T6453	compound	Fig.,4A
R5310	T6453	T6442	npadvmod	4A,abolished
R5311	T6454	T6442	punct	),abolished
R5312	T6455	T6442	punct	",",abolished
R5313	T6456	T6473	mark	although,observed
R5315	T6457	T6458	amod	strong,activation
R5316	T6458	T6473	nsubjpass	activation,observed
R5318	T6459	T6458	prep	of,activation
R5319	T6460	T6461	compound	PKD,kinases
R5320	T6461	T6459	pobj	kinases,of
R5322	T6462	T6464	punct	(,assessed
R5323	T6463	T6464	mark	as,assessed
R5325	T6464	T6473	advcl	assessed,observed
R5326	T6465	T6464	agent	by,assessed
R5327	T6466	T6465	pobj	autophosphorylation,by
R5328	T6467	T6466	prep	of,autophosphorylation
R5329	T6468	T6467	pobj	PKD1,of
R5330	T6469	T6466	prep	at,autophosphorylation
R5331	T6470	T6469	pobj	S916,at
R5332	T6471	T6464	punct	),assessed
R5333	T6472	T6473	auxpass	was,observed
R5335	T6473	T6442	advcl	observed,abolished
R5336	T6474	T6473	prep	in,observed
R5338	T6475	T6477	det	the,−
R5339	T6476	T6477	compound	PKCβ,−
R5340	T6477	T6474	pobj	−,in
R5341	T6478	T6442	conj	/,abolished
R5343	T6479	T6480	nummod	−,cells
R5344	T6480	T6478	dobj	cells,/
R5345	T6481	T6483	punct	(,4B
R5347	T6482	T6483	compound	Fig.,4B
R5348	T6483	T6478	parataxis	4B,/
R5349	T6484	T6483	punct	),4B
R5351	T6485	T6442	punct	.,abolished
R5303	T6503	T6500	pobj	cells,in
R5306	T6504	T6496	cc	and,mediate
R5307	T6505	T6508	advmod	hence,participate
R5309	T6506	T6508	aux	do,participate
R5314	T6507	T6508	neg	not,participate
R5317	T6508	T6496	conj	participate,mediate
R5321	T6509	T6508	prep	in,participate
R5324	T6510	T6509	pobj	DAG/PKC,in
R5334	T6511	T6490	conj	mediated,are
R5337	T6512	T6511	dobj	control,mediated
R5342	T6513	T6512	prep	of,control
R5346	T6514	T6513	pobj	NFκB,of
R5350	T6515	T6490	punct	.,are
R5353	T6486	T6490	advmod	Thus,are
R5354	T6487	T6490	punct	",",are
R5355	T6488	T6489	compound	PKD,kinases
R5356	T6489	T6490	nsubj	kinases,are
R5357	T6490	T6490	ROOT	are,are
R5358	T6491	T6492	advmod	neither,essential
R5359	T6492	T6490	acomp	essential,are
R5360	T6493	T6492	cc	nor,essential
R5361	T6494	T6492	conj	sufficient,essential
R5362	T6495	T6496	aux	to,mediate
R5363	T6496	T6494	xcomp	mediate,sufficient
R5364	T6497	T6499	amod	BCR-induced,activation
R5365	T6498	T6499	compound	NFκB,activation
R5366	T6499	T6496	dobj	activation,mediate
R5367	T6500	T6499	prep	in,activation
R5368	T6501	T6502	compound	DT40,B
R5369	T6502	T6503	compound	B,cells
R5864	T7377	T7381	amod	"40 B-lymphocyte cell line. Previously we have shown that PKDs have an essential role in regulating class II histone deacetylases in DT40 B-cells [Matthews, S.A., Liu, P., Spitaler, M., Olson, E.N., McKinsey, T.A., Cantrell, D.A. and Scharenberg, A.M. (2006) Essential role for protein kinase D family kinases in the regulation of class II histone deacetylases in B lymphocytes. Mol. Cell Biol. 26, 1569–1577]. We now show that PKDs are also required to regulate HSP27 phosphorylation in DT40 B-cells. However, in contrast to previous observations in other cell types, PKD enzymes do not regulate basic cellular processes such as proliferation or survival responses, nor NFκB transcriptional activity downstream of the B cell antigen receptor. Thus, PKDs have a selective role in DT40 B-cell biology. 1 Introduction The protein kinase D (PKD) serine/threonine kinase family has three members: PKD1, PKD2 and PKD3. Most cell types express at least two PKD isoforms but PKD enzymes are especially highly expressed in haematopoietic cells, where they are activated in response to antigen receptors stimulation [2,3]. A conserved signalling pathway linking antigen receptors to PKDs involves the activation of PLCγ and the subsequent production of diacylglycerol (DAG) which stimulates classical and/or novel protein kinase Cs (PKC) that phosphorylate two key regulatory serine residues in the activation loop of PKD kinases [3–6]. The N-terminal regulatory region of PKD enzymes contains a DAG binding domain and direct binding of DAG also contributes to PKD1 activation [7] as well as regulating the spatial location of PKD enzymes within cells [8–12]. PKD enzymes have been proposed to regulate numerous cellular functions, including cell proliferation [13–16], anti-apoptotic signals [17,18] and thymocyte development [19]. Expression of mutant catalytically inactive and constitutively activated PKDs can also modify Golgi function, cell adhesion and cell motility (reviewed in [20]). In particular, PKDs have been widely linked to the activation of the NFκB transcription factor and in regulating cell survival during oxidative stress [17,21–23]. Another recently proposed PKD1 substrate is HSP27 [24], a small heat shock protein involved in regulating cell migration and cell survival [25]. An essential role for PKD enzymes in regulating class II histone deacetylases (HDACs), enzymes that repress MEF2-dependent gene transcription, has also been demonstrated [1,26–28]. To investigate the biological role of PKDs we have generated DT40 B cell lines that lack expression of one or more members of the PKD family [1], allowing us to investigate the function(s) of PKD isoforms following B cell antigen receptor (BCR) stimulation, as well addressing the issue of functional redundancy between the different PKD family members. Previous studies have shown that PKDs are indispensable for HDAC regulation in B cells [1]. Herein we show that PKDs are also indispensable for HSP27 phosphorylation in B cells. However, PKD-null DT40 B cells are viable and proliferate normally. Moreover, loss of the entire cellular pool of PKD does not critically affect oxidative stress responses in B cells nor do PKD kinases play an essential role in regulating NFκB transcriptional activity. Together, these findings reveal that in B lymphocytes, PKD kinases are not critical regulators of many of the cellular processes previously ascribed to them in other cellular systems. 2 Materials and methods 2.1 Cell culture, transient transfections and cell stimulation The generation, culture and activation of PKD1−/−, PKD3−/− and PKD1/3−/− knockout DT40 B cell lines have been described previously [1]. Cells were lysed and protein extracts were analysed in Western blotting experiments as previously described [1]. Chloramphenicol acetyl transferase assays have been described previously [29]. 2.2 sIgM staining DT40 B cells (2 × 106 cells per point) were resuspended in 200 μl buffer (RPMI 1640 media, 1% foetal calf serum) containing anti-chicken M1 monoclonal antibody conjugated to FITC for 20 min on ice. The cells were washed twice and fluorescent intensity was analysed by flow cytometry. All results shown are representative of at two to four independent experiments unless otherwise indicated. 3 Results 3.1 Loss of HSP27 phosphorylation in DT40 B cells lacking expression of PKD family kinases DT40 B cells express two PKD isoforms, PKD1 and PKD3, and as previously described we have recently generated DT40 B cell lines that lack expression of either PKD1 or PKD3 or both enzymes [1]. In generating the double knockout cell lines we targeted the PKD1 loci in a PKD3−/− cell line that expressed a Flag-PKD3 transgene under the control of a doxycycline-inducible promoter. Hence, in the presence of doxycycline, Flag-PKD3 expression in PKD1/3 double knockout cells is comparable to endogenous PKD3 present in wild-type DT40 cells and removal of doxycycline from the culture media for 5 days results in a completely null PKD phenotype (Fig. 1A). Previously, we have demonstrated that phosphorylation and nuclear exclusion of class II histone deacetylases (HDACs) during BCR engagement is defective in PKD1/3−/− B cells and can restored upon re-expression of a single PKD isoform [1]. The small heat shock protein HSP27 has recently been proposed as a PKD1 substrate [24] and we accordingly assessed whether PKD-null DT40 cells have defective phosphorylation of HSP27 on serine 82, the proposed PKD1 substrate sequence. We initially investigated the regulation of HSP27 phosphorylation in single knockout DT40 B cells lacking either PKD1 or PKD3. As shown in Fig. 1B, activation of the BCR or treatment with the DAG-mimetic PdBu increased the levels of HSP27 phosphorylation at S82 in wild-type DT40 B cells. BCR and phorbol ester signals were also able to increase HSP27 phosphorylation in PKD1 or PKD3 single knockout DT40 B cells (Fig. 1B). However, BCR- and phorbol ester-induced phosphorylation of HSP27 on S82 was abolished in B cells that lacked both PKD1 and PKD3 (Fig. 1C). Significantly, doxycycline-induced expression of the Flag-PKD3 transgene in the double knockout cells was sufficient to restore normal regulation of HSP27 phosphorylation (Fig. 1C). In contrast, expression of a kinase-deficient PKD3 mutant protein in the double knockout cells was not able to restore BCR- or phorbol ester-induced HSP27 phosphorylation (Fig. 1D). Hence, PKD3 as well as PKD1 can regulate HSP27 phosphorylation and in DT40 B cells they are functionally redundant as HSP27 kinases. 3.2 Cellular proliferation and survival in DT40 B cells lacking expression of PKD family kinases PKD enzymes have previously been linked to the regulation of cell proliferation and survival (reviewed in [20]). To investigate the effect that loss of PKD kinases had on B cell survival and/or proliferation we cultured wild-type and PKD-null cells in the presence (PKD1/3−/−: Flag-PKD3+ve) or absence (PKD1/3−/−) of doxycycline and monitored exponential growth. As shown in Fig. 2A, PKD1/3−/− cells proliferated exponentially and re-expression of Flag-PKD3 in these cells had no impact on the rate of proliferation. Furthermore, the viability of PKD1/3−/− B cells during routine culturing was not significantly different from that of wild-type B cells (data not shown). It was noted that the population doubling time of PKD1/3−/− cells was slightly slower than that of wild type DT40 cells (12.7 ± 2.8 h versus 10.2 ± 0.4 h) but the failure of PKD3 re-expression to modify the proliferation rate of PKD1/3−/− cells suggests that these small differences were most likely the result of clonal variation and were not caused specifically by loss of PKD enzymes. Thus, PKD family enzymes are not essential for regulating basal survival and proliferation of DT40 B cells. PKD enzymes, specifically PKD1 and PKD2, have previously been linked to a protective role against oxidative stress-induced injury in 3T3 fibroblast, HeLa and epithelial cell lines [17,30–32]. We therefore addressed the role of PKD family kinases in regulating B cell survival in response to oxidative stress and other stress stimuli. As shown in Fig. 2B, loss of PKD1/3 expression had no significant impact on the survival of DT40 B cells in response to mitochondrial stress stimuli (H2O2 or serum deprivation); DNA damaging agents (etoposide or doxorubicin); ER pathway stress due to calcium overload (thapsigargin) or following prolonged treatment with phorbol esters or Trichostatin A, an inhibitor of class I/II HDACs. Thus, PKD kinases do not play an essential role in regulating B cell survival in response to a range of different stress stimuli. 3.3 Antigen receptor regulated signalling pathways in PKD-null DT40 B cells To further explore the contribution of PKD kinases to DT40 B cell biology we investigated whether specific BCR-regulated signalling events were defective in the PKD-null B cells. Initial experiments revealed that surface expression of the BCR was reduced in PKD1/3−/− (and in PKD1/3−/−:Flag-PKD3+ve) cells compared to wild-type DT40 B cells (Fig. 3A and data not shown). Nevertheless, BCR-crosslinking of PKD1/3−/− cells was sufficient to induce the activation of a number of signalling cascades, similar to that observed in wild-type cells (Fig. 3B). Hence, BCR-induced activation of the Akt, mTOR/p70 S6 kinase (as shown by S6 ribosomal protein phosphorylation) and MAPK signalling pathways was clearly detectable in PKD1/3-null B cells (Fig. 3B). Furthermore, enhanced tyrosine phosphorylation of multiple cellular proteins as well as an increase in intracellular calcium levels was also observed following BCR stimulation of PKD1/3-null B cells (data not shown). We did observe that the strength of BCR (but not phorbol ester)-induced regulation of the Erk1-RSK1 signalling pathway was reduced in PKD1/3−/− B cells compared to wild-type B cells (Fig. 3B). One interpretation of this data is that PKD enzymes may modulate Erk activation. Indeed, PKD enzymes have previously been linked to the growth factor-regulated Erk signalling in fibroblast and endothelial cell lines [33–35]. However, BCR-induced Erk phosphorylation was also reduced in PKD1/3−/−-Flag-PKD3+ B cells (data not shown) suggesting that reduced BCR levels on the surface of PKD1/3−/− (and PKD1/3−/−-Flag-PKD3+) B cells may itself impact on the strength of activation of this specific intracellular signalling pathway. To search for other potential PKD targets that may show defective regulation in PKD1/3−/− DT40 B cells, we used a PKD substrate phospho-antibody that recognises consensus phosphorylation sequences targeted by PKD enzymes (LxRxxpS/T) [36]. As shown in Fig. 3C, phorbol ester- and BCR-induced phosphorylation of cellular substrates detected by this phospho-antibody was similar in wild-type and PKD1/3−/− cells and is therefore independent of PKD enzymes. However, pretreatment of both wild-type and PKD1/3−/− DT40 B cells with GF109203X, a bisindoylmaleimide derivative that inhibits PKCs prevented the induction of proteins that contain phosphorylated LxRxxS/T motifs. Thus loss of PKD1/3 enzymes does not globally disrupt the phosphorylation of cellular proteins that contain LxRxxpS/T motifs. This result is perhaps not surprising as LxRxxS/T motifs also act as good substrates for other serine/threonine kinases such as MAPKAPK2. However these experiments do provide further evidence that phosphospecific antisera are not sufficiently selective to be designated kinase specific substrate antisera. BCR-induced signalling pathways culminate in the activation of gene transcription events that control B cell survival, proliferation and function. In this context, it has been proposed that PKD family members control of gene transcription through activation of the NFκB transcription factor. Thus, PKD-mediated activation of NFκB occurs downstream of a variety of different signals, including mROS/oxidative stress, lysophosphatidic acid and the Bcr-Abl oncogene [17,21,23,30,37]. Furthermore, expression of an activated PKD1 mutant enhances HPK1-mediated NFκB activation [38]. In B cells, NFκB is known to be regulated via DAG and PKCβ [39,40] but whether PKDs are key intermediaries for NFκB regulation has not been explored. The data (Fig. 4A) show that NFκB transcriptional activity was strongly induced in both wild-type and PKD1/3−/− DT40 B cells in response to either phorbol ester or BCR stimulation. In contrast, BCR and phorbol ester-induced NFκB transcriptional activity was abolished in PKCβ−/− DT40 B cells (Fig. 4A), although strong activation of PKD kinases (as assessed by autophosphorylation of PKD1 at S916) was observed in the PKCβ−/− cells (Fig. 4B). Thus, PKD kinases are neither essential nor sufficient to mediate BCR-induced NFκB activation in DT40 B cells and hence do not participate in DAG/PKC mediated control of NFκB. 4 Discussion Protein",kinases
R5865	T7378	T7381	compound	kinase,kinases
R5866	T7379	T7381	compound	D,kinases
R5867	T7380	T7381	compound	serine,kinases

UBERON-AE

Id	Subject	Object	Predicate	Lexical cue
T1863	4007-4012	http://purl.obolibrary.org/obo/UBERON_0001977	denotes	serum
T3782	8338-8343	http://purl.obolibrary.org/obo/UBERON_0001977	denotes	serum

