PMC:3585731 / 42882-45183 JSONTXT

Annnotations TAB JSON ListView MergeView

    testone

    {"project":"testone","denotations":[{"id":"T20788","span":{"begin":1186,"end":1201},"obj":"Phosphorylation"},{"id":"T20787","span":{"begin":982,"end":997},"obj":"Phosphorylation"},{"id":"T20786","span":{"begin":725,"end":740},"obj":"Phosphorylation"},{"id":"T20785","span":{"begin":616,"end":625},"obj":"Regulation"},{"id":"T20784","span":{"begin":572,"end":580},"obj":"Positive_regulation"},{"id":"T20783","span":{"begin":480,"end":495},"obj":"Phosphorylation"},{"id":"T20782","span":{"begin":445,"end":454},"obj":"Negative_regulation"},{"id":"T20781","span":{"begin":426,"end":432},"obj":"Regulation"},{"id":"T20780","span":{"begin":192,"end":207},"obj":"Phosphorylation"},{"id":"T20779","span":{"begin":169,"end":177},"obj":"Positive_regulation"},{"id":"T20778","span":{"begin":159,"end":168},"obj":"Regulation"},{"id":"T20777","span":{"begin":80,"end":90},"obj":"Regulation"},{"id":"T20741","span":{"begin":2248,"end":2252},"obj":"Protein"},{"id":"T20740","span":{"begin":2101,"end":2105},"obj":"Protein"},{"id":"T20739","span":{"begin":1375,"end":1379},"obj":"Protein"},{"id":"T20738","span":{"begin":1212,"end":1216},"obj":"Protein"},{"id":"T20737","span":{"begin":880,"end":887},"obj":"Protein"},{"id":"T20736","span":{"begin":763,"end":767},"obj":"Protein"},{"id":"T20735","span":{"begin":626,"end":630},"obj":"Protein"},{"id":"T20734","span":{"begin":604,"end":608},"obj":"Protein"},{"id":"T20733","span":{"begin":233,"end":237},"obj":"Protein"},{"id":"T20732","span":{"begin":154,"end":158},"obj":"Protein"}],"relations":[{"id":"R13912","pred":"causeOf","subj":"T20732","obj":"T20778"},{"id":"R13913","pred":"themeOf","subj":"T20734","obj":"T20784"},{"id":"R13914","pred":"causeOf","subj":"T20736","obj":"T20786"},{"id":"R13915","pred":"themeOf","subj":"T20738","obj":"T20788"},{"id":"R13928","pred":"themeOf","subj":"T20779","obj":"T20778"},{"id":"R13929","pred":"themeOf","subj":"T20780","obj":"T20779"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    2_test

    {"project":"2_test","denotations":[{"id":"23469174-18006659-90505462","span":{"begin":389,"end":391},"obj":"18006659"},{"id":"23469174-21779001-90505463","span":{"begin":1999,"end":2001},"obj":"21779001"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    pmc-enju-pas

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red":"arg2Of","subj":"T21834","obj":"T21828"},{"id":"R14481","pred":"arg2Of","subj":"T21834","obj":"T21832"},{"id":"R14482","pred":"arg2Of","subj":"T21834","obj":"T21833"},{"id":"R14483","pred":"arg1Of","subj":"T21838","obj":"T21837"},{"id":"R14484","pred":"arg1Of","subj":"T21838","obj":"T21839"},{"id":"R14488","pred":"arg2Of","subj":"T21840","obj":"T21839"},{"id":"R14489","pred":"arg1Of","subj":"T21840","obj":"T21841"},{"id":"R14490","pred":"arg2Of","subj":"T21842","obj":"T21841"},{"id":"R14491","pred":"arg1Of","subj":"T21843","obj":"T21835"},{"id":"R14492","pred":"arg1Of","subj":"T21843","obj":"T21836"}],"namespaces":[{"prefix":"_base","uri":"http://kmcs.nii.ac.jp/enju/"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    bionlp-st-ge-2016-coref

    {"project":"bionlp-st-ge-2016-coref","denotations":[{"id":"T21051","span":{"begin":626,"end":630},"obj":"Antecedent"},{"id":"T21050","span":{"begin":670,"end":687},"obj":"Anaphor"}],"relations":[{"id":"R13989","pred":"boundBy","subj":"T21050","obj":"T21051"}],"namespaces":[{"prefix":"_base","uri":"https://bionlp.dbcls.jp/ontology/ge.owl#"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    bionlp-st-ge-2016-test-proteins

    {"project":"bionlp-st-ge-2016-test-proteins","denotations":[{"id":"T21068","span":{"begin":2248,"end":2252},"obj":"Protein"},{"id":"T21067","span":{"begin":2101,"end":2105},"obj":"Protein"},{"id":"T21066","span":{"begin":1375,"end":1379},"obj":"Protein"},{"id":"T21065","span":{"begin":1212,"end":1216},"obj":"Protein"},{"id":"T21064","span":{"begin":880,"end":887},"obj":"Protein"},{"id":"T21063","span":{"begin":763,"end":767},"obj":"Protein"},{"id":"T21062","span":{"begin":626,"end":630},"obj":"Protein"},{"id":"T21061","span":{"begin":604,"end":608},"obj":"Protein"},{"id":"T21060","span":{"begin":233,"end":237},"obj":"Protein"},{"id":"T21059","span":{"begin":154,"end":158},"obj":"Protein"}],"namespaces":[{"prefix":"_base","uri":"http://bionlp.dbcls.jp/ontology/ge.owl#"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    bionlp-st-ge-2016-uniprot