GO-BP

Id	Subject	Object	Predicate	Lexical cue
T504	1127-1137	http://purl.obolibrary.org/obo/GO_0023052	denotes	signalling
T505	1777-1784	http://purl.obolibrary.org/obo/GO_0023052	denotes	signals
T506	1127-1145	http://purl.obolibrary.org/obo/GO_0007165	denotes	signalling pathway
T507	1325-1328	http://purl.obolibrary.org/obo/GO_0004697	denotes	PKC
T508	1704-1712	http://purl.obolibrary.org/obo/GO_0007349	denotes	cellular
T509	3105-3113	http://purl.obolibrary.org/obo/GO_0007349	denotes	cellular
T510	3388-3396	http://purl.obolibrary.org/obo/GO_0007349	denotes	cellular
T511	3444-3452	http://purl.obolibrary.org/obo/GO_0007349	denotes	cellular
T512	1734-1752	http://purl.obolibrary.org/obo/GO_0008283	denotes	cell proliferation
T513	1807-1818	http://purl.obolibrary.org/obo/GO_0032502	denotes	development
T514	1935-1948	http://purl.obolibrary.org/obo/GO_0007155	denotes	cell adhesion
T515	1953-1966	http://purl.obolibrary.org/obo/GO_0048870	denotes	cell motility
T516	2061-2074	http://purl.obolibrary.org/obo/GO_0006351	denotes	transcription
T517	2423-2436	http://purl.obolibrary.org/obo/GO_0006351	denotes	transcription
T518	3252-3267	http://purl.obolibrary.org/obo/GO_0006351	denotes	transcriptional
T519	2214-2232	http://purl.obolibrary.org/obo/GO_0006986	denotes	heat shock protein
T520	2214-2232	http://purl.obolibrary.org/obo/GO_0034620	denotes	heat shock protein
T521	2214-2232	http://purl.obolibrary.org/obo/GO_0042026	denotes	heat shock protein
T522	2256-2270	http://purl.obolibrary.org/obo/GO_0016477	denotes	cell migration
T523	2895-2905	http://purl.obolibrary.org/obo/GO_0065007	denotes	regulation
T524	2980-2995	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T525	3153-3179	http://purl.obolibrary.org/obo/GO_1902883	denotes	oxidative stress responses
T526	3153-3179	http://purl.obolibrary.org/obo/GO_0006979	denotes	oxidative stress responses
T527	3153-3179	http://purl.obolibrary.org/obo/GO_0097468	denotes	oxidative stress responses
T528	3153-3179	http://purl.obolibrary.org/obo/GO_1902884	denotes	oxidative stress responses
T529	3153-3179	http://purl.obolibrary.org/obo/GO_0034599	denotes	oxidative stress responses
T530	3163-3179	http://purl.obolibrary.org/obo/GO_0006950	denotes	stress responses
T531	3388-3406	http://purl.obolibrary.org/obo/GO_0009987	denotes	cellular processes
T2272	4324-4339	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T2273	5085-5100	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T2274	5443-5458	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T2275	5570-5585	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T2276	5759-5774	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T2277	5872-5887	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T2278	5984-5999	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T2279	6238-6253	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T2280	6420-6435	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T2281	6494-6509	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T2282	5295-5313	http://purl.obolibrary.org/obo/GO_0006986	denotes	heat shock protein
T2283	5295-5313	http://purl.obolibrary.org/obo/GO_0034620	denotes	heat shock protein
T3833	8125-8153	http://purl.obolibrary.org/obo/GO_1902884	denotes	response to oxidative stress
T3834	8125-8153	http://purl.obolibrary.org/obo/GO_0034599	denotes	response to oxidative stress
T3835	8288-8320	http://purl.obolibrary.org/obo/GO_1990046	denotes	response to mitochondrial stress
T6532	10637-10652	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T6533	10757-10772	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T6534	11193-11208	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T6535	9445-9449	http://purl.obolibrary.org/obo/GO_0004707	denotes	MAPK
T6536	9445-9460	http://purl.obolibrary.org/obo/GO_0000165	denotes	MAPK signalling
T6537	9586-9594	http://purl.obolibrary.org/obo/GO_0007349	denotes	cellular
T6538	10776-10784	http://purl.obolibrary.org/obo/GO_0007349	denotes	cellular
T21	316-326	http://purl.obolibrary.org/obo/GO_0065007	denotes	regulation
T22	468-483	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T23	602-610	http://purl.obolibrary.org/obo/GO_0007349	denotes	cellular
T24	602-620	http://purl.obolibrary.org/obo/GO_0009987	denotes	cellular processes
T25	675-690	http://purl.obolibrary.org/obo/GO_0006351	denotes	transcriptional
T3820	6726-6736	http://purl.obolibrary.org/obo/GO_0065007	denotes	regulation
T3821	6726-6758	http://purl.obolibrary.org/obo/GO_0030888	denotes	regulation of cell proliferation
T3822	6726-6758	http://purl.obolibrary.org/obo/GO_0051140	denotes	regulation of cell proliferation
T3823	6726-6758	http://purl.obolibrary.org/obo/GO_0060251	denotes	regulation of cell proliferation
T3824	6726-6758	http://purl.obolibrary.org/obo/GO_0070666	denotes	regulation of cell proliferation
T3825	6726-6758	http://purl.obolibrary.org/obo/GO_1904073	denotes	regulation of cell proliferation
T3826	6726-6758	http://purl.obolibrary.org/obo/GO_1904697	denotes	regulation of cell proliferation
T3827	6726-6758	http://purl.obolibrary.org/obo/GO_1904441	denotes	regulation of cell proliferation
T3828	6740-6758	http://purl.obolibrary.org/obo/GO_0008283	denotes	cell proliferation
T3829	7034-7040	http://purl.obolibrary.org/obo/GO_0040007	denotes	growth
T3830	8125-8153	http://purl.obolibrary.org/obo/GO_1902883	denotes	response to oxidative stress
T3831	8125-8153	http://purl.obolibrary.org/obo/GO_0006979	denotes	response to oxidative stress
T3832	8125-8153	http://purl.obolibrary.org/obo/GO_0097468	denotes	response to oxidative stress
T2284	5295-5313	http://purl.obolibrary.org/obo/GO_0042026	denotes	heat shock protein
T2285	5550-5560	http://purl.obolibrary.org/obo/GO_0065007	denotes	regulation
T2286	6218-6228	http://purl.obolibrary.org/obo/GO_0065007	denotes	regulation
T2287	5831-5838	http://purl.obolibrary.org/obo/GO_0023052	denotes	signals
T6516	8732-8742	http://purl.obolibrary.org/obo/GO_0023052	denotes	signalling
T6517	8898-8908	http://purl.obolibrary.org/obo/GO_0023052	denotes	signalling
T6518	9253-9263	http://purl.obolibrary.org/obo/GO_0023052	denotes	signalling
T6519	9450-9460	http://purl.obolibrary.org/obo/GO_0023052	denotes	signalling
T6520	9844-9854	http://purl.obolibrary.org/obo/GO_0023052	denotes	signalling
T6521	10101-10111	http://purl.obolibrary.org/obo/GO_0023052	denotes	signalling
T6522	10446-10456	http://purl.obolibrary.org/obo/GO_0023052	denotes	signalling
T6523	11579-11589	http://purl.obolibrary.org/obo/GO_0023052	denotes	signalling
T6524	11941-11948	http://purl.obolibrary.org/obo/GO_0023052	denotes	signals
T6525	8732-8751	http://purl.obolibrary.org/obo/GO_0007165	denotes	signalling pathways
T6526	9450-9469	http://purl.obolibrary.org/obo/GO_0007165	denotes	signalling pathways
T6527	9253-9272	http://purl.obolibrary.org/obo/GO_0007165	denotes	signalling cascades
T6528	9416-9439	http://purl.obolibrary.org/obo/GO_0006468	denotes	protein phosphorylation
T6529	9424-9439	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T6530	9558-9573	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T6531	10187-10202	http://purl.obolibrary.org/obo/GO_0016310	denotes	phosphorylation
T6539	11212-11220	http://purl.obolibrary.org/obo/GO_0007349	denotes	cellular
T6540	9816-9826	http://purl.obolibrary.org/obo/GO_0065007	denotes	regulation
T6541	10532-10542	http://purl.obolibrary.org/obo/GO_0065007	denotes	regulation
T6542	12261-12271	http://purl.obolibrary.org/obo/GO_0065007	denotes	regulation
T6543	10073-10079	http://purl.obolibrary.org/obo/GO_0040007	denotes	growth
T6544	10432-10464	http://purl.obolibrary.org/obo/GO_0030522	denotes	intracellular signalling pathway
T6545	10432-10464	http://purl.obolibrary.org/obo/GO_0035556	denotes	intracellular signalling pathway
T6546	10432-10464	http://purl.obolibrary.org/obo/GO_1902532	denotes	intracellular signalling pathway
T6547	10432-10464	http://purl.obolibrary.org/obo/GO_1902531	denotes	intracellular signalling pathway
T6548	10432-10464	http://purl.obolibrary.org/obo/GO_1902533	denotes	intracellular signalling pathway
T6549	11635-11648	http://purl.obolibrary.org/obo/GO_0006351	denotes	transcription
T6550	11792-11805	http://purl.obolibrary.org/obo/GO_0006351	denotes	transcription
T6551	11837-11850	http://purl.obolibrary.org/obo/GO_0006351	denotes	transcription
T6552	12329-12344	http://purl.obolibrary.org/obo/GO_0006351	denotes	transcriptional
T6553	12524-12539	http://purl.obolibrary.org/obo/GO_0006351	denotes	transcriptional
T6554	12884-12887	http://purl.obolibrary.org/obo/GO_0004697	denotes	PKC

GO-MF

Id	Subject	Object	Predicate	Lexical cue
T1483	1325-1328	http://purl.obolibrary.org/obo/GO_0004697	denotes	PKC
T1484	1492-1499	http://purl.obolibrary.org/obo/GO_0005488	denotes	binding
T1485	1518-1525	http://purl.obolibrary.org/obo/GO_0005488	denotes	binding
T2014	4052-4060	http://purl.obolibrary.org/obo/GO_0003823	denotes	antibody
T6581	9406-9423	http://purl.obolibrary.org/obo/GO_0003735	denotes	ribosomal protein
T6582	9445-9449	http://purl.obolibrary.org/obo/GO_0004707	denotes	MAPK
T6583	10602-10610	http://purl.obolibrary.org/obo/GO_0003823	denotes	antibody
T6584	10821-10829	http://purl.obolibrary.org/obo/GO_0003823	denotes	antibody
T6585	12884-12887	http://purl.obolibrary.org/obo/GO_0004697	denotes	PKC

GO-CC

Id	Subject	Object	Predicate	Lexical cue
T1499	1919-1924	http://purl.obolibrary.org/obo/GO_0005794	denotes	Golgi
T1500	3388-3406	http://purl.obolibrary.org/obo/GO_0042995	denotes	cellular processes
T1816	3536-3540	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T1817	3642-3646	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T2015	3908-3913	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T2016	3923-3928	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T2017	4103-4108	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T2018	4052-4060	http://purl.obolibrary.org/obo/GO_0019815	denotes	antibody
T2019	4052-4060	http://purl.obolibrary.org/obo/GO_0042571	denotes	antibody
T4613	6632-6637	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T4614	6922-6927	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T4615	7073-7078	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T4616	7146-7151	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T4617	7238-7243	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T4618	7326-7331	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T4619	7410-7415	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T4620	7464-7469	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T4621	7589-7594	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T4622	7839-7844	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T4623	8279-8284	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T4624	8633-8637	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T4625	8406-8408	http://purl.obolibrary.org/obo/GO_0005783	denotes	ER
T6555	8771-8776	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6556	8949-8954	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6557	9077-9082	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6558	9112-9117	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6559	9192-9197	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6560	9312-9317	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6561	9510-9515	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6562	9720-9725	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6563	9890-9895	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6564	9920-9925	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6565	10246-10251	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6566	10361-10366	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6567	10563-10568	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6568	10869-10874	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6569	10981-10986	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6570	12150-12155	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6571	12414-12419	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6572	12581-12586	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6573	12721-12726	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6574	12842-12847	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T6575	9630-9643	http://purl.obolibrary.org/obo/GO_0005622	denotes	intracellular
T6576	10432-10445	http://purl.obolibrary.org/obo/GO_0005622	denotes	intracellular
T6577	10602-10610	http://purl.obolibrary.org/obo/GO_0019815	denotes	antibody
T6578	10821-10829	http://purl.obolibrary.org/obo/GO_0019815	denotes	antibody
T6579	10602-10610	http://purl.obolibrary.org/obo/GO_0042571	denotes	antibody
T6580	10821-10829	http://purl.obolibrary.org/obo/GO_0042571	denotes	antibody
T1486	920-924	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T1487	1734-1738	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T1488	1935-1939	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T1489	1953-1957	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T1490	2100-2104	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T1491	2256-2260	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T1492	2275-2279	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T1493	2544-2548	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T1494	2693-2697	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T3137	4350-4355	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T3138	4404-4409	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T3139	4861-4866	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T3140	4926-4931	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T3141	5214-5219	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T3142	5422-5427	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T3143	5612-5617	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T3144	5802-5807	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T3145	5927-5932	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T3146	6035-6040	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T3147	6179-6184	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T3148	6354-6359	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T3149	6524-6529	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T400	139-144	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T401	494-499	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T402	556-560	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T403	720-724	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T404	786-790	http://purl.obolibrary.org/obo/GO_0005623	denotes	cell
T405	602-620	http://purl.obolibrary.org/obo/GO_0042995	denotes	cellular processes
T1495	2911-2916	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T1496	3001-3006	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T1497	3033-3038	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells
T1498	3185-3190	http://purl.obolibrary.org/obo/GO_0005623	denotes	cells