    {"project":"bionlp-st-ge-2016-uniprot","denotations":[{"id":"T22948","span":{"begin":1988,"end":1990},"obj":"http://www.uniprot.org/uniprot/P03372"},{"id":"T22939","span":{"begin":2248,"end":2252},"obj":"http://www.uniprot.org/uniprot/P01375"},{"id":"T22938","span":{"begin":2101,"end":2105},"obj":"http://www.uniprot.org/uniprot/P01375"},{"id":"T22937","span":{"begin":1375,"end":1379},"obj":"http://www.uniprot.org/uniprot/P01375"},{"id":"T22925","span":{"begin":1212,"end":1216},"obj":"http://www.uniprot.org/uniprot/Q13546"},{"id":"T22924","span":{"begin":763,"end":767},"obj":"http://www.uniprot.org/uniprot/Q13546"},{"id":"T22923","span":{"begin":604,"end":608},"obj":"http://www.uniprot.org/uniprot/Q13546"},{"id":"T22922","span":{"begin":233,"end":237},"obj":"http://www.uniprot.org/uniprot/Q13546"},{"id":"T22921","span":{"begin":154,"end":158},"obj":"http://www.uniprot.org/uniprot/Q13546"},{"id":"T22869","span":{"begin":1735,"end":1738},"obj":"http://www.uniprot.org/uniprot/P31751"},{"id":"T22868","span":{"begin":1636,"end":1639},"obj":"http://www.uniprot.org/uniprot/P31751"},{"id":"T22867","span":{"begin":1439,"end":1442},"obj":"http://www.uniprot.org/uniprot/P31751"},{"id":"T22866","span":{"begin":1339,"end":1342},"obj":"http://www.uniprot.org/uniprot/P31751"},{"id":"T22865","span":{"begin":1205,"end":1208},"obj":"http://www.uniprot.org/uniprot/P31751"},{"id":"T22864","span":{"begin":1030,"end":1033},"obj":"http://www.uniprot.org/uniprot/P31751"},{"id":"T22863","span":{"begin":884,"end":887},"obj":"http://www.uniprot.org/uniprot/P31751"},{"id":"T22862","span":{"begin":744,"end":747},"obj":"http://www.uniprot.org/uniprot/P31751"},{"id":"T22861","span":{"begin":632,"end":635},"obj":"http://www.uniprot.org/uniprot/P31751"},{"id":"T22860","span":{"begin":181,"end":184},"obj":"http://www.uniprot.org/uniprot/P31751"},{"id":"T22859","span":{"begin":94,"end":97},"obj":"http://www.uniprot.org/uniprot/P31751"},{"id":"T22835","span":{"begin":1735,"end":1738},"obj":"http://www.uniprot.org/uniprot/P31749"},{"id":"T22834","span":{"begin":1636,"end":1639},"obj":"http://www.uniprot.org/uniprot/P31749"},{"id":"T22833","span":{"begin":1439,"end":1442},"obj":"http://www.uniprot.org/uniprot/P31749"},{"id":"T22832","span":{"begin":1339,"end":1342},"obj":"http://www.uniprot.org/uniprot/P31749"},{"id":"T22831","span":{"begin":1205,"end":1208},"obj":"http://www.uniprot.org/uniprot/P31749"},{"id":"T22830","span":{"begin":1030,"end":1033},"obj":"http://www.uniprot.org/uniprot/P31749"},{"id":"T22829","span":{"begin":884,"end":887},"obj":"http://www.uniprot.org/uniprot/P31749"},{"id":"T22828","span":{"begin":744,"end":747},"obj":"http://www.uniprot.org/uniprot/P31749"},{"id":"T22827","span":{"begin":632,"end":635},"obj":"http://www.uniprot.org/uniprot/P31749"},{"id":"T22826","span":{"begin":181,"end":184},"obj":"http://www.uniprot.org/uniprot/P31749"},{"id":"T22825","span":{"begin":94,"end":97},"obj":"http://www.uniprot.org/uniprot/P31749"},{"id":"T22903","span":{"begin":1735,"end":1738},"obj":"http://www.uniprot.org/uniprot/Q9Y243"},{"id":"T22902","span":{"begin":1636,"end":1639},"obj":"http://www.uniprot.org/uniprot/Q9Y243"},{"id":"T22901","span":{"begin":1439,"end":1442},"obj":"http://www.uniprot.org/uniprot/Q9Y243"},{"id":"T22900","span":{"begin":1339,"end":1342},"obj":"http://www.uniprot.org/uniprot/Q9Y243"},{"id":"T22899","span":{"begin":1205,"end":1208},"obj":"http://www.uniprot.org/uniprot/Q9Y243"},{"id":"T22898","span":{"begin":1030,"end":1033},"obj":"http://www.uniprot.org/uniprot/Q9Y243"},{"id":"T22897","span":{"begin":884,"end":887},"obj":"http://www.uniprot.org/uniprot/Q9Y243"},{"id":"T22896","span":{"begin":744,"end":747},"obj":"http://www.uniprot.org/uniprot/Q9Y243"},{"id":"T22895","span":{"begin":632,"end":635},"obj":"http://www.uniprot.org/uniprot/Q9Y243"},{"id":"T22894","span":{"begin":181,"end":184},"obj":"http://www.uniprot.org/uniprot/Q9Y243"},{"id":"T22893","span":{"begin":94,"end":97},"obj":"http://www.uniprot.org/uniprot/Q9Y243"}],"namespaces":[{"prefix":"_base","uri":"http://www.uniprot.org/uniprot/"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    GO-BP