sentences

Id	Subject	Object	Predicate	Lexical cue
T17	378-409	Sentence	denotes	Mol. Cell Biol. 26, 1569–1577].
T489	398-914	Sentence	denotes	1569–1577]. We now show that PKDs are also required to regulate HSP27 phosphorylation in DT40 B-cells. However, in contrast to previous observations in other cell types, PKD enzymes do not regulate basic cellular processes such as proliferation or survival responses, nor NFκB transcriptional activity downstream of the B cell antigen receptor. Thus, PKDs have a selective role in DT40 B-cell biology. 1 Introduction The protein kinase D (PKD) serine/threonine kinase family has three members: PKD1, PKD2 and PKD3.
T490	915-1114	Sentence	denotes	Most cell types express at least two PKD isoforms but PKD enzymes are especially highly expressed in haematopoietic cells, where they are activated in response to antigen receptors stimulation [2,3].
T491	1115-1428	Sentence	denotes	A conserved signalling pathway linking antigen receptors to PKDs involves the activation of PLCγ and the subsequent production of diacylglycerol (DAG) which stimulates classical and/or novel protein kinase Cs (PKC) that phosphorylate two key regulatory serine residues in the activation loop of PKD kinases [3–6].
T492	1429-1651	Sentence	denotes	The N-terminal regulatory region of PKD enzymes contains a DAG binding domain and direct binding of DAG also contributes to PKD1 activation [7] as well as regulating the spatial location of PKD enzymes within cells [8–12].
T493	1652-1824	Sentence	denotes	PKD enzymes have been proposed to regulate numerous cellular functions, including cell proliferation [13–16], anti-apoptotic signals [17,18] and thymocyte development [19].
T494	1825-1986	Sentence	denotes	Expression of mutant catalytically inactive and constitutively activated PKDs can also modify Golgi function, cell adhesion and cell motility (reviewed in [20]).
T495	1987-2149	Sentence	denotes	In particular, PKDs have been widely linked to the activation of the NFκB transcription factor and in regulating cell survival during oxidative stress [17,21–23].
T496	2150-2294	Sentence	denotes	Another recently proposed PKD1 substrate is HSP27 [24], a small heat shock protein involved in regulating cell migration and cell survival [25].
T497	2295-2475	Sentence	denotes	An essential role for PKD enzymes in regulating class II histone deacetylases (HDACs), enzymes that repress MEF2-dependent gene transcription, has also been demonstrated [1,26–28].
T498	2476-2829	Sentence	denotes	To investigate the biological role of PKDs we have generated DT40 B cell lines that lack expression of one or more members of the PKD family [1], allowing us to investigate the function(s) of PKD isoforms following B cell antigen receptor (BCR) stimulation, as well addressing the issue of functional redundancy between the different PKD family members.
T499	2830-2921	Sentence	denotes	Previous studies have shown that PKDs are indispensable for HDAC regulation in B cells [1].
T500	2922-3007	Sentence	denotes	Herein we show that PKDs are also indispensable for HSP27 phosphorylation in B cells.
T501	3008-3075	Sentence	denotes	However, PKD-null DT40 B cells are viable and proliferate normally.
T502	3076-3277	Sentence	denotes	Moreover, loss of the entire cellular pool of PKD does not critically affect oxidative stress responses in B cells nor do PKD kinases play an essential role in regulating NFκB transcriptional activity.
T503	3278-3461	Sentence	denotes	Together, these findings reveal that in B lymphocytes, PKD kinases are not critical regulators of many of the cellular processes previously ascribed to them in other cellular systems.
T1671	3553-3688	Sentence	denotes	The generation, culture and activation of PKD1−/−, PKD3−/− and PKD1/3−/− knockout DT40 B cell lines have been described previously [1].
T1672	3689-3801	Sentence	denotes	Cells were lysed and protein extracts were analysed in Western blotting experiments as previously described [1].
T1673	3802-3880	Sentence	denotes	Chloramphenicol acetyl transferase assays have been described previously [29].
T1865	3901-4098	Sentence	denotes	DT40 B cells (2 × 106 cells per point) were resuspended in 200 μl buffer (RPMI 1640 media, 1% foetal calf serum) containing anti-chicken M1 monoclonal antibody conjugated to FITC for 20 min on ice.
T1866	4099-4184	Sentence	denotes	The cells were washed twice and fluorescent intensity was analysed by flow cytometry.
T1867	4185-4291	Sentence	denotes	All results shown are representative of at two to four independent experiments unless otherwise indicated.
T2260	4397-4588	Sentence	denotes	DT40 B cells express two PKD isoforms, PKD1 and PKD3, and as previously described we have recently generated DT40 B cell lines that lack expression of either PKD1 or PKD3 or both enzymes [1].
T2261	4589-4774	Sentence	denotes	In generating the double knockout cell lines we targeted the PKD1 loci in a PKD3−/− cell line that expressed a Flag-PKD3 transgene under the control of a doxycycline-inducible promoter.
T2262	4775-5046	Sentence	denotes	Hence, in the presence of doxycycline, Flag-PKD3 expression in PKD1/3 double knockout cells is comparable to endogenous PKD3 present in wild-type DT40 cells and removal of doxycycline from the culture media for 5 days results in a completely null PKD phenotype (Fig. 1A).
T2263	5047-5284	Sentence	denotes	Previously, we have demonstrated that phosphorylation and nuclear exclusion of class II histone deacetylases (HDACs) during BCR engagement is defective in PKD1/3−/− B cells and can restored upon re-expression of a single PKD isoform [1].
T2264	5285-5519	Sentence	denotes	The small heat shock protein HSP27 has recently been proposed as a PKD1 substrate [24] and we accordingly assessed whether PKD-null DT40 cells have defective phosphorylation of HSP27 on serine 82, the proposed PKD1 substrate sequence.
T2265	5520-5646	Sentence	denotes	We initially investigated the regulation of HSP27 phosphorylation in single knockout DT40 B cells lacking either PKD1 or PKD3.
T2266	5647-5808	Sentence	denotes	As shown in Fig. 1B, activation of the BCR or treatment with the DAG-mimetic PdBu increased the levels of HSP27 phosphorylation at S82 in wild-type DT40 B cells.
T2267	5809-5943	Sentence	denotes	BCR and phorbol ester signals were also able to increase HSP27 phosphorylation in PKD1 or PKD3 single knockout DT40 B cells (Fig. 1B).
T2268	5944-6082	Sentence	denotes	However, BCR- and phorbol ester-induced phosphorylation of HSP27 on S82 was abolished in B cells that lacked both PKD1 and PKD3 (Fig. 1C).
T2269	6083-6264	Sentence	denotes	Significantly, doxycycline-induced expression of the Flag-PKD3 transgene in the double knockout cells was sufficient to restore normal regulation of HSP27 phosphorylation (Fig. 1C).
T2270	6265-6446	Sentence	denotes	In contrast, expression of a kinase-deficient PKD3 mutant protein in the double knockout cells was not able to restore BCR- or phorbol ester-induced HSP27 phosphorylation (Fig. 1D).
T2271	6447-6579	Sentence	denotes	Hence, PKD3 as well as PKD1 can regulate HSP27 phosphorylation and in DT40 B cells they are functionally redundant as HSP27 kinases.
T3809	6679-6791	Sentence	denotes	PKD enzymes have previously been linked to the regulation of cell proliferation and survival (reviewed in [20]).
T3810	6792-6955	Sentence	denotes	To investigate the effect that loss of PKD kinases had on B cell survival and/or proliferation we cultured wild-type and PKD-null cells in the presence (PKD1/3−/−:
T3811	6956-7041	Sentence	denotes	Flag-PKD3+ve) or absence (PKD1/3−/−) of doxycycline and monitored exponential growth.
T3812	7042-7195	Sentence	denotes	As shown in Fig. 2A, PKD1/3−/− cells proliferated exponentially and re-expression of Flag-PKD3 in these cells had no impact on the rate of proliferation.
T3813	7196-7349	Sentence	denotes	Furthermore, the viability of PKD1/3−/− B cells during routine culturing was not significantly different from that of wild-type B cells (data not shown).
T3814	7350-7737	Sentence	denotes	It was noted that the population doubling time of PKD1/3−/− cells was slightly slower than that of wild type DT40 cells (12.7 ± 2.8 h versus 10.2 ± 0.4 h) but the failure of PKD3 re-expression to modify the proliferation rate of PKD1/3−/− cells suggests that these small differences were most likely the result of clonal variation and were not caused specifically by loss of PKD enzymes.
T3815	7738-7845	Sentence	denotes	Thus, PKD family enzymes are not essential for regulating basal survival and proliferation of DT40 B cells.
T3816	7846-8037	Sentence	denotes	PKD enzymes, specifically PKD1 and PKD2, have previously been linked to a protective role against oxidative stress-induced injury in 3T3 fibroblast, HeLa and epithelial cell lines [17,30–32].
T3817	8038-8179	Sentence	denotes	We therefore addressed the role of PKD family kinases in regulating B cell survival in response to oxidative stress and other stress stimuli.
T3818	8180-8568	Sentence	denotes	As shown in Fig. 2B, loss of PKD1/3 expression had no significant impact on the survival of DT40 B cells in response to mitochondrial stress stimuli (H2O2 or serum deprivation); DNA damaging agents (etoposide or doxorubicin); ER pathway stress due to calcium overload (thapsigargin) or following prolonged treatment with phorbol esters or Trichostatin A, an inhibitor of class I/II HDACs.
T3819	8569-8698	Sentence	denotes	Thus, PKD kinases do not play an essential role in regulating B cell survival in response to a range of different stress stimuli.
T5008	8777-8955	Sentence	denotes	To further explore the contribution of PKD kinases to DT40 B cell biology we investigated whether specific BCR-regulated signalling events were defective in the PKD-null B cells.
T5009	8956-9147	Sentence	denotes	Initial experiments revealed that surface expression of the BCR was reduced in PKD1/3−/− (and in PKD1/3−/−:Flag-PKD3+ve) cells compared to wild-type DT40 B cells (Fig. 3A and data not shown).
T5010	9148-9328	Sentence	denotes	Nevertheless, BCR-crosslinking of PKD1/3−/− cells was sufficient to induce the activation of a number of signalling cascades, similar to that observed in wild-type cells (Fig. 3B).
T5011	9329-9526	Sentence	denotes	Hence, BCR-induced activation of the Akt, mTOR/p70 S6 kinase (as shown by S6 ribosomal protein phosphorylation) and MAPK signalling pathways was clearly detectable in PKD1/3-null B cells (Fig. 3B).
T5012	9527-9743	Sentence	denotes	Furthermore, enhanced tyrosine phosphorylation of multiple cellular proteins as well as an increase in intracellular calcium levels was also observed following BCR stimulation of PKD1/3-null B cells (data not shown).
T5013	9744-9936	Sentence	denotes	We did observe that the strength of BCR (but not phorbol ester)-induced regulation of the Erk1-RSK1 signalling pathway was reduced in PKD1/3−/− B cells compared to wild-type B cells (Fig. 3B).
T5014	9937-10017	Sentence	denotes	One interpretation of this data is that PKD enzymes may modulate Erk activation.
T5015	10018-10161	Sentence	denotes	Indeed, PKD enzymes have previously been linked to the growth factor-regulated Erk signalling in fibroblast and endothelial cell lines [33–35].
T5016	10162-10465	Sentence	denotes	However, BCR-induced Erk phosphorylation was also reduced in PKD1/3−/−-Flag-PKD3+ B cells (data not shown) suggesting that reduced BCR levels on the surface of PKD1/3−/− (and PKD1/3−/−-Flag-PKD3+) B cells may itself impact on the strength of activation of this specific intracellular signalling pathway.
T5017	10466-10704	Sentence	denotes	To search for other potential PKD targets that may show defective regulation in PKD1/3−/− DT40 B cells, we used a PKD substrate phospho-antibody that recognises consensus phosphorylation sequences targeted by PKD enzymes (LxRxxpS/T) [36].
T5018	10705-10919	Sentence	denotes	As shown in Fig. 3C, phorbol ester- and BCR-induced phosphorylation of cellular substrates detected by this phospho-antibody was similar in wild-type and PKD1/3−/− cells and is therefore independent of PKD enzymes.
T5019	10920-11134	Sentence	denotes	However, pretreatment of both wild-type and PKD1/3−/− DT40 B cells with GF109203X, a bisindoylmaleimide derivative that inhibits PKCs prevented the induction of proteins that contain phosphorylated LxRxxS/T motifs.
T5020	11135-11260	Sentence	denotes	Thus loss of PKD1/3 enzymes does not globally disrupt the phosphorylation of cellular proteins that contain LxRxxpS/T motifs.
T5021	11261-11398	Sentence	denotes	This result is perhaps not surprising as LxRxxS/T motifs also act as good substrates for other serine/threonine kinases such as MAPKAPK2.
T5022	11399-11566	Sentence	denotes	However these experiments do provide further evidence that phosphospecific antisera are not sufficiently selective to be designated kinase specific substrate antisera.
T5023	11567-11713	Sentence	denotes	BCR-induced signalling pathways culminate in the activation of gene transcription events that control B cell survival, proliferation and function.
T5024	11714-11858	Sentence	denotes	In this context, it has been proposed that PKD family members control of gene transcription through activation of the NFκB transcription factor.
T5025	11859-12047	Sentence	denotes	Thus, PKD-mediated activation of NFκB occurs downstream of a variety of different signals, including mROS/oxidative stress, lysophosphatidic acid and the Bcr-Abl oncogene [17,21,23,30,37].
T5026	12048-12144	Sentence	denotes	Furthermore, expression of an activated PKD1 mutant enhances HPK1-mediated NFκB activation [38].
T5027	12145-12294	Sentence	denotes	In B cells, NFκB is known to be regulated via DAG and PKCβ [39,40] but whether PKDs are key intermediaries for NFκB regulation has not been explored.
T5028	12295-12475	Sentence	denotes	The data (Fig. 4A) show that NFκB transcriptional activity was strongly induced in both wild-type and PKD1/3−/− DT40 B cells in response to either phorbol ester or BCR stimulation.
T5029	12476-12737	Sentence	denotes	In contrast, BCR and phorbol ester-induced NFκB transcriptional activity was abolished in PKCβ−/− DT40 B cells (Fig. 4A), although strong activation of PKD kinases (as assessed by autophosphorylation of PKD1 at S916) was observed in the PKCβ−/− cells (Fig. 4B).
T5030	12738-12913	Sentence	denotes	Thus, PKD kinases are neither essential nor sufficient to mediate BCR-induced NFκB activation in DT40 B cells and hence do not participate in DAG/PKC mediated control of NFκB.
T16	27-377	Sentence	denotes	Previously we have shown that PKDs have an essential role in regulating class II histone deacetylases in DT40 B-cells [Matthews, S.A., Liu, P., Spitaler, M., Olson, E.N., McKinsey, T.A., Cantrell, D.A. and Scharenberg, A.M. (2006) Essential role for protein kinase D family kinases in the regulation of class II histone deacetylases in B lymphocytes.
T18	410-500	Sentence	denotes	We now show that PKDs are also required to regulate HSP27 phosphorylation in DT40 B-cells.
T19	501-742	Sentence	denotes	However, in contrast to previous observations in other cell types, PKD enzymes do not regulate basic cellular processes such as proliferation or survival responses, nor NFκB transcriptional activity downstream of the B cell antigen receptor.
T20	743-799	Sentence	denotes	Thus, PKDs have a selective role in DT40 B-cell biology.
T4	27-377	Sentence	denotes	Previously we have shown that PKDs have an essential role in regulating class II histone deacetylases in DT40 B-cells [Matthews, S.A., Liu, P., Spitaler, M., Olson, E.N., McKinsey, T.A., Cantrell, D.A. and Scharenberg, A.M. (2006) Essential role for protein kinase D family kinases in the regulation of class II histone deacetylases in B lymphocytes.
T5	378-382	Sentence	denotes	Mol.
T6	383-393	Sentence	denotes	Cell Biol.
T7	394-409	Sentence	denotes	26, 1569–1577].
T8	410-500	Sentence	denotes	We now show that PKDs are also required to regulate HSP27 phosphorylation in DT40 B-cells.
T9	501-742	Sentence	denotes	However, in contrast to previous observations in other cell types, PKD enzymes do not regulate basic cellular processes such as proliferation or survival responses, nor NFκB transcriptional activity downstream of the B cell antigen receptor.
T10	743-799	Sentence	denotes	Thus, PKDs have a selective role in DT40 B-cell biology.
T11	801-816	Sentence	denotes	1 Introduction
T12	817-914	Sentence	denotes	The protein kinase D (PKD) serine/threonine kinase family has three members: PKD1, PKD2 and PKD3.
T13	915-1114	Sentence	denotes	Most cell types express at least two PKD isoforms but PKD enzymes are especially highly expressed in haematopoietic cells, where they are activated in response to antigen receptors stimulation [2,3].
T14	1115-1428	Sentence	denotes	A conserved signalling pathway linking antigen receptors to PKDs involves the activation of PLCγ and the subsequent production of diacylglycerol (DAG) which stimulates classical and/or novel protein kinase Cs (PKC) that phosphorylate two key regulatory serine residues in the activation loop of PKD kinases [3–6].
T15	1429-1651	Sentence	denotes	The N-terminal regulatory region of PKD enzymes contains a DAG binding domain and direct binding of DAG also contributes to PKD1 activation [7] as well as regulating the spatial location of PKD enzymes within cells [8–12].
T16	1652-1824	Sentence	denotes	PKD enzymes have been proposed to regulate numerous cellular functions, including cell proliferation [13–16], anti-apoptotic signals [17,18] and thymocyte development [19].
T17	1825-1986	Sentence	denotes	Expression of mutant catalytically inactive and constitutively activated PKDs can also modify Golgi function, cell adhesion and cell motility (reviewed in [20]).
T18	1987-2149	Sentence	denotes	In particular, PKDs have been widely linked to the activation of the NFκB transcription factor and in regulating cell survival during oxidative stress [17,21–23].
T19	2150-2294	Sentence	denotes	Another recently proposed PKD1 substrate is HSP27 [24], a small heat shock protein involved in regulating cell migration and cell survival [25].
T20	2295-2475	Sentence	denotes	An essential role for PKD enzymes in regulating class II histone deacetylases (HDACs), enzymes that repress MEF2-dependent gene transcription, has also been demonstrated [1,26–28].
T21	2476-2829	Sentence	denotes	To investigate the biological role of PKDs we have generated DT40 B cell lines that lack expression of one or more members of the PKD family [1], allowing us to investigate the function(s) of PKD isoforms following B cell antigen receptor (BCR) stimulation, as well addressing the issue of functional redundancy between the different PKD family members.
T22	2830-2921	Sentence	denotes	Previous studies have shown that PKDs are indispensable for HDAC regulation in B cells [1].
T23	2922-3007	Sentence	denotes	Herein we show that PKDs are also indispensable for HSP27 phosphorylation in B cells.
T24	3008-3075	Sentence	denotes	However, PKD-null DT40 B cells are viable and proliferate normally.
T25	3076-3277	Sentence	denotes	Moreover, loss of the entire cellular pool of PKD does not critically affect oxidative stress responses in B cells nor do PKD kinases play an essential role in regulating NFκB transcriptional activity.
T26	3278-3461	Sentence	denotes	Together, these findings reveal that in B lymphocytes, PKD kinases are not critical regulators of many of the cellular processes previously ascribed to them in other cellular systems.
T27	3463-3487	Sentence	denotes	2 Materials and methods
T28	3489-3552	Sentence	denotes	2.1 Cell culture, transient transfections and cell stimulation
T29	3553-3688	Sentence	denotes	The generation, culture and activation of PKD1−/−, PKD3−/− and PKD1/3−/− knockout DT40 B cell lines have been described previously [1].
T30	3689-3801	Sentence	denotes	Cells were lysed and protein extracts were analysed in Western blotting experiments as previously described [1].
T31	3802-3880	Sentence	denotes	Chloramphenicol acetyl transferase assays have been described previously [29].
T32	3882-3900	Sentence	denotes	2.2 sIgM staining
T33	3901-4098	Sentence	denotes	DT40 B cells (2 × 106 cells per point) were resuspended in 200 μl buffer (RPMI 1640 media, 1% foetal calf serum) containing anti-chicken M1 monoclonal antibody conjugated to FITC for 20 min on ice.
T34	4099-4184	Sentence	denotes	The cells were washed twice and fluorescent intensity was analysed by flow cytometry.
T35	4185-4291	Sentence	denotes	All results shown are representative of at two to four independent experiments unless otherwise indicated.
T36	4293-4303	Sentence	denotes	3 Results
T37	4305-4396	Sentence	denotes	3.1 Loss of HSP27 phosphorylation in DT40 B cells lacking expression of PKD family kinases
T38	4397-4588	Sentence	denotes	DT40 B cells express two PKD isoforms, PKD1 and PKD3, and as previously described we have recently generated DT40 B cell lines that lack expression of either PKD1 or PKD3 or both enzymes [1].
T39	4589-4774	Sentence	denotes	In generating the double knockout cell lines we targeted the PKD1 loci in a PKD3−/− cell line that expressed a Flag-PKD3 transgene under the control of a doxycycline-inducible promoter.
T40	4775-5046	Sentence	denotes	Hence, in the presence of doxycycline, Flag-PKD3 expression in PKD1/3 double knockout cells is comparable to endogenous PKD3 present in wild-type DT40 cells and removal of doxycycline from the culture media for 5 days results in a completely null PKD phenotype (Fig. 1A).
T41	5047-5284	Sentence	denotes	Previously, we have demonstrated that phosphorylation and nuclear exclusion of class II histone deacetylases (HDACs) during BCR engagement is defective in PKD1/3−/− B cells and can restored upon re-expression of a single PKD isoform [1].
T42	5285-5519	Sentence	denotes	The small heat shock protein HSP27 has recently been proposed as a PKD1 substrate [24] and we accordingly assessed whether PKD-null DT40 cells have defective phosphorylation of HSP27 on serine 82, the proposed PKD1 substrate sequence.
T43	5520-5646	Sentence	denotes	We initially investigated the regulation of HSP27 phosphorylation in single knockout DT40 B cells lacking either PKD1 or PKD3.
T44	5647-5808	Sentence	denotes	As shown in Fig. 1B, activation of the BCR or treatment with the DAG-mimetic PdBu increased the levels of HSP27 phosphorylation at S82 in wild-type DT40 B cells.
T45	5809-5943	Sentence	denotes	BCR and phorbol ester signals were also able to increase HSP27 phosphorylation in PKD1 or PKD3 single knockout DT40 B cells (Fig. 1B).
T46	5944-6082	Sentence	denotes	However, BCR- and phorbol ester-induced phosphorylation of HSP27 on S82 was abolished in B cells that lacked both PKD1 and PKD3 (Fig. 1C).
T47	6083-6264	Sentence	denotes	Significantly, doxycycline-induced expression of the Flag-PKD3 transgene in the double knockout cells was sufficient to restore normal regulation of HSP27 phosphorylation (Fig. 1C).
T48	6265-6446	Sentence	denotes	In contrast, expression of a kinase-deficient PKD3 mutant protein in the double knockout cells was not able to restore BCR- or phorbol ester-induced HSP27 phosphorylation (Fig. 1D).
T49	6447-6579	Sentence	denotes	Hence, PKD3 as well as PKD1 can regulate HSP27 phosphorylation and in DT40 B cells they are functionally redundant as HSP27 kinases.
T50	6581-6678	Sentence	denotes	3.2 Cellular proliferation and survival in DT40 B cells lacking expression of PKD family kinases
T51	6679-6791	Sentence	denotes	PKD enzymes have previously been linked to the regulation of cell proliferation and survival (reviewed in [20]).
T52	6792-6955	Sentence	denotes	To investigate the effect that loss of PKD kinases had on B cell survival and/or proliferation we cultured wild-type and PKD-null cells in the presence (PKD1/3−/−:
T53	6956-7041	Sentence	denotes	Flag-PKD3+ve) or absence (PKD1/3−/−) of doxycycline and monitored exponential growth.
T54	7042-7195	Sentence	denotes	As shown in Fig. 2A, PKD1/3−/− cells proliferated exponentially and re-expression of Flag-PKD3 in these cells had no impact on the rate of proliferation.
T55	7196-7349	Sentence	denotes	Furthermore, the viability of PKD1/3−/− B cells during routine culturing was not significantly different from that of wild-type B cells (data not shown).
T56	7350-7737	Sentence	denotes	It was noted that the population doubling time of PKD1/3−/− cells was slightly slower than that of wild type DT40 cells (12.7 ± 2.8 h versus 10.2 ± 0.4 h) but the failure of PKD3 re-expression to modify the proliferation rate of PKD1/3−/− cells suggests that these small differences were most likely the result of clonal variation and were not caused specifically by loss of PKD enzymes.
T57	7738-7845	Sentence	denotes	Thus, PKD family enzymes are not essential for regulating basal survival and proliferation of DT40 B cells.
T58	7846-8037	Sentence	denotes	PKD enzymes, specifically PKD1 and PKD2, have previously been linked to a protective role against oxidative stress-induced injury in 3T3 fibroblast, HeLa and epithelial cell lines [17,30–32].
T59	8038-8179	Sentence	denotes	We therefore addressed the role of PKD family kinases in regulating B cell survival in response to oxidative stress and other stress stimuli.
T60	8180-8568	Sentence	denotes	As shown in Fig. 2B, loss of PKD1/3 expression had no significant impact on the survival of DT40 B cells in response to mitochondrial stress stimuli (H2O2 or serum deprivation); DNA damaging agents (etoposide or doxorubicin); ER pathway stress due to calcium overload (thapsigargin) or following prolonged treatment with phorbol esters or Trichostatin A, an inhibitor of class I/II HDACs.
T61	8569-8698	Sentence	denotes	Thus, PKD kinases do not play an essential role in regulating B cell survival in response to a range of different stress stimuli.
T62	8700-8776	Sentence	denotes	3.3 Antigen receptor regulated signalling pathways in PKD-null DT40 B cells
T63	8777-8955	Sentence	denotes	To further explore the contribution of PKD kinases to DT40 B cell biology we investigated whether specific BCR-regulated signalling events were defective in the PKD-null B cells.
T64	8956-9147	Sentence	denotes	Initial experiments revealed that surface expression of the BCR was reduced in PKD1/3−/− (and in PKD1/3−/−:Flag-PKD3+ve) cells compared to wild-type DT40 B cells (Fig. 3A and data not shown).
T65	9148-9328	Sentence	denotes	Nevertheless, BCR-crosslinking of PKD1/3−/− cells was sufficient to induce the activation of a number of signalling cascades, similar to that observed in wild-type cells (Fig. 3B).
T66	9329-9526	Sentence	denotes	Hence, BCR-induced activation of the Akt, mTOR/p70 S6 kinase (as shown by S6 ribosomal protein phosphorylation) and MAPK signalling pathways was clearly detectable in PKD1/3-null B cells (Fig. 3B).
T67	9527-9743	Sentence	denotes	Furthermore, enhanced tyrosine phosphorylation of multiple cellular proteins as well as an increase in intracellular calcium levels was also observed following BCR stimulation of PKD1/3-null B cells (data not shown).
T68	9744-9936	Sentence	denotes	We did observe that the strength of BCR (but not phorbol ester)-induced regulation of the Erk1-RSK1 signalling pathway was reduced in PKD1/3−/− B cells compared to wild-type B cells (Fig. 3B).
T69	9937-10017	Sentence	denotes	One interpretation of this data is that PKD enzymes may modulate Erk activation.
T70	10018-10161	Sentence	denotes	Indeed, PKD enzymes have previously been linked to the growth factor-regulated Erk signalling in fibroblast and endothelial cell lines [33–35].
T71	10162-10465	Sentence	denotes	However, BCR-induced Erk phosphorylation was also reduced in PKD1/3−/−-Flag-PKD3+ B cells (data not shown) suggesting that reduced BCR levels on the surface of PKD1/3−/− (and PKD1/3−/−-Flag-PKD3+) B cells may itself impact on the strength of activation of this specific intracellular signalling pathway.
T72	10466-10704	Sentence	denotes	To search for other potential PKD targets that may show defective regulation in PKD1/3−/− DT40 B cells, we used a PKD substrate phospho-antibody that recognises consensus phosphorylation sequences targeted by PKD enzymes (LxRxxpS/T) [36].
T73	10705-10919	Sentence	denotes	As shown in Fig. 3C, phorbol ester- and BCR-induced phosphorylation of cellular substrates detected by this phospho-antibody was similar in wild-type and PKD1/3−/− cells and is therefore independent of PKD enzymes.
T74	10920-11134	Sentence	denotes	However, pretreatment of both wild-type and PKD1/3−/− DT40 B cells with GF109203X, a bisindoylmaleimide derivative that inhibits PKCs prevented the induction of proteins that contain phosphorylated LxRxxS/T motifs.
T75	11135-11260	Sentence	denotes	Thus loss of PKD1/3 enzymes does not globally disrupt the phosphorylation of cellular proteins that contain LxRxxpS/T motifs.
T76	11261-11398	Sentence	denotes	This result is perhaps not surprising as LxRxxS/T motifs also act as good substrates for other serine/threonine kinases such as MAPKAPK2.
T77	11399-11566	Sentence	denotes	However these experiments do provide further evidence that phosphospecific antisera are not sufficiently selective to be designated kinase specific substrate antisera.
T78	11567-11713	Sentence	denotes	BCR-induced signalling pathways culminate in the activation of gene transcription events that control B cell survival, proliferation and function.
T79	11714-11858	Sentence	denotes	In this context, it has been proposed that PKD family members control of gene transcription through activation of the NFκB transcription factor.
T80	11859-12047	Sentence	denotes	Thus, PKD-mediated activation of NFκB occurs downstream of a variety of different signals, including mROS/oxidative stress, lysophosphatidic acid and the Bcr-Abl oncogene [17,21,23,30,37].
T81	12048-12144	Sentence	denotes	Furthermore, expression of an activated PKD1 mutant enhances HPK1-mediated NFκB activation [38].
T82	12145-12294	Sentence	denotes	In B cells, NFκB is known to be regulated via DAG and PKCβ [39,40] but whether PKDs are key intermediaries for NFκB regulation has not been explored.
T83	12295-12475	Sentence	denotes	The data (Fig. 4A) show that NFκB transcriptional activity was strongly induced in both wild-type and PKD1/3−/− DT40 B cells in response to either phorbol ester or BCR stimulation.
T84	12476-12737	Sentence	denotes	In contrast, BCR and phorbol ester-induced NFκB transcriptional activity was abolished in PKCβ−/− DT40 B cells (Fig. 4A), although strong activation of PKD kinases (as assessed by autophosphorylation of PKD1 at S916) was observed in the PKCβ−/− cells (Fig. 4B).
T85	12738-12913	Sentence	denotes	Thus, PKD kinases are neither essential nor sufficient to mediate BCR-induced NFκB activation in DT40 B cells and hence do not participate in DAG/PKC mediated control of NFκB.
T86	12915-12928	Sentence	denotes	4 Discussion

ICD10

Id	Subject	Object	Predicate	Lexical cue
T3136	5300-5305	http://purl.bioontology.org/ontology/ICD10/R57.9	denotes	shock
T1482	2219-2224	http://purl.bioontology.org/ontology/ICD10/R57.9	denotes	shock
T4612	7969-7975	http://purl.bioontology.org/ontology/ICD10/T14.9	denotes	injury

events-check-again

Id	Subject	Object	Predicate	Lexical cue	Negation	Speculation
T3563	4895-4899	Protein	denotes	PKD3
T3564	5202-5206	Protein	denotes	PKD1
T3565	5207-5208	Protein	denotes	3
T3566	5314-5319	Protein	denotes	HSP27
T3567	5352-5356	Protein	denotes	PKD1
T3568	5433-5442	Negative_regulation	denotes	defective
T3569	5443-5458	Phosphorylation	denotes	phosphorylation
T3570	5462-5467	Protein	denotes	HSP27
T3571	5471-5480	Entity	denotes	serine 82
T3572	5495-5499	Protein	denotes	PKD1
T3573	5550-5560	Regulation	denotes	regulation		true
T3574	5564-5569	Protein	denotes	HSP27
T3575	5570-5585	Phosphorylation	denotes	phosphorylation
T3576	5618-5625	Negative_regulation	denotes	lacking
T3577	5618-5625	Negative_regulation	denotes	lacking
T3578	5633-5637	Protein	denotes	PKD1
T3579	5641-5645	Protein	denotes	PKD3
T3580	5729-5738	Positive_regulation	denotes	increased
T3581	5753-5758	Protein	denotes	HSP27
T3582	5759-5774	Phosphorylation	denotes	phosphorylation
T3583	5778-5781	Entity	denotes	S82
T3584	5857-5865	Positive_regulation	denotes	increase
T3585	5866-5871	Protein	denotes	HSP27
T3586	5872-5887	Phosphorylation	denotes	phosphorylation
T3587	5891-5895	Protein	denotes	PKD1
T3588	5899-5903	Protein	denotes	PKD3
T3589	5911-5919	Negative_regulation	denotes	knockout
T3590	5911-5919	Negative_regulation	denotes	knockout
T3591	5976-5983	Positive_regulation	denotes	induced
T3592	5984-5999	Phosphorylation	denotes	phosphorylation
T3593	6003-6008	Protein	denotes	HSP27
T3594	6012-6015	Entity	denotes	S82
T3595	6020-6029	Negative_regulation	denotes	abolished
T3596	6020-6029	Negative_regulation	denotes	abolished
T3597	6046-6052	Negative_regulation	denotes	lacked
T3598	6046-6052	Negative_regulation	denotes	lacked
T3599	6058-6062	Protein	denotes	PKD1
T3600	6067-6071	Protein	denotes	PKD3
T3601	6110-6117	Positive_regulation	denotes	induced
T3602	6118-6128	Gene_expression	denotes	expression
T3603	6141-6145	Protein	denotes	PKD3
T3604	6189-6210	Positive_regulation	denotes	sufficient to restore
T3605	6218-6228	Regulation	denotes	regulation
T3606	6232-6237	Protein	denotes	HSP27
T3607	6238-6253	Phosphorylation	denotes	phosphorylation
T3608	6278-6288	Gene_expression	denotes	expression
T3609	6301-6310	Negative_regulation	denotes	deficient
T3610	6311-6315	Protein	denotes	PKD3
T3611	6376-6383	Positive_regulation	denotes	restore	true
T3612	6406-6413	Positive_regulation	denotes	induced
T3613	6414-6419	Protein	denotes	HSP27
T3614	6420-6435	Phosphorylation	denotes	phosphorylation
T3615	6454-6458	Protein	denotes	PKD3
T3616	6470-6474	Protein	denotes	PKD1
T3617	6479-6487	Regulation	denotes	regulate
T3618	6479-6487	Regulation	denotes	regulate
T3619	6488-6493	Protein	denotes	HSP27
T3620	6494-6509	Phosphorylation	denotes	phosphorylation
T3621	6565-6570	Protein	denotes	HSP27
T4751	6945-6949	Protein	denotes	PKD1
T4752	6950-6951	Protein	denotes	3
T4753	6961-6965	Protein	denotes	PKD3
T4754	6982-6986	Protein	denotes	PKD1
T4755	6987-6988	Protein	denotes	3
T4756	7063-7067	Protein	denotes	PKD1
T4757	7068-7069	Protein	denotes	3
T4758	7110-7123	Gene_expression	denotes	re-expression
T4759	7132-7136	Protein	denotes	PKD3
T4760	7226-7230	Protein	denotes	PKD1
T4761	7231-7232	Protein	denotes	3
T4762	7400-7404	Protein	denotes	PKD1
T4763	7405-7406	Protein	denotes	3
T4764	7524-7528	Protein	denotes	PKD3
T4765	7529-7542	Gene_expression	denotes	re-expression
T4766	7579-7583	Protein	denotes	PKD1
T4767	7584-7585	Protein	denotes	3
T4768	7872-7876	Protein	denotes	PKD1
T4769	7881-7885	Protein	denotes	PKD2
T4770	8201-8205	Negative_regulation	denotes	loss
T4771	8201-8205	Negative_regulation	denotes	loss
T4772	8209-8213	Protein	denotes	PKD1
T4773	8214-8215	Protein	denotes	3
T4774	8216-8226	Gene_expression	denotes	expression
T4775	8216-8226	Gene_expression	denotes	expression
T6905	9035-9039	Protein	denotes	PKD1
T6906	9040-9041	Protein	denotes	3
T6907	9053-9057	Protein	denotes	PKD1
T6908	9058-9059	Protein	denotes	3
T6909	9068-9072	Protein	denotes	PKD3
T6910	9182-9186	Protein	denotes	PKD1
T6911	9187-9188	Protein	denotes	3
T6912	9340-9347	Positive_regulation	denotes	induced
T6913	9340-9347	Positive_regulation	denotes	induced
T6914	9340-9347	Positive_regulation	denotes	induced
T6915	9348-9358	Positive_regulation	denotes	activation
T6916	9348-9358	Positive_regulation	denotes	activation
T6917	9348-9358	Positive_regulation	denotes	activation
T6918	9366-9369	Protein	denotes	Akt
T6919	9371-9375	Protein	denotes	mTOR
T6920	9403-9423	Protein	denotes	S6 ribosomal protein
T6921	9424-9439	Phosphorylation	denotes	phosphorylation
T6922	9482-9492	Negative_regulation	denotes	detectable	true
T6923	9482-9492	Negative_regulation	denotes	detectable	true
T6924	9482-9492	Negative_regulation	denotes	detectable	true
T6925	9482-9492	Negative_regulation	denotes	detectable	true
T6926	9482-9492	Negative_regulation	denotes	detectable	true
T6927	9482-9492	Negative_regulation	denotes	detectable	true
T6928	9496-9500	Protein	denotes	PKD1
T6929	9501-9502	Protein	denotes	3
T6930	9503-9507	Negative_regulation	denotes	null
T6931	9503-9507	Negative_regulation	denotes	null
T6932	9706-9710	Protein	denotes	PKD1
T6933	9711-9712	Protein	denotes	3
T6934	9834-9838	Protein	denotes	Erk1
T6935	9839-9843	Protein	denotes	RSK1
T6942	10327-10328	Protein	denotes	3
T6943	10337-10341	Protein	denotes	PKD1
T425	441-449	Positive_regulation	denotes	required
T426	453-461	Regulation	denotes	regulate
T427	462-467	Protein	denotes	HSP27
T428	468-483	Phosphorylation	denotes	phosphorylation
T1575	894-898	Protein	denotes	PKD1
T1576	900-904	Protein	denotes	PKD2
T1577	909-913	Protein	denotes	PKD3
T1578	1518-1525	Binding	denotes	binding
T1579	1538-1549	Positive_regulation	denotes	contributes
T1580	1553-1557	Protein	denotes	PKD1
T1581	1558-1568	Positive_regulation	denotes	activation
T1582	2176-2180	Protein	denotes	PKD1
T1583	2194-2199	Protein	denotes	HSP27
T1584	2403-2407	Protein	denotes	MEF2
T1585	2956-2969	Positive_regulation	denotes	indispensable
T1586	2974-2979	Protein	denotes	HSP27
T1587	2980-2995	Phosphorylation	denotes	phosphorylation
T3540	4310-4314	Negative_regulation	denotes	Loss		true
T3541	4318-4323	Protein	denotes	HSP27
T3542	4324-4339	Phosphorylation	denotes	phosphorylation
T3543	4410-4417	Gene_expression	denotes	express
T3544	4410-4417	Gene_expression	denotes	express
T3545	4436-4440	Protein	denotes	PKD1
T3546	4445-4449	Protein	denotes	PKD3
T3547	4529-4533	Negative_regulation	denotes	lack
T3548	4529-4533	Negative_regulation	denotes	lack
T3549	4534-4544	Gene_expression	denotes	expression
T3550	4534-4544	Gene_expression	denotes	expression
T3551	4555-4559	Protein	denotes	PKD1
T3552	4563-4567	Protein	denotes	PKD3
T3553	4650-4654	Protein	denotes	PKD1
T3554	4665-4669	Protein	denotes	PKD3
T3555	4688-4697	Gene_expression	denotes	expressed
T3556	4705-4709	Protein	denotes	PKD3
T3557	4819-4823	Protein	denotes	PKD3
T3558	4824-4834	Gene_expression	denotes	expression
T3559	4838-4842	Protein	denotes	PKD1
T3560	4843-4844	Protein	denotes	3
T3561	4845-4860	Negative_regulation	denotes	double knockout
T3562	4845-4860	Negative_regulation	denotes	double knockout
T6936	9878-9882	Protein	denotes	PKD1
T6937	9883-9884	Protein	denotes	3
T6938	10223-10227	Protein	denotes	PKD1
T6939	10228-10229	Protein	denotes	3
T6940	10238-10242	Protein	denotes	PKD3
T6941	10322-10326	Protein	denotes	PKD1
T6944	10342-10343	Protein	denotes	3
T6945	10352-10356	Protein	denotes	PKD3
T6946	10546-10550	Protein	denotes	PKD1
T6947	10551-10552	Protein	denotes	3
T6948	10859-10863	Protein	denotes	PKD1
T6949	10864-10865	Protein	denotes	3
T6950	10964-10968	Protein	denotes	PKD1
T6951	10969-10970	Protein	denotes	3
T6952	11140-11144	Negative_regulation	denotes	loss
T6953	11140-11144	Negative_regulation	denotes	loss
T6954	11148-11152	Protein	denotes	PKD1
T6955	11153-11154	Protein	denotes	3
T6956	11389-11397	Protein	denotes	MAPKAPK2
T6957	12013-12029	Protein	denotes	Bcr-Abl oncogene
T6958	12061-12087	Positive_regulation	denotes	expression of an activated
T6959	12088-12092	Protein	denotes	PKD1
T6960	12109-12113	Protein	denotes	HPK1
T6961	12199-12203	Protein	denotes	PKCβ
T6962	12397-12401	Protein	denotes	PKD1
T6963	12402-12403	Protein	denotes	3
T6964	12566-12571	Protein	denotes	PKCβ−
T6965	12656-12675	Phosphorylation	denotes	autophosphorylation
T6966	12679-12683	Protein	denotes	PKD1
T6967	12687-12691	Entity	denotes	S916
T6968	12697-12705	Positive_regulation	denotes	observed
T6969	12713-12718	Protein	denotes	PKCβ−
T7775	12946-12952	Entity	denotes	serine
T1851	3595-3599	Protein	denotes	PKD1
T1852	3604-3608	Protein	denotes	PKD3
T1853	3616-3620	Protein	denotes	PKD1
T1854	3621-3622	Protein	denotes	3
T1855	3626-3634	Negative_regulation	denotes	knockout
T1856	3626-3634	Negative_regulation	denotes	knockout
T1857	3626-3634	Negative_regulation	denotes	knockout
T1858	3626-3634	Negative_regulation	denotes	knockout
R2918	T3541	T3542	themeOf	HSP27,phosphorylation
R2925	T3542	T3540	themeOf	phosphorylation,Loss
R2926	T3545	T3543	themeOf	PKD1,express
R2927	T3546	T3544	themeOf	PKD3,express
R2929	T3550	T3548	themeOf	expression,lack
R2930	T3551	T3550	themeOf	PKD1,expression
R2941	T3587	T3590	themeOf	PKD1,knockout
R2942	T3588	T3589	themeOf	PKD3,knockout
R2944	T3591	T3595	themeOf	induced,abolished
R2945	T3591	T3596	themeOf	induced,abolished
R2946	T3592	T3591	themeOf	phosphorylation,induced
R2948	T3594	T3592	themeOf	S82,phosphorylation
R2949	T3594	T3593	partOf	S82,HSP27
R2950	T3597	T3596	causeOf	lacked,abolished
R2951	T3598	T3595	causeOf	lacked,abolished
R2952	T3599	T3598	themeOf	PKD1,lacked
R2953	T3600	T3597	themeOf	PKD3,lacked
R2954	T3601	T3604	causeOf	induced,sufficient to restore
R2955	T3602	T3601	themeOf	expression,induced
R2957	T3603	T3602	themeOf	PKD3,expression
R2958	T3605	T3604	themeOf	regulation,sufficient to restore
R2959	T3606	T3607	themeOf	HSP27,phosphorylation
R2960	T3607	T3605	themeOf	phosphorylation,regulation
R2962	T3608	T3611	causeOf	expression,restore
R2963	T3610	T3608	themeOf	PKD3,expression
R2964	T3610	T3609	themeOf	PKD3,deficient
R2966	T3612	T3611	themeOf	induced,restore
R2967	T3613	T3614	themeOf	HSP27,phosphorylation
R2968	T3614	T3612	themeOf	phosphorylation,induced
R2969	T3615	T3618	causeOf	PKD3,regulate
R2971	T3616	T3617	causeOf	PKD1,regulate
R2973	T3619	T3620	themeOf	HSP27,phosphorylation
R2974	T3620	T3618	themeOf	phosphorylation,regulate
R2975	T3620	T3617	themeOf	phosphorylation,regulate
R3843	T4759	T4758	themeOf	PKD3,re-expression
R3844	T4764	T4765	themeOf	PKD3,re-expression
R3845	T4772	T4774	themeOf	PKD1,expression
R3846	T4773	T4775	themeOf	3,expression
R3847	T4774	T4771	themeOf	expression,loss
R3848	T4775	T4770	themeOf	expression,loss
R5508	T6931	T6926	causeOf	null,detectable
R5509	T6965	T6968	themeOf	autophosphorylation,observed
R5510	T6967	T6965	themeOf	S916,autophosphorylation
R5511	T6967	T6966	partOf	S916,PKD1
R410	T426	T425	themeOf	regulate,required
R411	T427	T428	themeOf	HSP27,phosphorylation
R412	T428	T426	themeOf	phosphorylation,regulate
R1400	T1578	T1579	causeOf	binding,contributes
R1402	T1580	T1578	themeOf	PKD1,binding
R1403	T1580	T1581	themeOf	PKD1,activation
R1404	T1581	T1579	themeOf	activation,contributes
R1405	T1586	T1587	themeOf	HSP27,phosphorylation
R1406	T1587	T1585	themeOf	phosphorylation,indispensable
R2928	T3549	T3547	themeOf	expression,lack
R2931	T3579	T3577	themeOf	PKD3,lacking
R2932	T3552	T3549	themeOf	PKD3,expression
R2933	T3582	T3580	themeOf	phosphorylation,increased
R2934	T3556	T3555	themeOf	PKD3,expressed
R2935	T3583	T3582	themeOf	S82,phosphorylation
R2936	T3583	T3581	partOf	S82,HSP27
R2937	T3585	T3586	themeOf	HSP27,phosphorylation
R2938	T3586	T3584	themeOf	phosphorylation,increase
R2939	T3557	T3558	themeOf	PKD3,expression
R2940	T3559	T3562	themeOf	PKD1,double knockout
R2943	T3560	T3561	themeOf	3,double knockout
R2947	T3569	T3568	themeOf	phosphorylation,defective
R2956	T3571	T3569	themeOf	serine 82,phosphorylation
R2961	T3571	T3570	partOf	serine 82,HSP27
R2965	T3574	T3575	themeOf	HSP27,phosphorylation
R2970	T3575	T3573	themeOf	phosphorylation,regulation
R2972	T3578	T3576	themeOf	PKD1,lacking
R1592	T1851	T1855	themeOf	PKD1,knockout
R1593	T1852	T1856	themeOf	PKD3,knockout
R1594	T1853	T1857	themeOf	PKD1,knockout
R1595	T1854	T1858	themeOf	3,knockout
R5479	T6912	T6922	themeOf	induced,detectable
R5486	T6912	T6924	themeOf	induced,detectable
R5487	T6913	T6927	themeOf	induced,detectable
R5488	T6913	T6926	themeOf	induced,detectable
R5489	T6914	T6923	themeOf	induced,detectable
R5490	T6914	T6925	themeOf	induced,detectable
R5491	T6915	T6914	themeOf	activation,induced
R5492	T6916	T6912	themeOf	activation,induced
R5493	T6917	T6913	themeOf	activation,induced
R5494	T6918	T6917	themeOf	Akt,activation
R5495	T6919	T6916	themeOf	mTOR,activation
R5496	T6920	T6921	themeOf	S6 ribosomal protein,phosphorylation
R5497	T6921	T6915	themeOf	phosphorylation,activation
R5498	T6928	T6931	themeOf	PKD1,null
R5499	T6929	T6930	themeOf	3,null
R5500	T6930	T6927	causeOf	null,detectable
R5501	T6954	T6953	themeOf	PKD1,loss
R5502	T6930	T6924	causeOf	null,detectable
R5503	T6930	T6925	causeOf	null,detectable
R5504	T6955	T6952	themeOf	3,loss
R5505	T6931	T6922	causeOf	null,detectable
R5506	T6931	T6923	causeOf	null,detectable
R5507	T6959	T6958	themeOf	PKD1,expression of an activated