    {"project":"GO-BP","denotations":[{"id":"T21213","span":{"begin":2233,"end":2244},"obj":"http://purl.obolibrary.org/obo/GO_0006412"},{"id":"T21212","span":{"begin":626,"end":630},"obj":"http://purl.obolibrary.org/obo/GO_0004740"},{"id":"T21211","span":{"begin":480,"end":509},"obj":"http://purl.obolibrary.org/obo/GO_0042327"},{"id":"T21210","span":{"begin":256,"end":267},"obj":"http://purl.obolibrary.org/obo/GO_0016791"},{"id":"T21208","span":{"begin":238,"end":253},"obj":"http://purl.obolibrary.org/obo/GO_0033673"},{"id":"T21203","span":{"begin":1954,"end":1964},"obj":"http://purl.obolibrary.org/obo/GO_0065007"},{"id":"T21202","span":{"begin":1288,"end":1298},"obj":"http://purl.obolibrary.org/obo/GO_0065007"},{"id":"T21201","span":{"begin":80,"end":90},"obj":"http://purl.obolibrary.org/obo/GO_0065007"},{"id":"T21182","span":{"begin":1765,"end":1770},"obj":"http://purl.obolibrary.org/obo/GO_0016265"},{"id":"T21181","span":{"begin":1365,"end":1370},"obj":"http://purl.obolibrary.org/obo/GO_0016265"},{"id":"T21164","span":{"begin":1380,"end":1389},"obj":"http://purl.obolibrary.org/obo/GO_0009058"},{"id":"T21161","span":{"begin":2297,"end":2300},"obj":"http://purl.obolibrary.org/obo/GO_0004705"},{"id":"T21160","span":{"begin":2094,"end":2097},"obj":"http://purl.obolibrary.org/obo/GO_0004705"},{"id":"T21159","span":{"begin":1968,"end":1971},"obj":"http://purl.obolibrary.org/obo/GO_0004705"},{"id":"T21158","span":{"begin":1868,"end":1871},"obj":"http://purl.obolibrary.org/obo/GO_0004705"},{"id":"T21143","span":{"begin":2170,"end":2181},"obj":"http://purl.obolibrary.org/obo/GO_0097528"},{"id":"T21142","span":{"begin":2032,"end":2043},"obj":"http://purl.obolibrary.org/obo/GO_0097528"},{"id":"T21141","span":{"begin":932,"end":943},"obj":"http://purl.obolibrary.org/obo/GO_0097528"},{"id":"T21140","span":{"begin":513,"end":524},"obj":"http://purl.obolibrary.org/obo/GO_0097528"},{"id":"T21139","span":{"begin":105,"end":116},"obj":"http://purl.obolibrary.org/obo/GO_0097528"},{"id":"T21132","span":{"begin":499,"end":524},"obj":"http://purl.obolibrary.org/obo/GO_0070266"},{"id":"T21119","span":{"begin":2170,"end":2181},"obj":"http://purl.obolibrary.org/obo/GO_0070266"},{"id":"T21118","span":{"begin":2032,"end":2043},"obj":"http://purl.obolibrary.org/obo/GO_0070266"},{"id":"T21117","span":{"begin":932,"end":943},"obj":"http://purl.obolibrary.org/obo/GO_0070266"},{"id":"T21116","span":{"begin":513,"end":524},"obj":"http://purl.obolibrary.org/obo/GO_0070266"},{"id":"T21115","span":{"begin":105,"end":116},"obj":"http://purl.obolibrary.org/obo/GO_0070266"},{"id":"T21111","span":{"begin":1186,"end":1201},"obj":"http://purl.obolibrary.org/obo/GO_0016310"},{"id":"T21110","span":{"begin":982,"end":997},"obj":"http://purl.obolibrary.org/obo/GO_0016310"},{"id":"T21109","span":{"begin":725,"end":740},"obj":"http://purl.obolibrary.org/obo/GO_0016310"},{"id":"T21108","span":{"begin":480,"end":495},"obj":"http://purl.obolibrary.org/obo/GO_0016310"},{"id":"T21107","span":{"begin":192,"end":207},"obj":"http://purl.obolibrary.org/obo/GO_0016310"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    GO-MF

    {"project":"GO-MF","denotations":[{"id":"T21275","span":{"begin":1123,"end":1131},"obj":"http://purl.obolibrary.org/obo/GO_0003823"},{"id":"T21274","span":{"begin":626,"end":630},"obj":"http://purl.obolibrary.org/obo/GO_0004740"},{"id":"T21273","span":{"begin":256,"end":267},"obj":"http://purl.obolibrary.org/obo/GO_0016791"},{"id":"T21272","span":{"begin":2297,"end":2300},"obj":"http://purl.obolibrary.org/obo/GO_0004705"},{"id":"T21271","span":{"begin":2094,"end":2097},"obj":"http://purl.obolibrary.org/obo/GO_0004705"},{"id":"T21270","span":{"begin":1968,"end":1971},"obj":"http://purl.obolibrary.org/obo/GO_0004705"},{"id":"T21269","span":{"begin":1868,"end":1871},"obj":"http://purl.obolibrary.org/obo/GO_0004705"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    GO-CC