bionlp-st-ge-2016-reference-tees

Id	Subject	Object	Predicate	Lexical cue
T435	57-61	Protein	denotes	PKDs
T436	99-128	Protein	denotes	class II histone deacetylases
T437	277-308	Protein	denotes	protein kinase D family kinases
T438	330-359	Protein	denotes	class II histone deacetylases
T439	316-326	Regulation	denotes	regulation
T440	427-431	Protein	denotes	PKDs
T441	462-467	Protein	denotes	HSP27
T442	468-483	Phosphorylation	denotes	phosphorylation
T443	453-461	Regulation	denotes	regulate
T444	441-449	Positive_regulation	denotes	required
T445	568-579	Protein	denotes	PKD enzymes
T446	670-674	Protein	denotes	NFκB
T447	718-741	Protein	denotes	B cell antigen receptor
T448	587-595	Regulation	denotes	regulate
T449	749-753	Protein	denotes	PKDs
T1588	821-837	Protein	denotes	protein kinase D
T1589	839-842	Protein	denotes	PKD
T1590	844-874	Protein	denotes	serine/threonine kinase family
T1591	894-898	Protein	denotes	PKD1
T1592	900-904	Protein	denotes	PKD2
T1593	909-913	Protein	denotes	PKD3
T1594	952-955	Protein	denotes	PKD
T1595	969-972	Protein	denotes	PKD
T1596	931-938	Gene_expression	denotes	express
T1597	1003-1012	Gene_expression	denotes	expressed
T1598	1175-1179	Protein	denotes	PKDs
T1599	1207-1211	Protein	denotes	PLCγ
T1600	1306-1323	Protein	denotes	protein kinase Cs
T1601	1325-1328	Protein	denotes	PKC
T1602	1410-1421	Protein	denotes	PKD kinases
T1603	1272-1282	Positive_regulation	denotes	stimulates
T1604	1272-1282	Positive_regulation	denotes	stimulates
T1605	1335-1348	Phosphorylation	denotes	phosphorylate
T1606	1335-1348	Phosphorylation	denotes	phosphorylate
T1607	1465-1476	Protein	denotes	PKD enzymes
T1608	1529-1532	Protein	denotes	DAG
T1609	1553-1557	Protein	denotes	PKD1
T1610	1619-1630	Protein	denotes	PKD enzymes
T1611	1518-1525	Binding	denotes	binding
T1612	1558-1568	Positive_regulation	denotes	activation
T1613	1607-1615	Localization	denotes	location
T1614	1538-1549	Positive_regulation	denotes	contributes
T1615	1584-1594	Regulation	denotes	regulating
T1616	1652-1655	Protein	denotes	PKD
T1617	1898-1902	Protein	denotes	PKDs
T1618	1825-1835	Gene_expression	denotes	Expression
T1619	1888-1897	Positive_regulation	denotes	activated
T1620	1888-1897	Positive_regulation	denotes	activated
T1621	2002-2006	Protein	denotes	PKDs
T1622	2056-2081	Protein	denotes	NFκB transcription factor
T1623	2038-2048	Positive_regulation	denotes	activation
T1624	2176-2180	Protein	denotes	PKD1
T1625	2317-2328	Protein	denotes	PKD enzymes
T1626	2343-2372	Protein	denotes	class II histone deacetylases
T1627	2374-2379	Protein	denotes	HDACs
T1628	2403-2407	Protein	denotes	MEF2
T1629	2332-2342	Regulation	denotes	regulating
T1630	2332-2342	Regulation	denotes	regulating
T1631	2514-2518	Protein	denotes	PKDs
T1632	2606-2609	Protein	denotes	PKD
T1633	2668-2671	Protein	denotes	PKD
T1634	2691-2714	Protein	denotes	B cell antigen receptor
T1635	2716-2719	Protein	denotes	BCR
T1636	2810-2828	Protein	denotes	PKD family members
T1637	2863-2867	Protein	denotes	PKDs
T1638	2890-2894	Protein	denotes	HDAC
T1639	2895-2905	Regulation	denotes	regulation
T1640	2942-2946	Protein	denotes	PKDs
T1641	2974-2979	Protein	denotes	HSP27
T1642	2980-2995	Phosphorylation	denotes	phosphorylation
T1643	2956-2969	Positive_regulation	denotes	indispensable
T1644	3017-3020	Protein	denotes	PKD
T1645	3122-3125	Protein	denotes	PKD
T1646	3198-3209	Protein	denotes	PKD kinases
T1647	3247-3251	Protein	denotes	NFκB
T1648	3086-3090	Negative_regulation	denotes	loss
T1649	3333-3344	Protein	denotes	PKD kinases
T3622	4318-4323	Protein	denotes	HSP27
T3623	4343-4349	Protein	denotes	DT40 B
T3624	4378-4388	Protein	denotes	PKD family
T3625	4324-4339	Phosphorylation	denotes	phosphorylation
T3626	4364-4374	Gene_expression	denotes	expression
T3628	4356-4363	Negative_regulation	denotes	lacking
T3629	4397-4403	Protein	denotes	DT40 B
T3630	4422-4425	Protein	denotes	PKD
T3631	4436-4440	Protein	denotes	PKD1
T3632	4445-4449	Protein	denotes	PKD3
T3633	4555-4559	Protein	denotes	PKD1
T3634	4563-4567	Protein	denotes	PKD3
T3635	4410-4417	Gene_expression	denotes	express
T3636	4410-4417	Gene_expression	denotes	express
T3637	4410-4417	Gene_expression	denotes	express
T3638	4534-4544	Gene_expression	denotes	expression
T3639	4534-4544	Gene_expression	denotes	expression
T3640	4529-4533	Negative_regulation	denotes	lack
T3641	4529-4533	Negative_regulation	denotes	lack
T3642	4650-4659	Protein	denotes	PKD1 loci
T3643	4665-4669	Protein	denotes	PKD3
T3644	4700-4704	Protein	denotes	Flag
T3645	4705-4709	Protein	denotes	PKD3
T3646	4688-4697	Gene_expression	denotes	expressed
T3647	4688-4697	Gene_expression	denotes	expressed
T3648	4814-4818	Protein	denotes	Flag
T3649	4819-4823	Protein	denotes	PKD3
T3650	4838-4844	Protein	denotes	PKD1/3
T3651	4895-4899	Protein	denotes	PKD3
T3652	4824-4834	Gene_expression	denotes	expression
T3653	4824-4834	Gene_expression	denotes	expression
T3654	5126-5155	Protein	denotes	class II histone deacetylases
T3655	5157-5162	Protein	denotes	HDACs
T3656	5171-5174	Protein	denotes	BCR
T3657	5202-5206	Protein	denotes	PKD1
T3658	5085-5100	Phosphorylation	denotes	phosphorylation
T3659	5085-5100	Phosphorylation	denotes	phosphorylation
T3660	5175-5185	Binding	denotes	engagement
T3661	5228-5236	Positive_regulation	denotes	restored
T3662	5228-5236	Positive_regulation	denotes	restored
T3663	5289-5313	Protein	denotes	small heat shock protein
T3664	5314-5319	Protein	denotes	HSP27
T3665	5352-5356	Protein	denotes	PKD1
T3666	5408-5411	Protein	denotes	PKD
T3667	5462-5467	Protein	denotes	HSP27
T3668	5495-5499	Protein	denotes	PKD1
T3669	5471-5477	Entity	denotes	serine
T3670	5443-5458	Phosphorylation	denotes	phosphorylation
T3671	5433-5442	Negative_regulation	denotes	defective
T3672	5564-5569	Protein	denotes	HSP27
T3673	5633-5637	Protein	denotes	PKD1
T3675	5570-5585	Phosphorylation	denotes	phosphorylation
T3676	5618-5625	Negative_regulation	denotes	lacking
T3677	5618-5625	Negative_regulation	denotes	lacking
T3678	5550-5560	Regulation	denotes	regulation
T3679	5659-5662	Protein	denotes	Fig
T3680	5686-5689	Protein	denotes	BCR
T3681	5753-5758	Protein	denotes	HSP27
T3682	5668-5678	Positive_regulation	denotes	activation
T3683	5729-5738	Positive_regulation	denotes	increased
T3684	5759-5774	Phosphorylation	denotes	phosphorylation
T3685	5809-5812	Protein	denotes	BCR
T3686	5866-5871	Protein	denotes	HSP27
T3687	5891-5895	Protein	denotes	PKD1
T3688	5899-5903	Protein	denotes	PKD3
T3689	5872-5887	Phosphorylation	denotes	phosphorylation
T3690	5911-5919	Negative_regulation	denotes	knockout
T3691	5911-5919	Negative_regulation	denotes	knockout
T3692	5857-5865	Positive_regulation	denotes	increase
T3693	5953-5956	Protein	denotes	BCR
T3694	6003-6008	Protein	denotes	HSP27
T3695	6058-6062	Protein	denotes	PKD1
T3696	6067-6071	Protein	denotes	PKD3
T3697	6073-6080	Protein	denotes	Fig. 1C
T3698	6012-6015	Entity	denotes	S82
T3699	6046-6052	Negative_regulation	denotes	lacked
T3700	6046-6052	Negative_regulation	denotes	lacked
T3701	6046-6052	Negative_regulation	denotes	lacked
T3702	5984-5999	Phosphorylation	denotes	phosphorylation
T3703	5984-5999	Phosphorylation	denotes	phosphorylation
T3704	6020-6029	Negative_regulation	denotes	abolished
T3705	6020-6029	Negative_regulation	denotes	abolished
T3706	6136-6140	Protein	denotes	Flag
T3707	6141-6145	Protein	denotes	PKD3
T3708	6232-6237	Protein	denotes	HSP27
T3709	6118-6128	Gene_expression	denotes	expression
T3710	6118-6128	Gene_expression	denotes	expression
T3711	6238-6253	Phosphorylation	denotes	phosphorylation
T3712	6098-6117	Positive_regulation	denotes	doxycycline-induced
T3713	6098-6117	Positive_regulation	denotes	doxycycline-induced
T3714	6218-6228	Regulation	denotes	regulation
T3715	6203-6210	Positive_regulation	denotes	restore
T3716	6311-6315	Protein	denotes	PKD3
T3717	6414-6419	Protein	denotes	HSP27
T3718	6278-6288	Gene_expression	denotes	expression
T3719	6294-6310	Negative_regulation	denotes	kinase-deficient
T3720	6420-6435	Phosphorylation	denotes	phosphorylation
T3721	6376-6383	Positive_regulation	denotes	restore
T3722	6400-6413	Positive_regulation	denotes	ester-induced
T3723	6454-6458	Protein	denotes	PKD3
T3724	6470-6474	Protein	denotes	PKD1
T3725	6488-6493	Protein	denotes	HSP27
T3726	6565-6578	Protein	denotes	HSP27 kinases
T3727	6494-6509	Phosphorylation	denotes	phosphorylation
T3728	6479-6487	Regulation	denotes	regulate
T3729	6479-6487	Regulation	denotes	regulate
T4793	7226-7230	Protein	denotes	PKD1
T4794	7400-7404	Protein	denotes	PKD1
T4795	7524-7528	Protein	denotes	PKD3
T4796	7579-7583	Protein	denotes	PKD1
T4797	7725-7736	Protein	denotes	PKD enzymes
T4798	7529-7542	Gene_expression	denotes	re-expression
T4799	7717-7721	Negative_regulation	denotes	loss
T4800	7744-7762	Protein	denotes	PKD family enzymes
T4801	7832-7838	Protein	denotes	DT40 B
T4802	7846-7857	Protein	denotes	PKD enzymes
T4803	7872-7876	Protein	denotes	PKD1
T4804	7881-7885	Protein	denotes	PKD2
T4805	8073-8091	Protein	denotes	PKD family kinases
T4806	8192-8195	Protein	denotes	Fig
T4807	8209-8213	Protein	denotes	PKD1
T4808	8214-8215	Protein	denotes	3
T4809	8272-8278	Protein	denotes	DT40 B
T4810	8557-8567	Protein	denotes	I/II HDACs
T4811	8216-8226	Gene_expression	denotes	expression
T4812	8216-8226	Gene_expression	denotes	expression
T4813	8538-8547	Negative_regulation	denotes	inhibitor
T4814	8201-8205	Negative_regulation	denotes	loss
T4815	8201-8205	Negative_regulation	denotes	loss
T4816	8575-8586	Protein	denotes	PKD kinases
T7787	0-12960	Protein	denotes	40 B-lymphocyte cell line. Previously we have shown that PKDs have an essential role in regulating class II histone deacetylases in DT40 B-cells [Matthews, S.A., Liu, P., Spitaler, M., Olson, E.N., McKinsey, T.A., Cantrell, D.A. and Scharenberg, A.M. (2006) Essential role for protein kinase D family kinases in the regulation of class II histone deacetylases in B lymphocytes. Mol. Cell Biol. 26, 1569–1577]. We now show that PKDs are also required to regulate HSP27 phosphorylation in DT40 B-cells. However, in contrast to previous observations in other cell types, PKD enzymes do not regulate basic cellular processes such as proliferation or survival responses, nor NFκB transcriptional activity downstream of the B cell antigen receptor. Thus, PKDs have a selective role in DT40 B-cell biology. 1 Introduction The protein kinase D (PKD) serine/threonine kinase family has three members: PKD1, PKD2 and PKD3. Most cell types express at least two PKD isoforms but PKD enzymes are especially highly expressed in haematopoietic cells, where they are activated in response to antigen receptors stimulation [2,3]. A conserved signalling pathway linking antigen receptors to PKDs involves the activation of PLCγ and the subsequent production of diacylglycerol (DAG) which stimulates classical and/or novel protein kinase Cs (PKC) that phosphorylate two key regulatory serine residues in the activation loop of PKD kinases [3–6]. The N-terminal regulatory region of PKD enzymes contains a DAG binding domain and direct binding of DAG also contributes to PKD1 activation [7] as well as regulating the spatial location of PKD enzymes within cells [8–12]. PKD enzymes have been proposed to regulate numerous cellular functions, including cell proliferation [13–16], anti-apoptotic signals [17,18] and thymocyte development [19]. Expression of mutant catalytically inactive and constitutively activated PKDs can also modify Golgi function, cell adhesion and cell motility (reviewed in [20]). In particular, PKDs have been widely linked to the activation of the NFκB transcription factor and in regulating cell survival during oxidative stress [17,21–23]. Another recently proposed PKD1 substrate is HSP27 [24], a small heat shock protein involved in regulating cell migration and cell survival [25]. An essential role for PKD enzymes in regulating class II histone deacetylases (HDACs), enzymes that repress MEF2-dependent gene transcription, has also been demonstrated [1,26–28]. To investigate the biological role of PKDs we have generated DT40 B cell lines that lack expression of one or more members of the PKD family [1], allowing us to investigate the function(s) of PKD isoforms following B cell antigen receptor (BCR) stimulation, as well addressing the issue of functional redundancy between the different PKD family members. Previous studies have shown that PKDs are indispensable for HDAC regulation in B cells [1]. Herein we show that PKDs are also indispensable for HSP27 phosphorylation in B cells. However, PKD-null DT40 B cells are viable and proliferate normally. Moreover, loss of the entire cellular pool of PKD does not critically affect oxidative stress responses in B cells nor do PKD kinases play an essential role in regulating NFκB transcriptional activity. Together, these findings reveal that in B lymphocytes, PKD kinases are not critical regulators of many of the cellular processes previously ascribed to them in other cellular systems. 2 Materials and methods 2.1 Cell culture, transient transfections and cell stimulation The generation, culture and activation of PKD1−/−, PKD3−/− and PKD1/3−/− knockout DT40 B cell lines have been described previously [1]. Cells were lysed and protein extracts were analysed in Western blotting experiments as previously described [1]. Chloramphenicol acetyl transferase assays have been described previously [29]. 2.2 sIgM staining DT40 B cells (2 × 106 cells per point) were resuspended in 200 μl buffer (RPMI 1640 media, 1% foetal calf serum) containing anti-chicken M1 monoclonal antibody conjugated to FITC for 20 min on ice. The cells were washed twice and fluorescent intensity was analysed by flow cytometry. All results shown are representative of at two to four independent experiments unless otherwise indicated. 3 Results 3.1 Loss of HSP27 phosphorylation in DT40 B cells lacking expression of PKD family kinases DT40 B cells express two PKD isoforms, PKD1 and PKD3, and as previously described we have recently generated DT40 B cell lines that lack expression of either PKD1 or PKD3 or both enzymes [1]. In generating the double knockout cell lines we targeted the PKD1 loci in a PKD3−/− cell line that expressed a Flag-PKD3 transgene under the control of a doxycycline-inducible promoter. Hence, in the presence of doxycycline, Flag-PKD3 expression in PKD1/3 double knockout cells is comparable to endogenous PKD3 present in wild-type DT40 cells and removal of doxycycline from the culture media for 5 days results in a completely null PKD phenotype (Fig. 1A). Previously, we have demonstrated that phosphorylation and nuclear exclusion of class II histone deacetylases (HDACs) during BCR engagement is defective in PKD1/3−/− B cells and can restored upon re-expression of a single PKD isoform [1]. The small heat shock protein HSP27 has recently been proposed as a PKD1 substrate [24] and we accordingly assessed whether PKD-null DT40 cells have defective phosphorylation of HSP27 on serine 82, the proposed PKD1 substrate sequence. We initially investigated the regulation of HSP27 phosphorylation in single knockout DT40 B cells lacking either PKD1 or PKD3. As shown in Fig. 1B, activation of the BCR or treatment with the DAG-mimetic PdBu increased the levels of HSP27 phosphorylation at S82 in wild-type DT40 B cells. BCR and phorbol ester signals were also able to increase HSP27 phosphorylation in PKD1 or PKD3 single knockout DT40 B cells (Fig. 1B). However, BCR- and phorbol ester-induced phosphorylation of HSP27 on S82 was abolished in B cells that lacked both PKD1 and PKD3 (Fig. 1C). Significantly, doxycycline-induced expression of the Flag-PKD3 transgene in the double knockout cells was sufficient to restore normal regulation of HSP27 phosphorylation (Fig. 1C). In contrast, expression of a kinase-deficient PKD3 mutant protein in the double knockout cells was not able to restore BCR- or phorbol ester-induced HSP27 phosphorylation (Fig. 1D). Hence, PKD3 as well as PKD1 can regulate HSP27 phosphorylation and in DT40 B cells they are functionally redundant as HSP27 kinases. 3.2 Cellular proliferation and survival in DT40 B cells lacking expression of PKD family kinases PKD enzymes have previously been linked to the regulation of cell proliferation and survival (reviewed in [20]). To investigate the effect that loss of PKD kinases had on B cell survival and/or proliferation we cultured wild-type and PKD-null cells in the presence (PKD1/3−/−: Flag-PKD3+ve) or absence (PKD1/3−/−) of doxycycline and monitored exponential growth. As shown in Fig. 2A, PKD1/3−/− cells proliferated exponentially and re-expression of Flag-PKD3 in these cells had no impact on the rate of proliferation. Furthermore, the viability of PKD1/3−/− B cells during routine culturing was not significantly different from that of wild-type B cells (data not shown). It was noted that the population doubling time of PKD1/3−/− cells was slightly slower than that of wild type DT40 cells (12.7 ± 2.8 h versus 10.2 ± 0.4 h) but the failure of PKD3 re-expression to modify the proliferation rate of PKD1/3−/− cells suggests that these small differences were most likely the result of clonal variation and were not caused specifically by loss of PKD enzymes. Thus, PKD family enzymes are not essential for regulating basal survival and proliferation of DT40 B cells. PKD enzymes, specifically PKD1 and PKD2, have previously been linked to a protective role against oxidative stress-induced injury in 3T3 fibroblast, HeLa and epithelial cell lines [17,30–32]. We therefore addressed the role of PKD family kinases in regulating B cell survival in response to oxidative stress and other stress stimuli. As shown in Fig. 2B, loss of PKD1/3 expression had no significant impact on the survival of DT40 B cells in response to mitochondrial stress stimuli (H2O2 or serum deprivation); DNA damaging agents (etoposide or doxorubicin); ER pathway stress due to calcium overload (thapsigargin) or following prolonged treatment with phorbol esters or Trichostatin A, an inhibitor of class I/II HDACs. Thus, PKD kinases do not play an essential role in regulating B cell survival in response to a range of different stress stimuli. 3.3 Antigen receptor regulated signalling pathways in PKD-null DT40 B cells To further explore the contribution of PKD kinases to DT40 B cell biology we investigated whether specific BCR-regulated signalling events were defective in the PKD-null B cells. Initial experiments revealed that surface expression of the BCR was reduced in PKD1/3−/− (and in PKD1/3−/−:Flag-PKD3+ve) cells compared to wild-type DT40 B cells (Fig. 3A and data not shown). Nevertheless, BCR-crosslinking of PKD1/3−/− cells was sufficient to induce the activation of a number of signalling cascades, similar to that observed in wild-type cells (Fig. 3B). Hence, BCR-induced activation of the Akt, mTOR/p70 S6 kinase (as shown by S6 ribosomal protein phosphorylation) and MAPK signalling pathways was clearly detectable in PKD1/3-null B cells (Fig. 3B). Furthermore, enhanced tyrosine phosphorylation of multiple cellular proteins as well as an increase in intracellular calcium levels was also observed following BCR stimulation of PKD1/3-null B cells (data not shown). We did observe that the strength of BCR (but not phorbol ester)-induced regulation of the Erk1-RSK1 signalling pathway was reduced in PKD1/3−/− B cells compared to wild-type B cells (Fig. 3B). One interpretation of this data is that PKD enzymes may modulate Erk activation. Indeed, PKD enzymes have previously been linked to the growth factor-regulated Erk signalling in fibroblast and endothelial cell lines [33–35]. However, BCR-induced Erk phosphorylation was also reduced in PKD1/3−/−-Flag-PKD3+ B cells (data not shown) suggesting that reduced BCR levels on the surface of PKD1/3−/− (and PKD1/3−/−-Flag-PKD3+) B cells may itself impact on the strength of activation of this specific intracellular signalling pathway. To search for other potential PKD targets that may show defective regulation in PKD1/3−/− DT40 B cells, we used a PKD substrate phospho-antibody that recognises consensus phosphorylation sequences targeted by PKD enzymes (LxRxxpS/T) [36]. As shown in Fig. 3C, phorbol ester- and BCR-induced phosphorylation of cellular substrates detected by this phospho-antibody was similar in wild-type and PKD1/3−/− cells and is therefore independent of PKD enzymes. However, pretreatment of both wild-type and PKD1/3−/− DT40 B cells with GF109203X, a bisindoylmaleimide derivative that inhibits PKCs prevented the induction of proteins that contain phosphorylated LxRxxS/T motifs. Thus loss of PKD1/3 enzymes does not globally disrupt the phosphorylation of cellular proteins that contain LxRxxpS/T motifs. This result is perhaps not surprising as LxRxxS/T motifs also act as good substrates for other serine/threonine kinases such as MAPKAPK2. However these experiments do provide further evidence that phosphospecific antisera are not sufficiently selective to be designated kinase specific substrate antisera. BCR-induced signalling pathways culminate in the activation of gene transcription events that control B cell survival, proliferation and function. In this context, it has been proposed that PKD family members control of gene transcription through activation of the NFκB transcription factor. Thus, PKD-mediated activation of NFκB occurs downstream of a variety of different signals, including mROS/oxidative stress, lysophosphatidic acid and the Bcr-Abl oncogene [17,21,23,30,37]. Furthermore, expression of an activated PKD1 mutant enhances HPK1-mediated NFκB activation [38]. In B cells, NFκB is known to be regulated via DAG and PKCβ [39,40] but whether PKDs are key intermediaries for NFκB regulation has not been explored. The data (Fig. 4A) show that NFκB transcriptional activity was strongly induced in both wild-type and PKD1/3−/− DT40 B cells in response to either phorbol ester or BCR stimulation. In contrast, BCR and phorbol ester-induced NFκB transcriptional activity was abolished in PKCβ−/− DT40 B cells (Fig. 4A), although strong activation of PKD kinases (as assessed by autophosphorylation of PKD1 at S916) was observed in the PKCβ−/− cells (Fig. 4B). Thus, PKD kinases are neither essential nor sufficient to mediate BCR-induced NFκB activation in DT40 B cells and hence do not participate in DAG/PKC mediated control of NFκB. 4 Discussion Protein kinase D serine kinases
T4776	6660-6670	Protein	denotes	PKD family
T4777	6646-6656	Gene_expression	denotes	expression
T4778	6638-6645	Negative_regulation	denotes	lacking
T4779	6679-6682	Protein	denotes	PKD
T4780	6831-6842	Protein	denotes	PKD kinases
T4781	6913-6916	Protein	denotes	PKD
T4782	6945-6949	Protein	denotes	PKD1
T4783	6956-6960	Protein	denotes	Flag
T4784	6961-6965	Protein	denotes	PKD3
T4785	6982-6986	Protein	denotes	PKD1
T4786	6823-6827	Negative_regulation	denotes	loss
T4787	7054-7057	Protein	denotes	Fig
T4788	7063-7067	Protein	denotes	PKD1
T4789	7127-7131	Protein	denotes	Flag
T4790	7132-7136	Protein	denotes	PKD3
T4791	7110-7123	Gene_expression	denotes	re-expression
T4792	7110-7123	Gene_expression	denotes	re-expression
T3674	5641-5645	Protein	denotes	PKD3
T1859	3595-3599	Protein	denotes	PKD1
T1860	3604-3608	Protein	denotes	PKD3
T1861	3616-3620	Protein	denotes	PKD1
T1862	3802-3836	Protein	denotes	Chloramphenicol acetyl transferase
T2020	4025-4060	Protein	denotes	anti-chicken M1 monoclonal antibody
R1413	T1609	T1612	themeOf	PKD1,activation
R1414	T1610	T1613	themeOf	PKD enzymes,location
R1415	T1611	T1614	causeOf	binding,contributes
R1416	T1612	T1614	themeOf	activation,contributes
R1417	T1613	T1615	themeOf	location,regulating
R1418	T1617	T1618	themeOf	PKDs,Expression
R1419	T1617	T1619	themeOf	PKDs,activated
R1420	T1618	T1620	themeOf	Expression,activated
R1421	T1622	T1623	themeOf	NFκB transcription factor,activation
R1422	T1626	T1629	themeOf	class II histone deacetylases,regulating
R1423	T1627	T1630	themeOf	HDACs,regulating
R1424	T1638	T1639	themeOf	HDAC,regulation
R1425	T1640	T1643	causeOf	PKDs,indispensable
R1426	T1641	T1642	themeOf	HSP27,phosphorylation
R1427	T1642	T1643	themeOf	phosphorylation,indispensable
R1428	T1645	T1648	themeOf	PKD,loss
R2977	T3626	T3628	themeOf	expression,lacking
R2978	T3630	T3635	themeOf	PKD,express
R2979	T3631	T3636	themeOf	PKD1,express
R2980	T3622	T3625	themeOf	HSP27,phosphorylation
R2981	T3632	T3637	themeOf	PKD3,express
R2982	T3624	T3626	themeOf	PKD family,expression
R2983	T3633	T3638	themeOf	PKD1,expression
R2984	T3634	T3639	themeOf	PKD3,expression
R2985	T3638	T3640	themeOf	expression,lack
R2986	T3674	T3677	themeOf	PKD3,lacking
R2987	T3675	T3678	themeOf	phosphorylation,regulation
R2988	T3639	T3641	themeOf	expression,lack
R2989	T3644	T3646	themeOf	Flag,expressed
R2990	T3680	T3682	themeOf	BCR,activation
R2991	T3681	T3684	themeOf	HSP27,phosphorylation
R2992	T3682	T3683	themeOf	activation,increased
R2993	T3686	T3689	themeOf	HSP27,phosphorylation
R2994	T3645	T3647	themeOf	PKD3,expressed
R2995	T3648	T3652	themeOf	Flag,expression
R2999	T3649	T3653	themeOf	PKD3,expression
R3001	T3654	T3658	themeOf	class II histone deacetylases,phosphorylation
R3003	T3694	T3703	themeOf	HSP27,phosphorylation
R3004	T3694	T3698	partOf	HSP27,S82
R3005	T3695	T3699	themeOf	PKD1,lacked
R3006	T3696	T3700	themeOf	PKD3,lacked
R3007	T3697	T3701	themeOf	Fig. 1C,lacked
R3008	T3698	T3702	Site	S82,phosphorylation
R3009	T3698	T3703	Site	S82,phosphorylation
R3010	T3655	T3659	themeOf	HDACs,phosphorylation
R3011	T3702	T3704	themeOf	phosphorylation,abolished
R3012	T3656	T3660	themeOf	BCR,engagement
R3013	T3703	T3705	themeOf	phosphorylation,abolished
R3014	T3706	T3709	themeOf	Flag,expression
R3015	T3707	T3710	themeOf	PKD3,expression
R3016	T3658	T3661	themeOf	phosphorylation,restored
R3017	T3708	T3711	themeOf	HSP27,phosphorylation
R3018	T3709	T3712	themeOf	expression,doxycycline-induced
R3019	T3659	T3662	themeOf	phosphorylation,restored
R3020	T3667	T3670	themeOf	HSP27,phosphorylation
R3021	T3710	T3713	themeOf	expression,doxycycline-induced
R3022	T3711	T3714	themeOf	phosphorylation,regulation
R3023	T3714	T3715	themeOf	regulation,restore
R3024	T3716	T3718	themeOf	PKD3,expression
R3025	T3717	T3720	themeOf	HSP27,phosphorylation
R3026	T3667	T3669	partOf	HSP27,serine
R3027	T3718	T3719	themeOf	expression,kinase-deficient
R3028	T3718	T3721	causeOf	expression,restore
R3029	T3668	T3669	partOf	PKD1,serine
R3030	T3720	T3721	themeOf	phosphorylation,restore
R3031	T3720	T3722	themeOf	phosphorylation,ester-induced
R3032	T3669	T3670	Site	serine,phosphorylation
R3033	T3723	T3728	causeOf	PKD3,regulate
R3034	T3670	T3671	themeOf	phosphorylation,defective
R3035	T3724	T3729	causeOf	PKD1,regulate
R3036	T3725	T3727	themeOf	HSP27,phosphorylation
R3037	T3672	T3675	themeOf	HSP27,phosphorylation
R3038	T3727	T3728	themeOf	phosphorylation,regulate
R3039	T3727	T3729	themeOf	phosphorylation,regulate
R3040	T3673	T3676	themeOf	PKD1,lacking
R3849	T4776	T4777	themeOf	PKD family,expression
R3850	T4777	T4778	themeOf	expression,lacking
R3851	T4780	T4786	themeOf	PKD kinases,loss
R3852	T4789	T4791	themeOf	Flag,re-expression
R3853	T4790	T4792	themeOf	PKD3,re-expression
R3854	T4795	T4798	themeOf	PKD3,re-expression
R3855	T4797	T4799	themeOf	PKD enzymes,loss
R3856	T4807	T4811	themeOf	PKD1,expression
R3857	T4808	T4812	themeOf	3,expression
R3858	T4810	T4813	themeOf	I/II HDACs,inhibitor
R3859	T4811	T4814	themeOf	expression,loss
R3860	T4812	T4815	themeOf	expression,loss
R1401	T1594	T1596	themeOf	PKD,express
R1407	T1595	T1597	themeOf	PKD,expressed
R1408	T1600	T1603	themeOf	protein kinase Cs,stimulates
R1409	T1600	T1605	themeOf	protein kinase Cs,phosphorylate
R1410	T1601	T1604	themeOf	PKC,stimulates
R1411	T1601	T1606	themeOf	PKC,phosphorylate
R1412	T1608	T1611	themeOf	DAG,binding
R363	T438	T439	themeOf	class II histone deacetylases,regulation
R364	T440	T443	causeOf	PKDs,regulate
R365	T440	T444	causeOf	PKDs,required
R366	T441	T442	themeOf	HSP27,phosphorylation
R367	T442	T443	themeOf	phosphorylation,regulate
R368	T443	T444	themeOf	regulate,required
R369	T445	T448	causeOf	PKD enzymes,regulate
R370	T447	T448	themeOf	B cell antigen receptor,regulate
R2996	T3687	T3690	themeOf	PKD1,knockout
R2997	T3688	T3691	themeOf	PKD3,knockout
R2998	T3689	T3692	themeOf	phosphorylation,increase
R3000	T3693	T3702	themeOf	BCR,phosphorylation
R3002	T3693	T3698	partOf	BCR,S82