    {"project":"GO-CC","denotations":[{"id":"T21281","span":{"begin":1042,"end":1047},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T21280","span":{"begin":533,"end":538},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T21303","span":{"begin":1988,"end":1990},"obj":"http://purl.obolibrary.org/obo/GO_0005783"},{"id":"T21302","span":{"begin":1123,"end":1131},"obj":"http://purl.obolibrary.org/obo/GO_0042571"},{"id":"T21301","span":{"begin":1123,"end":1131},"obj":"http://purl.obolibrary.org/obo/GO_0019815"},{"id":"T21299","span":{"begin":2207,"end":2213},"obj":"http://purl.obolibrary.org/obo/GO_0031931"},{"id":"T21298","span":{"begin":2128,"end":2134},"obj":"http://purl.obolibrary.org/obo/GO_0031931"},{"id":"T21297","span":{"begin":1937,"end":1943},"obj":"http://purl.obolibrary.org/obo/GO_0031931"},{"id":"T21296","span":{"begin":1858,"end":1864},"obj":"http://purl.obolibrary.org/obo/GO_0031931"},{"id":"T21295","span":{"begin":1563,"end":1569},"obj":"http://purl.obolibrary.org/obo/GO_0031931"},{"id":"T21294","span":{"begin":1473,"end":1479},"obj":"http://purl.obolibrary.org/obo/GO_0031931"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    sentences

    {"project":"sentences","denotations":[{"id":"T20956","span":{"begin":2070,"end":2301},"obj":"Sentence"},{"id":"T20955","span":{"begin":1897,"end":2069},"obj":"Sentence"},{"id":"T20954","span":{"begin":1821,"end":1896},"obj":"Sentence"},{"id":"T20953","span":{"begin":1678,"end":1820},"obj":"Sentence"},{"id":"T20952","span":{"begin":1504,"end":1677},"obj":"Sentence"},{"id":"T20951","span":{"begin":1391,"end":1503},"obj":"Sentence"},{"id":"T20950","span":{"begin":1300,"end":1390},"obj":"Sentence"},{"id":"T20949","span":{"begin":945,"end":1299},"obj":"Sentence"},{"id":"T20948","span":{"begin":833,"end":944},"obj":"Sentence"},{"id":"T20947","span":{"begin":698,"end":832},"obj":"Sentence"},{"id":"T20946","span":{"begin":540,"end":697},"obj":"Sentence"},{"id":"T20945","span":{"begin":394,"end":539},"obj":"Sentence"},{"id":"T20944","span":{"begin":289,"end":393},"obj":"Sentence"},{"id":"T20943","span":{"begin":209,"end":288},"obj":"Sentence"},{"id":"T20942","span":{"begin":118,"end":208},"obj":"Sentence"},{"id":"T20941","span":{"begin":0,"end":117},"obj":"Sentence"},{"id":"T266","span":{"begin":0,"end":117},"obj":"Sentence"},{"id":"T267","span":{"begin":118,"end":208},"obj":"Sentence"},{"id":"T268","span":{"begin":209,"end":288},"obj":"Sentence"},{"id":"T269","span":{"begin":289,"end":393},"obj":"Sentence"},{"id":"T270","span":{"begin":394,"end":539},"obj":"Sentence"},{"id":"T271","span":{"begin":540,"end":697},"obj":"Sentence"},{"id":"T272","span":{"begin":698,"end":832},"obj":"Sentence"},{"id":"T273","span":{"begin":833,"end":944},"obj":"Sentence"},{"id":"T274","span":{"begin":945,"end":1299},"obj":"Sentence"},{"id":"T275","span":{"begin":1300,"end":1390},"obj":"Sentence"},{"id":"T276","span":{"begin":1391,"end":1503},"obj":"Sentence"},{"id":"T277","span":{"begin":1504,"end":1677},"obj":"Sentence"},{"id":"T278","span":{"begin":1678,"end":1820},"obj":"Sentence"},{"id":"T279","span":{"begin":1821,"end":1896},"obj":"Sentence"},{"id":"T280","span":{"begin":1897,"end":2069},"obj":"Sentence"},{"id":"T281","span":{"begin":2070,"end":2301},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    simple1

    {"project":"simple1","denotations":[{"id":"T21320","span":{"begin":2248,"end":2252},"obj":"Protein"},{"id":"T21319","span":{"begin":2101,"end":2105},"obj":"Protein"},{"id":"T21318","span":{"begin":1375,"end":1379},"obj":"Protein"},{"id":"T21317","span":{"begin":1212,"end":1216},"obj":"Protein"},{"id":"T21316","span":{"begin":880,"end":887},"obj":"Protein"},{"id":"T21315","span":{"begin":763,"end":767},"obj":"Protein"},{"id":"T21314","span":{"begin":626,"end":630},"obj":"Protein"},{"id":"T21313","span":{"begin":604,"end":608},"obj":"Protein"},{"id":"T21312","span":{"begin":233,"end":237},"obj":"Protein"},{"id":"T21311","span":{"begin":154,"end":158},"obj":"Protein"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    BioNLP16_DUT