bionlp-st-ge-2016-reference

Id	Subject	Object	Predicate	Lexical cue	Negation	Speculation
T2250	6414-6419	Protein	denotes	HSP27
T2251	6420-6435	Phosphorylation	denotes	phosphorylation
T2252	6454-6458	Protein	denotes	PKD3
T2253	6470-6474	Protein	denotes	PKD1
T2254	6479-6487	Regulation	denotes	regulate
T2255	6479-6487	Regulation	denotes	regulate
T2256	6488-6493	Protein	denotes	HSP27
T2257	6494-6509	Phosphorylation	denotes	phosphorylation
T2258	6565-6570	Protein	denotes	HSP27
T4955	9366-9369	Protein	denotes	Akt
T4956	9371-9375	Protein	denotes	mTOR
T4957	9403-9423	Protein	denotes	S6 ribosomal protein
T4958	9424-9439	Phosphorylation	denotes	phosphorylation
T4959	9482-9492	Negative_regulation	denotes	detectable	true
T4960	9482-9492	Negative_regulation	denotes	detectable	true
T4961	9482-9492	Negative_regulation	denotes	detectable	true
T4962	9482-9492	Negative_regulation	denotes	detectable	true
T4963	9482-9492	Negative_regulation	denotes	detectable	true
T4964	9482-9492	Negative_regulation	denotes	detectable	true
T4965	9496-9500	Protein	denotes	PKD1
T4966	9501-9502	Protein	denotes	3
T4967	9503-9507	Negative_regulation	denotes	null
T4968	9503-9507	Negative_regulation	denotes	null
T4969	9706-9710	Protein	denotes	PKD1
T4970	9711-9712	Protein	denotes	3
T4971	9834-9838	Protein	denotes	Erk1
T4972	9839-9843	Protein	denotes	RSK1
T4973	9878-9882	Protein	denotes	PKD1
T4974	9883-9884	Protein	denotes	3
T4975	10223-10227	Protein	denotes	PKD1
T4976	10228-10229	Protein	denotes	3
T4977	10238-10242	Protein	denotes	PKD3
T4978	10322-10326	Protein	denotes	PKD1
T4979	10327-10328	Protein	denotes	3
T4980	10337-10341	Protein	denotes	PKD1
T4981	10342-10343	Protein	denotes	3
T4982	10352-10356	Protein	denotes	PKD3
T4983	10546-10550	Protein	denotes	PKD1
T4984	10551-10552	Protein	denotes	3
T4985	10859-10863	Protein	denotes	PKD1
T4986	10864-10865	Protein	denotes	3
T4987	10964-10968	Protein	denotes	PKD1
T4988	10969-10970	Protein	denotes	3
T4989	11140-11144	Negative_regulation	denotes	loss
T4990	11140-11144	Negative_regulation	denotes	loss
T4991	11148-11152	Protein	denotes	PKD1
T4992	11153-11154	Protein	denotes	3
T4993	11389-11397	Protein	denotes	MAPKAPK2
T4994	12013-12029	Protein	denotes	Bcr-Abl oncogene
T4995	12061-12087	Positive_regulation	denotes	expression of an activated
T4996	12088-12092	Protein	denotes	PKD1
T4997	12109-12113	Protein	denotes	HPK1
T4998	12199-12203	Protein	denotes	PKCβ
T4999	12397-12401	Protein	denotes	PKD1
T5000	12402-12403	Protein	denotes	3
T5001	12566-12571	Protein	denotes	PKCβ−
T5002	12656-12675	Phosphorylation	denotes	autophosphorylation
T5003	12679-12683	Protein	denotes	PKD1
T5004	12687-12691	Entity	denotes	S916
T5005	12697-12705	Positive_regulation	denotes	observed
T5006	12713-12718	Protein	denotes	PKCβ−
T10	441-449	Positive_regulation	denotes	required
T11	453-461	Regulation	denotes	regulate
T12	462-467	Protein	denotes	HSP27
T13	468-483	Phosphorylation	denotes	phosphorylation
T2177	4310-4314	Negative_regulation	denotes	Loss		true
T2178	4318-4323	Protein	denotes	HSP27
T2179	4324-4339	Phosphorylation	denotes	phosphorylation
T2180	4410-4417	Gene_expression	denotes	express
T2181	4410-4417	Gene_expression	denotes	express
T2182	4436-4440	Protein	denotes	PKD1
T2183	4445-4449	Protein	denotes	PKD3
T2184	4529-4533	Negative_regulation	denotes	lack
T2185	4529-4533	Negative_regulation	denotes	lack
T2186	4534-4544	Gene_expression	denotes	expression
T2187	4534-4544	Gene_expression	denotes	expression
T2188	4555-4559	Protein	denotes	PKD1
T2189	4563-4567	Protein	denotes	PKD3
T2190	4650-4654	Protein	denotes	PKD1
T2191	4665-4669	Protein	denotes	PKD3
T2192	4688-4697	Gene_expression	denotes	expressed
T2193	4705-4709	Protein	denotes	PKD3
T2194	4819-4823	Protein	denotes	PKD3
T2195	4824-4834	Gene_expression	denotes	expression
T2196	4838-4842	Protein	denotes	PKD1
T2197	4843-4844	Protein	denotes	3
T2198	4845-4860	Negative_regulation	denotes	double knockout
T2199	4845-4860	Negative_regulation	denotes	double knockout
T2200	4895-4899	Protein	denotes	PKD3
T2201	5202-5206	Protein	denotes	PKD1
T2202	5207-5208	Protein	denotes	3
T2203	5314-5319	Protein	denotes	HSP27
T2204	5352-5356	Protein	denotes	PKD1
T2205	5433-5442	Negative_regulation	denotes	defective
T2206	5443-5458	Phosphorylation	denotes	phosphorylation
T2207	5462-5467	Protein	denotes	HSP27
T2208	5471-5480	Entity	denotes	serine 82
T2209	5495-5499	Protein	denotes	PKD1
T2210	5550-5560	Regulation	denotes	regulation		true
T2211	5564-5569	Protein	denotes	HSP27
T2212	5570-5585	Phosphorylation	denotes	phosphorylation
T2213	5618-5625	Negative_regulation	denotes	lacking
T2214	5618-5625	Negative_regulation	denotes	lacking
T2215	5633-5637	Protein	denotes	PKD1
T2216	5641-5645	Protein	denotes	PKD3
T2217	5729-5738	Positive_regulation	denotes	increased
T2218	5753-5758	Protein	denotes	HSP27
T2219	5759-5774	Phosphorylation	denotes	phosphorylation
T2220	5778-5781	Entity	denotes	S82
T2221	5857-5865	Positive_regulation	denotes	increase
T2222	5866-5871	Protein	denotes	HSP27
T2223	5872-5887	Phosphorylation	denotes	phosphorylation
T2224	5891-5895	Protein	denotes	PKD1
T2225	5899-5903	Protein	denotes	PKD3
T2226	5911-5919	Negative_regulation	denotes	knockout
T2227	5911-5919	Negative_regulation	denotes	knockout
T2228	5976-5983	Positive_regulation	denotes	induced
T2229	5984-5999	Phosphorylation	denotes	phosphorylation
T2230	6003-6008	Protein	denotes	HSP27
T2231	6012-6015	Entity	denotes	S82
T2232	6020-6029	Negative_regulation	denotes	abolished
T2233	6020-6029	Negative_regulation	denotes	abolished
T2234	6046-6052	Negative_regulation	denotes	lacked
T2235	6046-6052	Negative_regulation	denotes	lacked
T2236	6058-6062	Protein	denotes	PKD1
T2237	6067-6071	Protein	denotes	PKD3
T2238	6110-6117	Positive_regulation	denotes	induced
T2239	6118-6128	Gene_expression	denotes	expression
T2240	6141-6145	Protein	denotes	PKD3
T2241	6189-6210	Positive_regulation	denotes	sufficient to restore
T2242	6218-6228	Regulation	denotes	regulation
T2243	6232-6237	Protein	denotes	HSP27
T2244	6238-6253	Phosphorylation	denotes	phosphorylation
T2245	6278-6288	Gene_expression	denotes	expression
T2246	6301-6310	Negative_regulation	denotes	deficient
T2247	6311-6315	Protein	denotes	PKD3
T2248	6376-6383	Positive_regulation	denotes	restore	true
T2249	6406-6413	Positive_regulation	denotes	induced
T3783	6945-6949	Protein	denotes	PKD1
T3784	6950-6951	Protein	denotes	3
T3785	6961-6965	Protein	denotes	PKD3
T3786	6982-6986	Protein	denotes	PKD1
T3787	6987-6988	Protein	denotes	3
T3788	7063-7067	Protein	denotes	PKD1
T3789	7068-7069	Protein	denotes	3
T3790	7110-7123	Gene_expression	denotes	re-expression
T3791	7132-7136	Protein	denotes	PKD3
T3792	7226-7230	Protein	denotes	PKD1
T3793	7231-7232	Protein	denotes	3
T3794	7400-7404	Protein	denotes	PKD1
T3795	7405-7406	Protein	denotes	3
T3796	7524-7528	Protein	denotes	PKD3
T3797	7529-7542	Gene_expression	denotes	re-expression
T3798	7579-7583	Protein	denotes	PKD1
T3799	7584-7585	Protein	denotes	3
T3800	7872-7876	Protein	denotes	PKD1
T3801	7881-7885	Protein	denotes	PKD2
T3802	8201-8205	Negative_regulation	denotes	loss
T3803	8201-8205	Negative_regulation	denotes	loss
T3804	8209-8213	Protein	denotes	PKD1
T3805	8214-8215	Protein	denotes	3
T3806	8216-8226	Gene_expression	denotes	expression
T3807	8216-8226	Gene_expression	denotes	expression
T476	894-898	Protein	denotes	PKD1
T477	900-904	Protein	denotes	PKD2
T478	909-913	Protein	denotes	PKD3
T479	1518-1525	Binding	denotes	binding
T480	1538-1549	Positive_regulation	denotes	contributes
T481	1553-1557	Protein	denotes	PKD1
T482	1558-1568	Positive_regulation	denotes	activation
T483	2176-2180	Protein	denotes	PKD1
T484	2194-2199	Protein	denotes	HSP27
T485	2403-2407	Protein	denotes	MEF2
T486	2956-2969	Positive_regulation	denotes	indispensable
T487	2974-2979	Protein	denotes	HSP27
T488	2980-2995	Phosphorylation	denotes	phosphorylation
T1662	3595-3599	Protein	denotes	PKD1
T1663	3604-3608	Protein	denotes	PKD3
T1664	3616-3620	Protein	denotes	PKD1
T1665	3621-3622	Protein	denotes	3
T1666	3626-3634	Negative_regulation	denotes	knockout
T1667	3626-3634	Negative_regulation	denotes	knockout
T1668	3626-3634	Negative_regulation	denotes	knockout
T1669	3626-3634	Negative_regulation	denotes	knockout
T6995	12946-12952	Entity	denotes	serine
T4942	9035-9039	Protein	denotes	PKD1
T4943	9040-9041	Protein	denotes	3
T4944	9053-9057	Protein	denotes	PKD1
T4945	9058-9059	Protein	denotes	3
T4946	9068-9072	Protein	denotes	PKD3
T4947	9182-9186	Protein	denotes	PKD1
T4948	9187-9188	Protein	denotes	3
T4949	9340-9347	Positive_regulation	denotes	induced
T4950	9340-9347	Positive_regulation	denotes	induced
T4951	9340-9347	Positive_regulation	denotes	induced
T4952	9348-9358	Positive_regulation	denotes	activation
T4953	9348-9358	Positive_regulation	denotes	activation
T4954	9348-9358	Positive_regulation	denotes	activation
R1883	T2253	T2254	causeOf	PKD1,regulate
R1884	T2256	T2257	themeOf	HSP27,phosphorylation
R1885	T2257	T2255	themeOf	phosphorylation,regulate
R1886	T2257	T2254	themeOf	phosphorylation,regulate
R371	T11	T10	themeOf	regulate,required
R372	T12	T13	themeOf	HSP27,phosphorylation
R373	T13	T11	themeOf	phosphorylation,regulate
R1839	T2186	T2184	themeOf	expression,lack
R1842	T2189	T2186	themeOf	PKD3,expression
R1843	T2193	T2192	themeOf	PKD3,expressed
R1844	T2194	T2195	themeOf	PKD3,expression
R1845	T2196	T2199	themeOf	PKD1,double knockout
R1846	T2197	T2198	themeOf	3,double knockout
R1847	T2206	T2205	themeOf	phosphorylation,defective
R1848	T2208	T2206	themeOf	serine 82,phosphorylation
R1849	T2208	T2207	partOf	serine 82,HSP27
R1850	T2211	T2212	themeOf	HSP27,phosphorylation
R1851	T2212	T2210	themeOf	phosphorylation,regulation
R1852	T2215	T2213	themeOf	PKD1,lacking
R1853	T2216	T2214	themeOf	PKD3,lacking
R1854	T2219	T2217	themeOf	phosphorylation,increased
R1855	T2220	T2219	themeOf	S82,phosphorylation
R1856	T2220	T2218	partOf	S82,HSP27
R1857	T2222	T2223	themeOf	HSP27,phosphorylation
R1858	T2223	T2221	themeOf	phosphorylation,increase
R1835	T2178	T2179	themeOf	HSP27,phosphorylation
R1836	T2179	T2177	themeOf	phosphorylation,Loss
R1837	T2182	T2180	themeOf	PKD1,express
R1838	T2183	T2181	themeOf	PKD3,express
R1840	T2187	T2185	themeOf	expression,lack
R1841	T2188	T2187	themeOf	PKD1,expression
R1859	T2224	T2227	themeOf	PKD1,knockout
R1860	T2225	T2226	themeOf	PKD3,knockout
R1861	T2228	T2232	themeOf	induced,abolished
R1862	T2228	T2233	themeOf	induced,abolished
R1863	T2229	T2228	themeOf	phosphorylation,induced
R1864	T2231	T2229	themeOf	S82,phosphorylation
R1865	T2231	T2230	partOf	S82,HSP27
R1866	T2234	T2233	causeOf	lacked,abolished
R1867	T2235	T2232	causeOf	lacked,abolished
R1868	T2236	T2235	themeOf	PKD1,lacked
R1869	T2237	T2234	themeOf	PKD3,lacked
R1870	T2238	T2241	causeOf	induced,sufficient to restore
R1871	T2239	T2238	themeOf	expression,induced
R1872	T2240	T2239	themeOf	PKD3,expression
R1873	T2242	T2241	themeOf	regulation,sufficient to restore
R1874	T2243	T2244	themeOf	HSP27,phosphorylation
R1875	T2244	T2242	themeOf	phosphorylation,regulation
R1876	T2245	T2248	causeOf	expression,restore
R1877	T2247	T2245	themeOf	PKD3,expression
R1878	T2247	T2246	themeOf	PKD3,deficient
R1879	T2249	T2248	themeOf	induced,restore
R1880	T2250	T2251	themeOf	HSP27,phosphorylation
R1881	T2251	T2249	themeOf	phosphorylation,induced
R1882	T2252	T2255	causeOf	PKD3,regulate
R3050	T3791	T3790	themeOf	PKD3,re-expression
R3051	T3796	T3797	themeOf	PKD3,re-expression
R3052	T3804	T3806	themeOf	PKD1,expression
R3053	T3805	T3807	themeOf	3,expression
R3054	T3806	T3803	themeOf	expression,loss
R3055	T3807	T3802	themeOf	expression,loss
R424	T479	T480	causeOf	binding,contributes
R425	T481	T479	themeOf	PKD1,binding
R426	T481	T482	themeOf	PKD1,activation
R427	T482	T480	themeOf	activation,contributes
R428	T487	T488	themeOf	HSP27,phosphorylation
R429	T488	T486	themeOf	phosphorylation,indispensable
R1433	T1662	T1666	themeOf	PKD1,knockout
R1434	T1663	T1667	themeOf	PKD3,knockout
R1435	T1664	T1668	themeOf	PKD1,knockout
R1436	T1665	T1669	themeOf	3,knockout
R3904	T4949	T4959	themeOf	induced,detectable
R3905	T4949	T4961	themeOf	induced,detectable
R3906	T4950	T4964	themeOf	induced,detectable
R3907	T4950	T4963	themeOf	induced,detectable
R3908	T4951	T4960	themeOf	induced,detectable
R3909	T4951	T4962	themeOf	induced,detectable
R3910	T4952	T4951	themeOf	activation,induced
R3911	T4953	T4949	themeOf	activation,induced
R3912	T4954	T4950	themeOf	activation,induced
R3913	T4955	T4954	themeOf	Akt,activation
R3914	T4956	T4953	themeOf	mTOR,activation
R3915	T4957	T4958	themeOf	S6 ribosomal protein,phosphorylation
R3916	T4958	T4952	themeOf	phosphorylation,activation
R3917	T4965	T4968	themeOf	PKD1,null
R3918	T4966	T4967	themeOf	3,null
R3919	T4967	T4964	causeOf	null,detectable
R3920	T4967	T4961	causeOf	null,detectable
R3921	T4967	T4962	causeOf	null,detectable
R3922	T4968	T4959	causeOf	null,detectable
R3923	T4968	T4960	causeOf	null,detectable
R3924	T4968	T4963	causeOf	null,detectable
R3925	T4991	T4990	themeOf	PKD1,loss
R3926	T4992	T4989	themeOf	3,loss
R3927	T4996	T4995	themeOf	PKD1,expression of an activated
R3928	T5002	T5005	themeOf	autophosphorylation,observed
R3929	T5004	T5002	themeOf	S916,autophosphorylation
R3930	T5004	T5003	partOf	S916,PKD1

bionlp-st-ge-2016-uniprot

Id	Subject	Object	Predicate	Lexical cue
T1737	3616-3620	P98161	denotes	PKD1
T2676	4318-4323	P04792	denotes	HSP27
T2677	4436-4440	P98161	denotes	PKD1
T2678	4445-4449	Q99853	denotes	PKD3
T2679	4555-4559	P98161	denotes	PKD1
T2680	4563-4567	Q99853	denotes	PKD3
T2681	4650-4654	P98161	denotes	PKD1
T2682	4665-4669	Q99853	denotes	PKD3
T2683	4705-4709	Q99853	denotes	PKD3
T2684	4819-4823	Q99853	denotes	PKD3
T2685	4838-4842	P98161	denotes	PKD1
T2686	4895-4899	Q99853	denotes	PKD3
T2687	5171-5174	P11274	denotes	BCR
T2688	5202-5206	P98161	denotes	PKD1
T2689	5314-5319	P04792	denotes	HSP27
T2690	5352-5356	P98161	denotes	PKD1
T2691	5462-5467	P04792	denotes	HSP27
T2692	5495-5499	P98161	denotes	PKD1
T2693	5564-5569	P04792	denotes	HSP27
T4193	6945-6949	P98161	denotes	PKD1
T4194	6961-6965	Q99853	denotes	PKD3
T4195	6982-6986	P98161	denotes	PKD1
T4196	7063-7067	P98161	denotes	PKD1
T4197	7132-7136	Q99853	denotes	PKD3
T4198	7226-7230	P98161	denotes	PKD1
T4199	7400-7404	P98161	denotes	PKD1
T4200	7524-7528	Q99853	denotes	PKD3
T4201	7579-7583	P98161	denotes	PKD1
T4202	7872-7876	P98161	denotes	PKD1
T4203	8209-8213	P98161	denotes	PKD1
T4204	8406-8408	P03372	denotes	ER
T5705	8884-8887	P11274	denotes	BCR
T5706	9016-9019	P11274	denotes	BCR
T5707	9035-9039	P98161	denotes	PKD1
T5708	9053-9057	P98161	denotes	PKD1
T5709	9068-9072	Q99853	denotes	PKD3
T5710	9162-9165	P11274	denotes	BCR
T5711	9182-9186	P98161	denotes	PKD1
T5712	9336-9339	P11274	denotes	BCR
T5713	9366-9369	P31751	denotes	Akt
T5714	9366-9369	Q9Y243	denotes	Akt
T5715	9366-9369	P31749	denotes	Akt
T5716	9371-9375	P42345	denotes	mTOR
T5717	9496-9500	P98161	denotes	PKD1
T5718	9687-9690	P11274	denotes	BCR
T5719	9706-9710	P98161	denotes	PKD1
T5720	9780-9783	P11274	denotes	BCR
T5721	9834-9838	P27361	denotes	Erk1
T5722	9878-9882	P98161	denotes	PKD1
T5723	10171-10174	P11274	denotes	BCR
T5724	10223-10227	P98161	denotes	PKD1
T5725	10238-10242	Q99853	denotes	PKD3
T5726	10293-10296	P11274	denotes	BCR
T5727	10322-10326	P98161	denotes	PKD1
T5728	10337-10341	P98161	denotes	PKD1
T5729	10352-10356	Q99853	denotes	PKD3
T5730	10546-10550	P98161	denotes	PKD1
T5731	10745-10748	P11274	denotes	BCR
T5732	10859-10863	P98161	denotes	PKD1
T5733	10964-10968	P98161	denotes	PKD1
T5734	11148-11152	P98161	denotes	PKD1
T5735	11567-11570	P11274	denotes	BCR
T5736	12013-12016	P11274	denotes	Bcr
T5737	12017-12020	P00519	denotes	Abl
T5738	12088-12092	P98161	denotes	PKD1
T5739	12397-12401	P98161	denotes	PKD1
T5740	12459-12462	P11274	denotes	BCR
T5741	12489-12492	P11274	denotes	BCR
T5742	12679-12683	P98161	denotes	PKD1
T5743	12804-12807	P11274	denotes	BCR
T986	894-898	P98161	denotes	PKD1
T987	909-913	Q99853	denotes	PKD3
T988	1553-1557	P98161	denotes	PKD1
T989	2176-2180	P98161	denotes	PKD1
T990	2194-2199	P04792	denotes	HSP27
T991	2716-2719	P11274	denotes	BCR
T992	2974-2979	P04792	denotes	HSP27
T1735	3595-3599	P98161	denotes	PKD1
T1736	3604-3608	Q99853	denotes	PKD3
T204	462-467	P04792	denotes	HSP27
T2694	5633-5637	P98161	denotes	PKD1
T2695	5641-5645	Q99853	denotes	PKD3
T2696	5686-5689	P11274	denotes	BCR
T2697	5753-5758	P04792	denotes	HSP27
T2698	5809-5812	P11274	denotes	BCR
T2699	5849-5853	P00519	denotes	able
T2700	5866-5871	P04792	denotes	HSP27
T2701	5891-5895	P98161	denotes	PKD1
T2702	5899-5903	Q99853	denotes	PKD3
T2703	5953-5956	P11274	denotes	BCR
T2704	6003-6008	P04792	denotes	HSP27
T2705	6058-6062	P98161	denotes	PKD1
T2706	6067-6071	Q99853	denotes	PKD3
T2707	6141-6145	Q99853	denotes	PKD3
T2708	6232-6237	P04792	denotes	HSP27
T2709	6311-6315	Q99853	denotes	PKD3
T2710	6368-6372	P00519	denotes	able
T2711	6384-6387	P11274	denotes	BCR
T2712	6414-6419	P04792	denotes	HSP27
T2713	6454-6458	Q99853	denotes	PKD3
T2714	6470-6474	P98161	denotes	PKD1
T2715	6488-6493	P04792	denotes	HSP27
T2716	6565-6570	P04792	denotes	HSP27

test2

Id	Subject	Object	Predicate	Lexical cue	Negation	Speculation
T3755	6945-6949	Protein	denotes	PKD1
T3756	6950-6951	Protein	denotes	3
T5	441-449	Positive_regulation	denotes	required
T6	453-461	Regulation	denotes	regulate
T7	462-467	Protein	denotes	HSP27
T8	468-483	Phosphorylation	denotes	phosphorylation
T463	894-898	Protein	denotes	PKD1
T464	900-904	Protein	denotes	PKD2
T465	909-913	Protein	denotes	PKD3
T466	1518-1525	Binding	denotes	binding
T467	1538-1549	Positive_regulation	denotes	contributes
T468	1553-1557	Protein	denotes	PKD1
T469	1558-1568	Positive_regulation	denotes	activation
T470	2176-2180	Protein	denotes	PKD1
T471	2194-2199	Protein	denotes	HSP27
T472	2403-2407	Protein	denotes	MEF2
T473	2956-2969	Positive_regulation	denotes	indispensable
T474	2974-2979	Protein	denotes	HSP27
T475	2980-2995	Phosphorylation	denotes	phosphorylation
T1658	3595-3599	Protein	denotes	PKD1
T1659	3604-3608	Protein	denotes	PKD3
T1660	3616-3620	Protein	denotes	PKD1
T1661	3621-3622	Protein	denotes	3
T2103	4318-4323	Protein	denotes	HSP27		true
T2104	4324-4339	Phosphorylation	denotes	phosphorylation
T2105	4410-4417	Gene_expression	denotes	express
T2106	4436-4440	Protein	denotes	PKD1
T2107	4445-4449	Protein	denotes	PKD3
T2108	4529-4533	Negative_regulation	denotes	lack
T2109	4534-4544	Gene_expression	denotes	expression
T2110	4555-4559	Protein	denotes	PKD1
T2111	4563-4567	Protein	denotes	PKD3
T2112	4650-4654	Protein	denotes	PKD1
T2113	4665-4669	Protein	denotes	PKD3
T2114	4688-4697	Gene_expression	denotes	expressed
T2115	4705-4709	Protein	denotes	PKD3
T2116	4819-4823	Protein	denotes	PKD3
T2117	4824-4834	Gene_expression	denotes	expression		true
T2118	4838-4842	Protein	denotes	PKD1
T2119	4843-4844	Protein	denotes	3
T2120	4852-4860	Negative_regulation	denotes	knockout
T2121	4895-4899	Protein	denotes	PKD3
T2122	5202-5206	Protein	denotes	PKD1
T2123	5207-5208	Protein	denotes	3
T2124	5314-5319	Protein	denotes	HSP27
T2125	5352-5356	Protein	denotes	PKD1
T2126	5433-5442	Negative_regulation	denotes	defective
T2127	5443-5458	Phosphorylation	denotes	phosphorylation
T2128	5462-5467	Protein	denotes	HSP27
T2129	5471-5477	Entity	denotes	serine
T2130	5495-5499	Protein	denotes	PKD1
T2131	5550-5560	Regulation	denotes	regulation
T2132	5564-5569	Protein	denotes	HSP27
T2133	5570-5585	Phosphorylation	denotes	phosphorylation
T2134	5596-5604	Negative_regulation	denotes	knockout
T2135	5618-5625	Negative_regulation	denotes	lacking
T2136	5633-5637	Protein	denotes	PKD1
T2137	5641-5645	Protein	denotes	PKD3
T2138	5729-5738	Positive_regulation	denotes	increased
T2139	5753-5758	Protein	denotes	HSP27
T2140	5759-5774	Phosphorylation	denotes	phosphorylation	true
T2141	5778-5781	Entity	denotes	S82
T2142	5857-5865	Positive_regulation	denotes	increase
T2143	5866-5871	Protein	denotes	HSP27
T2144	5872-5887	Phosphorylation	denotes	phosphorylation
T2145	5891-5895	Protein	denotes	PKD1
T2146	5899-5903	Protein	denotes	PKD3
T2147	5911-5919	Negative_regulation	denotes	knockout
T2148	5976-5983	Positive_regulation	denotes	induced
T2149	5984-5999	Phosphorylation	denotes	phosphorylation
T2150	6003-6008	Protein	denotes	HSP27
T2151	6012-6015	Entity	denotes	S82
T2152	6020-6029	Negative_regulation	denotes	abolished
T2153	6046-6052	Negative_regulation	denotes	lacked
T2154	6058-6062	Protein	denotes	PKD1
T2155	6067-6071	Protein	denotes	PKD3
T2156	6110-6117	Positive_regulation	denotes	induced
T2157	6118-6128	Gene_expression	denotes	expression
T2158	6141-6145	Protein	denotes	PKD3
T2159	6218-6228	Regulation	denotes	regulation
T2160	6232-6237	Protein	denotes	HSP27
T2161	6238-6253	Phosphorylation	denotes	phosphorylation
T2162	6278-6288	Gene_expression	denotes	expression
T2163	6294-6300	Negative_regulation	denotes	kinase
T2164	6301-6310	Negative_regulation	denotes	deficient
T2165	6311-6315	Protein	denotes	PKD3
T2166	6376-6383	Positive_regulation	denotes	restore
T2167	6406-6413	Positive_regulation	denotes	induced
T2168	6414-6419	Protein	denotes	HSP27
T2169	6420-6435	Phosphorylation	denotes	phosphorylation
T2170	6454-6458	Protein	denotes	PKD3
T2171	6470-6474	Protein	denotes	PKD1
T2172	6479-6487	Regulation	denotes	regulate
T2173	6488-6493	Protein	denotes	HSP27
T2174	6494-6509	Phosphorylation	denotes	phosphorylation
T2175	6552-6561	Negative_regulation	denotes	redundant
T2176	6565-6570	Protein	denotes	HSP27
T3757	6961-6965	Protein	denotes	PKD3
T3758	6982-6986	Protein	denotes	PKD1
T3759	6987-6988	Protein	denotes	3
T3760	7063-7067	Protein	denotes	PKD1
T3761	7068-7069	Protein	denotes	3
T3762	7110-7112	Positive_regulation	denotes	re
T3763	7112-7113	Gene_expression	denotes	-
T3764	7113-7123	Gene_expression	denotes	expression
T3765	7132-7136	Protein	denotes	PKD3
T3766	7226-7230	Protein	denotes	PKD1
T3767	7231-7232	Protein	denotes	3
T3768	7400-7404	Protein	denotes	PKD1
T3769	7405-7406	Protein	denotes	3
T3770	7524-7528	Protein	denotes	PKD3
T3771	7529-7532	Gene_expression	denotes	re-
T3772	7532-7542	Gene_expression	denotes	expression
T3773	7579-7583	Protein	denotes	PKD1
T3774	7584-7585	Protein	denotes	3
T3775	7872-7876	Protein	denotes	PKD1
T3776	7881-7885	Protein	denotes	PKD2
T3777	8201-8205	Negative_regulation	denotes	loss
T3778	8209-8213	Protein	denotes	PKD1
T3779	8214-8215	Protein	denotes	3
T3780	8216-8226	Gene_expression	denotes	expression
T3781	8538-8547	Negative_regulation	denotes	inhibitor
T4882	8998-9008	Gene_expression	denotes	expression
T4883	9024-9031	Negative_regulation	denotes	reduced
T4884	9035-9039	Protein	denotes	PKD1
T4885	9040-9041	Protein	denotes	3
T4886	9053-9057	Protein	denotes	PKD1
T4887	9058-9059	Protein	denotes	3
T4888	9068-9072	Protein	denotes	PKD3
T4889	9182-9186	Protein	denotes	PKD1	true
T4890	9187-9188	Protein	denotes	3
T4891	9340-9347	Positive_regulation	denotes	induced	true
T4892	9348-9358	Positive_regulation	denotes	activation
T4893	9366-9369	Protein	denotes	Akt	true
T4894	9371-9375	Protein	denotes	mTOR	true
T4895	9403-9423	Protein	denotes	S6 ribosomal protein	true
T4896	9424-9439	Phosphorylation	denotes	phosphorylation	true
T4897	9496-9500	Protein	denotes	PKD1
T4898	9501-9502	Protein	denotes	3
T4899	9503-9507	Negative_regulation	denotes	null
T4900	9706-9710	Protein	denotes	PKD1
T4901	9711-9712	Protein	denotes	3
T4902	9713-9717	Negative_regulation	denotes	null
T4903	9816-9826	Regulation	denotes	regulation
T4904	9834-9838	Protein	denotes	Erk1
T4905	9839-9843	Protein	denotes	RSK1
T4906	9867-9874	Negative_regulation	denotes	reduced
T4907	9878-9882	Protein	denotes	PKD1
T4908	9883-9884	Protein	denotes	3
T4909	10175-10182	Positive_regulation	denotes	induced
T4910	10187-10202	Phosphorylation	denotes	phosphorylation
T4911	10212-10219	Negative_regulation	denotes	reduced
T4912	10223-10227	Protein	denotes	PKD1
T4913	10228-10229	Protein	denotes	3
T4914	10238-10242	Protein	denotes	PKD3
T4915	10322-10326	Protein	denotes	PKD1
T4916	10327-10328	Protein	denotes	3
T4917	10337-10341	Protein	denotes	PKD1
T4918	10342-10343	Protein	denotes	3
T4919	10352-10356	Protein	denotes	PKD3
T4920	10546-10550	Protein	denotes	PKD1
T4921	10551-10552	Protein	denotes	3
T4922	10859-10863	Protein	denotes	PKD1
T4923	10864-10865	Protein	denotes	3
T4924	10964-10968	Protein	denotes	PKD1
T4925	10969-10970	Protein	denotes	3
T4926	11140-11144	Negative_regulation	denotes	loss
T4927	11148-11152	Protein	denotes	PKD1
T4928	11153-11154	Protein	denotes	3
T4929	11389-11397	Protein	denotes	MAPKAPK2
T4930	12013-12029	Protein	denotes	Bcr-Abl oncogene
T4931	12078-12087	Positive_regulation	denotes	activated
T4932	12088-12092	Protein	denotes	PKD1
T4933	12109-12113	Protein	denotes	HPK1
T4934	12177-12186	Regulation	denotes	regulated
T4935	12199-12203	Protein	denotes	PKCβ
T4936	12397-12401	Protein	denotes	PKD1
T4937	12402-12403	Protein	denotes	3
T4938	12566-12571	Protein	denotes	PKCβ−
T4939	12656-12675	Phosphorylation	denotes	autophosphorylation
T4940	12679-12683	Protein	denotes	PKD1
T4941	12713-12718	Protein	denotes	PKCβ−
R1820	T2154	T2153	themeOf	PKD1,lacked
R1821	T2155	T2153	themeOf	PKD3,lacked
R1822	T2157	T2156	themeOf	expression,induced
R1823	T2158	T2157	themeOf	PKD3,expression
R1825	T2161	T2159	themeOf	phosphorylation,regulation
R4	T6	T5	themeOf	regulate,required
R5	T7	T8	themeOf	HSP27,phosphorylation
R6	T8	T6	themeOf	phosphorylation,regulate
R419	T466	T467	causeOf	binding,contributes
R420	T468	T469	themeOf	PKD1,activation
R421	T469	T467	themeOf	activation,contributes
R422	T474	T475	themeOf	HSP27,phosphorylation
R423	T475	T473	themeOf	phosphorylation,indispensable
R1790	T2103	T2104	themeOf	HSP27,phosphorylation
R1791	T2106	T2105	themeOf	PKD1,express
R1792	T2107	T2105	themeOf	PKD3,express
R1793	T2109	T2108	themeOf	expression,lack
R1794	T2110	T2109	themeOf	PKD1,expression
R1795	T2111	T2109	themeOf	PKD3,expression
R1796	T2115	T2114	themeOf	PKD3,expressed
R1797	T2116	T2117	themeOf	PKD3,expression
R1798	T2118	T2120	themeOf	PKD1,knockout
R1799	T2127	T2126	themeOf	phosphorylation,defective
R1800	T2132	T2133	themeOf	HSP27,phosphorylation
R1801	T2133	T2131	themeOf	phosphorylation,regulation
R1802	T2134	T2131	causeOf	knockout,regulation
R1803	T2135	T2131	causeOf	lacking,regulation
R1804	T2136	T2135	themeOf	PKD1,lacking
R1805	T2137	T2135	themeOf	PKD3,lacking
R1806	T2139	T2140	themeOf	HSP27,phosphorylation
R1807	T2140	T2138	themeOf	phosphorylation,increased
R1808	T2141	T2140	themeOf	S82,phosphorylation
R1809	T2141	T2139	partOf	S82,HSP27
R1810	T2143	T2144	themeOf	HSP27,phosphorylation
R1811	T2144	T2142	themeOf	phosphorylation,increase
R1812	T2145	T2147	themeOf	PKD1,knockout
R1813	T2146	T2147	themeOf	PKD3,knockout
R1814	T2148	T2152	themeOf	induced,abolished
R1815	T2149	T2148	themeOf	phosphorylation,induced
R1816	T2149	T2152	themeOf	phosphorylation,abolished
R1817	T2151	T2149	themeOf	S82,phosphorylation
R1818	T2151	T2150	partOf	S82,HSP27
R1819	T2153	T2152	causeOf	lacked,abolished
R1824	T2160	T2161	themeOf	HSP27,phosphorylation
R1826	T2165	T2164	themeOf	PKD3,deficient
R1827	T2165	T2162	themeOf	PKD3,expression
R1828	T2167	T2166	themeOf	induced,restore
R1829	T2168	T2169	themeOf	HSP27,phosphorylation
R1830	T2169	T2167	themeOf	phosphorylation,induced
R1831	T2170	T2172	causeOf	PKD3,regulate
R1832	T2171	T2172	causeOf	PKD1,regulate
R1833	T2173	T2174	themeOf	HSP27,phosphorylation
R1834	T2174	T2172	themeOf	phosphorylation,regulate
R3047	T3778	T3780	themeOf	PKD1,expression
R3048	T3779	T3780	themeOf	3,expression
R3049	T3780	T3777	themeOf	expression,loss
R3888	T4882	T4883	themeOf	expression,reduced
R3889	T4892	T4891	themeOf	activation,induced
R3890	T4893	T4892	themeOf	Akt,activation
R3891	T4894	T4892	themeOf	mTOR,activation
R3892	T4895	T4896	themeOf	S6 ribosomal protein,phosphorylation
R3893	T4896	T4892	themeOf	phosphorylation,activation
R3894	T4897	T4899	themeOf	PKD1,null
R3895	T4898	T4899	themeOf	3,null
R3896	T4900	T4902	themeOf	PKD1,null
R3897	T4901	T4902	themeOf	3,null
R3898	T4909	T4911	themeOf	induced,reduced
R3899	T4910	T4909	themeOf	phosphorylation,induced
R3900	T4910	T4911	themeOf	phosphorylation,reduced
R3901	T4927	T4926	themeOf	PKD1,loss
R3902	T4935	T4934	causeOf	PKCβ,regulated
R3903	T4940	T4939	themeOf	PKD1,autophosphorylation

PMC:1942070 / 237-13197 JSONTXT

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PMC:1942070 / 237-13197 JSON TXT