    {"project":"BioNLP16_DUT","denotations":[{"id":"T22801","span":{"begin":1348,"end":1355},"obj":"Positive_regulation"},{"id":"T22767","span":{"begin":2248,"end":2252},"obj":"Protein"},{"id":"T22766","span":{"begin":2101,"end":2105},"obj":"Protein"},{"id":"T22765","span":{"begin":1375,"end":1379},"obj":"Protein"},{"id":"T22764","span":{"begin":1212,"end":1216},"obj":"Protein"},{"id":"T22763","span":{"begin":880,"end":887},"obj":"Protein"},{"id":"T22762","span":{"begin":763,"end":767},"obj":"Protein"},{"id":"T22761","span":{"begin":626,"end":630},"obj":"Protein"},{"id":"T22760","span":{"begin":604,"end":608},"obj":"Protein"},{"id":"T22759","span":{"begin":233,"end":237},"obj":"Protein"},{"id":"T22758","span":{"begin":154,"end":158},"obj":"Protein"},{"id":"T22800","span":{"begin":1380,"end":1389},"obj":"Gene_expression"},{"id":"T22799","span":{"begin":1186,"end":1201},"obj":"Phosphorylation"}],"relations":[{"id":"R15386","pred":"themeOf","subj":"T22764","obj":"T22799"},{"id":"R15387","pred":"themeOf","subj":"T22765","obj":"T22800"},{"id":"R15401","pred":"themeOf","subj":"T22800","obj":"T22801"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    BioNLP16_Messiy

    {"project":"BioNLP16_Messiy","denotations":[{"id":"T23098","span":{"begin":2248,"end":2252},"obj":"Protein"},{"id":"T23097","span":{"begin":2101,"end":2105},"obj":"Protein"},{"id":"T23096","span":{"begin":1375,"end":1379},"obj":"Protein"},{"id":"T23095","span":{"begin":1212,"end":1216},"obj":"Protein"},{"id":"T23094","span":{"begin":880,"end":887},"obj":"Protein"},{"id":"T23093","span":{"begin":763,"end":767},"obj":"Protein"},{"id":"T23092","span":{"begin":626,"end":630},"obj":"Protein"},{"id":"T23091","span":{"begin":604,"end":608},"obj":"Protein"},{"id":"T23090","span":{"begin":233,"end":237},"obj":"Protein"},{"id":"T23089","span":{"begin":154,"end":158},"obj":"Protein"},{"id":"T23132","span":{"begin":1380,"end":1389},"obj":"Gene_expression"},{"id":"T23131","span":{"begin":1348,"end":1355},"obj":"Positive_regulation"},{"id":"T23130","span":{"begin":1186,"end":1201},"obj":"Phosphorylation"}],"relations":[{"id":"R15463","pred":"themeOf","subj":"T23095","obj":"T23130"},{"id":"R15464","pred":"themeOf","subj":"T23096","obj":"T23132"},{"id":"R15476","pred":"themeOf","subj":"T23132","obj":"T23131"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    DLUT931

    {"project":"DLUT931","denotations":[{"id":"T23010","span":{"begin":2214,"end":2225},"obj":"Positive_regulation"},{"id":"T23009","span":{"begin":1348,"end":1355},"obj":"Positive_regulation"},{"id":"T23008","span":{"begin":1380,"end":1389},"obj":"Gene_expression"},{"id":"T23007","span":{"begin":1288,"end":1298},"obj":"Regulation"},{"id":"T23006","span":{"begin":1186,"end":1201},"obj":"Phosphorylation"},{"id":"T23005","span":{"begin":846,"end":854},"obj":"Negative_regulation"},{"id":"T23004","span":{"begin":725,"end":740},"obj":"Phosphorylation"},{"id":"T23003","span":{"begin":616,"end":625},"obj":"Binding"},{"id":"T23002","span":{"begin":245,"end":253},"obj":"Negative_regulation"},{"id":"T22962","span":{"begin":626,"end":630},"obj":"Protein"},{"id":"T22961","span":{"begin":604,"end":608},"obj":"Protein"},{"id":"T22960","span":{"begin":233,"end":237},"obj":"Protein"},{"id":"T22959","span":{"begin":154,"end":158},"obj":"Protein"},{"id":"T22968","span":{"begin":2248,"end":2252},"obj":"Protein"},{"id":"T22967","span":{"begin":2101,"end":2105},"obj":"Protein"},{"id":"T22966","span":{"begin":1375,"end":1379},"obj":"Protein"},{"id":"T22965","span":{"begin":1212,"end":1216},"obj":"Protein"},{"id":"T22964","span":{"begin":880,"end":887},"obj":"Protein"},{"id":"T22963","span":{"begin":763,"end":767},"obj":"Protein"}],"relations":[{"id":"R15437","pred":"themeOf","subj":"T23006","obj":"T23007"},{"id":"R15438","pred":"themeOf","subj":"T23008","obj":"T23009"},{"id":"R15412","pred":"themeOf","subj":"T22960","obj":"T23002"},{"id":"R15413","pred":"themeOf","subj":"T22961","obj":"T23003"},{"id":"R15414","pred":"themeOf","subj":"T22962","obj":"T23003"},{"id":"R15415","pred":"themeOf","subj":"T22963","obj":"T23004"},{"id":"R15416","pred":"themeOf","subj":"T22964","obj":"T23005"},{"id":"R15417","pred":"themeOf","subj":"T22965","obj":"T23006"},{"id":"R15418","pred":"themeOf","subj":"T22966","obj":"T23008"},{"id":"R15419","pred":"themeOf","subj":"T22968","obj":"T23010"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    bionlp-st-ge-2016-test-ihmc

    {"project":"bionlp-st-ge-2016-test-ihmc","denotations":[{"id":"T23594","span":{"begin":632,"end":635},"obj":"Protein"},{"id":"T23590","span":{"begin":604,"end":658},"obj":"Protein"},{"id":"T23587","span":{"begin":315,"end":392},"obj":"Protein"},{"id":"T23582","span":{"begin":816,"end":831},"obj":"Entity"},{"id":"T23580","span":{"begin":2297,"end":2300},"obj":"Protein"},{"id":"T23578","span":{"begin":1147,"end":1161},"obj":"Entity"},{"id":"T23577","span":{"begin":228,"end":287},"obj":"Protein"},{"id":"T23576","span":{"begin":741,"end":747},"obj":"Protein"},{"id":"T23573","span":{"begin":154,"end":168},"obj":"Protein"},{"id":"T23572","span":{"begin":1439,"end":1460},"obj":"Entity"},{"id":"T23571","span":{"begin":1474,"end":1502},"obj":"Entity"},{"id":"T23566","span":{"begin":1439,"end":1442},"obj":"Protein"},{"id":"T23565","span":{"begin":1563,"end":1569},"obj":"Entity"},{"id":"T23564","span":{"begin":94,"end":97},"obj":"Protein"},{"id":"T23561","span":{"begin":1721,"end":1749},"obj":"Entity"},{"id":"T23555","span":{"begin":238,"end":244},"obj":"Protein"},{"id":"T23547","span":{"begin":433,"end":443},"obj":"Entity"},{"id":"T23546","span":{"begin":1212,"end":1216},"obj":"Protein"},{"id":"T23544","span":{"begin":181,"end":191},"obj":"Entity"},{"id":"T23543","span":{"begin":748,"end":774},"obj":"Protein"},{"id":"T23542","span":{"begin":1965,"end":1971},"obj":"Protein"},{"id":"T23537","span":{"begin":581,"end":590},"obj":"Entity"},{"id":"T23533","span":{"begin":1858,"end":1864},"obj":"Entity"},{"id":"T23531","span":{"begin":1988,"end":2002},"obj":"Protein"},{"id":"T23529","span":{"begin":456,"end":468},"obj":"Entity"},{"id":"T23526","span":{"begin":228,"end":287},"obj":"Protein"},{"id":"T23520","span":{"begin":626,"end":630},"obj":"Protein"},{"id":"T23519","span":{"begin":1865,"end":1871},"obj":"Protein"},{"id":"T23518","span":{"begin":2091,"end":2097},"obj":"Protein"},{"id":"T23514","span":{"begin":604,"end":608},"obj":"Protein"},{"id":"T23513","span":{"begin":281,"end":287},"obj":"Entity"},{"id":"T23508","span":{"begin":670,"end":687},"obj":"Protein"},{"id":"T23507","span":{"begin":1339,"end":1342},"obj":"Protein"},{"id":"T23506","span":{"begin":181,"end":184},"obj":"Protein"},{"id":"T23505","span":{"begin":1375,"end":1389},"obj":"Protein"},{"id":"T23504","span":{"begin":1625,"end":1650},"obj":"Entity"},{"id":"T23502","span":{"begin":1636,"end":1639},"obj":"Protein"},{"id":"T23501","span":{"begin":375,"end":392},"obj":"Entity"},{"id":"T23500","span":{"begin":1123,"end":1131},"obj":"Protein"},{"id":"T23497","span":{"begin":855,"end":887},"obj":"Entity"},{"id":"T23496","span":{"begin":998,"end":1015},"obj":"Entity"},{"id":"T23495","span":{"begin":763,"end":767},"obj":"Protein"},{"id":"T23493","span":{"begin":880,"end":887},"obj":"Protein"},{"id":"T23492","span":{"begin":2101,"end":2105},"obj":"Protein"},{"id":"T23491","span":{"begin":473,"end":479},"obj":"Entity"},{"id":"T23490","span":{"begin":816,"end":822},"obj":"Entity"},{"id":"T23485","span":{"begin":1735,"end":1738},"obj":"Protein"},{"id":"T23482","span":{"begin":1019,"end":1033},"obj":"Protein"},{"id":"T23481","span":{"begin":1317,"end":1389},"obj":"Entity"},{"id":"T23474","span":{"begin":787,"end":803},"obj":"Entity"},{"id":"T23473","span":{"begin":445,"end":469},"obj":"Entity"},{"id":"T23652","span":{"begin":1934,"end":1971},"obj":"Regulation"},{"id":"T23650","span":{"begin":315,"end":392},"obj":"Gene_expression"},{"id":"T23647","span":{"begin":1847,"end":1871},"obj":"Binding"},{"id":"T23645","span":{"begin":178,"end":207},"obj":"Phosphorylation"},{"id":"T23644","span":{"begin":2076,"end":2097},"obj":"Positive_regulation"},{"id":"T23641","span":{"begin":698,"end":811},"obj":"Phosphorylation"},{"id":"T23635","span":{"begin":2229,"end":2252},"obj":"Translation"},{"id":"T23633","span":{"begin":150,"end":207},"obj":"Regulation"},{"id":"T23628","span":{"begin":228,"end":287},"obj":"Negative_regulation"},{"id":"T23626","span":{"begin":150,"end":207},"obj":"Positive_regulation"},{"id":"T23621","span":{"begin":1202,"end":1208},"obj":"Protein"},{"id":"T23619","span":{"begin":1147,"end":1153},"obj":"Entity"},{"id":"T23615","span":{"begin":2207,"end":2213},"obj":"Entity"},{"id":"T23609","span":{"begin":2245,"end":2252},"obj":"Protein"},{"id":"T23605","span":{"begin":873,"end":887},"obj":"Entity"}],"relations":[{"id":"R15649","pred":"themeOf","subj":"T23506","obj":"T23645"},{"id":"R15651","pred":"themeOf","subj":"T23518","obj":"T23644"},{"id":"R15652","pred":"themeOf","subj":"T23519","obj":"T23647"},{"id":"R15657","pred":"themeOf","subj":"T23533","obj":"T23647"},{"id":"R15660","pred":"themeOf","subj":"T23542","obj":"T23652"},{"id":"R15661","pred":"causeOf","subj":"T23543","obj":"T23641"},{"id":"R15662","pred":"partOf","subj":"T23544","obj":"T23506"},{"id":"R15663","pred":"siteOf","subj":"T23544","obj":"T23645"},{"id":"R15667","pred":"causeOf","subj":"T23555","obj":"T23628"},{"id":"R15669","pred":"causeOf","subj":"T23573","obj":"T23633"},{"id":"R15670","pred":"themeO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results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

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results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    bionlp-st-ge-2016-test-tees

    {"project":"bionlp-st-ge-2016-test-tees","denotations":[{"id":"T23244","span":{"begin":2159,"end":2166},"obj":"Regulation"},{"id":"T23243","span":{"begin":2080,"end":2090},"obj":"Positive_regulation"},{"id":"T23242","span":{"begin":2297,"end":2300},"obj":"Protein"},{"id":"T23241","span":{"begin":2248,"end":2252},"obj":"Protein"},{"id":"T23240","span":{"begin":2207,"end":2213},"obj":"Protein"},{"id":"T23239","span":{"begin":2128,"end":2134},"obj":"Protein"},{"id":"T23238","span":{"begin":2101,"end":2105},"obj":"Protein"},{"id":"T23237","span":{"begin":2094,"end":2097},"obj":"Protein"},{"id":"T23236","span":{"begin":1954,"end":1964},"obj":"Regulation"},{"id":"T23235","span":{"begin":1968,"end":1971},"obj":"Protein"},{"id":"T23234","span":{"begin":1868,"end":1871},"obj":"Protein"},{"id":"T23233","span":{"begin":1563,"end":1569},"obj":"Protein"},{"id":"T23232","span":{"begin":1439,"end":1442},"obj":"Protein"},{"id":"T23231","span":{"begin":1380,"end":1389},"obj":"Gene_expression"},{"id":"T23230","span":{"begin":1375,"end":1379},"obj":"Protein"},{"id":"T23229","span":{"begin":1339,"end":1342},"obj":"Protein"},{"id":"T23228","span":{"begin":1288,"end":1298},"obj":"Regulation"},{"id":"T23227","span":{"begin":1288,"end":1298},"obj":"Regulation"},{"id":"T23226","span":{"begin":1186,"end":1201},"obj":"Phosphorylation"},{"id":"T23225","span":{"begin":1186,"end":1201},"obj":"Phosphorylation"},{"id":"T23224","span":{"begin":1212,"end":1216},"obj":"Protein"},{"id":"T23223","span":{"begin":1205,"end":1208},"obj":"Protein"},{"id":"T23222","span":{"begin":884,"end":887},"obj":"Protein"},{"id":"T23221","span":{"begin":880,"end":883},"obj":"Protein"},{"id":"T23220","span":{"begin":725,"end":740},"obj":"Phosphorylation"},{"id":"T23219","span":{"begin":725,"end":740},"obj":"Phosphorylation"},{"id":"T23218","span":{"begin":751,"end":774},"obj":"Protein"},{"id":"T23217","span":{"begin":744,"end":747},"obj":"Protein"},{"id":"T23216","span":{"begin":632,"end":635},"obj":"Protein"},{"id":"T23215","span":{"begin":626,"end":630},"obj":"Protein"},{"id":"T23214","span":{"begin":604,"end":615},"obj":"Protein"},{"id":"T23213","span":{"begin":426,"end":432},"obj":"Regulation"},{"id":"T23212","span":{"begin":426,"end":432},"obj":"Regulation"},{"id":"T23211","span":{"begin":499,"end":509},"obj":"Positive_regulation"},{"id":"T23210","span":{"begin":480,"end":495},"obj":"Phosphorylation"},{"id":"T23209","span":{"begin":445,"end":454},"obj":"Negative_regulation"},{"id":"T23208","span":{"begin":473,"end":479},"obj":"Protein"},{"id":"T23207","span":{"begin":440,"end":444},"obj":"Protein"},{"id":"T23206","span":{"begin":307,"end":311},"obj":"Protein"},{"id":"T23205","span":{"begin":273,"end":280},"obj":"Regulation"},{"id":"T23204","span":{"begin":281,"end":287},"obj":"Protein"},{"id":"T23203","span":{"begin":233,"end":244},"obj":"Protein"},{"id":"T23202","span":{"begin":159,"end":168},"obj":"Regulation"},{"id":"T23201","span":{"begin":169,"end":177},"obj":"Positive_regulation"},{"id":"T23200","span":{"begin":192,"end":207},"obj":"Phosphorylation"},{"id":"T23199","span":{"begin":181,"end":184},"obj":"Protein"},{"id":"T23198","span":{"begin":154,"end":158},"obj":"Protein"},{"id":"T23197","span":{"begin":80,"end":90},"obj":"Regulation"},{"id":"T23196","span":{"begin":94,"end":97},"obj":"Protein"}],"relations":[{"id":"R15509","pred":"themeOf","subj":"T23196","obj":"T23197"},{"id":"R15510","pred":"causeOf","subj":"T23198","obj":"T23202"},{"id":"R15511","pred":"themeOf","subj":"T23199","obj":"T23200"},{"id":"R15512","pred":"themeOf","subj":"T23200","obj":"T23201"},{"id":"R15513","pred":"themeOf","subj":"T23201","obj":"T23202"},{"id":"R15514","pred":"themeOf","subj":"T23204","obj":"T23205"},{"id":"R15515","pred":"themeOf","subj":"T23207","obj":"T23209"},{"id":"R15516","pred":"themeOf","subj":"T23208","obj":"T23210"},{"id":"R15517","pred":"causeOf","subj":"T23209","obj":"T23212"},{"id":"R15518","pred":"causeOf","subj":"T23209","obj":"T23213"},{"id":"R15519","pred":"themeOf","subj":"T23210","obj":"T23211"},{"id":"R15520","pred":"themeOf","subj":"T23210","obj":"T23212"},{"id":"R15521","pred":"themeOf","subj":"T23211","obj":"T23213"},{"id":"R15522","pred":"themeOf","subj":"T23217","obj":"T23219"},{"id":"R15523","pred":"themeOf","subj":"T23218","obj":"T23220"},{"id":"R15524","pred":"themeOf","subj":"T23223","obj":"T23225"},{"id":"R15525","pred":"themeOf","subj":"T23224","obj":"T23226"},{"id":"R15526","pred":"themeOf","subj":"T23225","obj":"T23227"},{"id":"R15527","pred":"themeOf","subj":"T23226","obj":"T23228"},{"id":"R15528","pred":"themeOf","subj":"T23230","obj":"T23231"},{"id":"R15529","pred":"themeOf","subj":"T23235","obj":"T23236"},{"id":"R15530","pred":"themeOf","subj":"T23237","obj":"T23243"},{"id":"R15531","pred":"causeOf","subj":"T23238","obj":"T23243"},{"id":"R15532","pred":"themeOf","subj":"T23243","obj":"T23244"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}

    test3

    {"project":"test3","denotations":[{"id":"T20886","span":{"begin":2248,"end":2252},"obj":"Protein"},{"id":"T20885","span":{"begin":2214,"end":2225},"obj":"Positive_regulation"},{"id":"T20884","span":{"begin":2101,"end":2105},"obj":"Protein"},{"id":"T20883","span":{"begin":1380,"end":1389},"obj":"Gene_expression"},{"id":"T20882","span":{"begin":1375,"end":1379},"obj":"Protein"},{"id":"T20881","span":{"begin":1288,"end":1298},"obj":"Regulation"},{"id":"T20880","span":{"begin":1212,"end":1216},"obj":"Protein"},{"id":"T20879","span":{"begin":1186,"end":1201},"obj":"Phosphorylation"},{"id":"T20878","span":{"begin":982,"end":997},"obj":"Phosphorylation"},{"id":"T20877","span":{"begin":880,"end":887},"obj":"Protein"},{"id":"T20876","span":{"begin":763,"end":767},"obj":"Protein"},{"id":"T20875","span":{"begin":725,"end":740},"obj":"Phosphorylation"},{"id":"T20874","span":{"begin":626,"end":630},"obj":"Protein"},{"id":"T20873","span":{"begin":604,"end":608},"obj":"Protein"},{"id":"T20872","span":{"begin":480,"end":495},"obj":"Phosphorylation"},{"id":"T20871","span":{"begin":233,"end":237},"obj":"Protein"},{"id":"T20870","span":{"begin":192,"end":207},"obj":"Phosphorylation"},{"id":"T20869","span":{"begin":169,"end":177},"obj":"Positive_regulation"},{"id":"T20868","span":{"begin":159,"end":168},"obj":"Regulation"},{"id":"T20867","span":{"begin":154,"end":158},"obj":"Protein"},{"id":"T20866","span":{"begin":80,"end":90},"obj":"Regulation"},{"id":"T20823","span":{"begin":2248,"end":2252},"obj":"Protein"},{"id":"T20822","span":{"begin":2101,"end":2105},"obj":"Protein"},{"id":"T20821","span":{"begin":1375,"end":1379},"obj":"Protein"},{"id":"T20820","span":{"begin":1212,"end":1216},"obj":"Protein"},{"id":"T20819","span":{"begin":880,"end":887},"obj":"Protein"},{"id":"T20818","span":{"begin":763,"end":767},"obj":"Protein"},{"id":"T20817","span":{"begin":626,"end":630},"obj":"Protein"},{"id":"T20816","span":{"begin":604,"end":608},"obj":"Protein"},{"id":"T20815","span":{"begin":233,"end":237},"obj":"Protein"},{"id":"T20814","span":{"begin":154,"end":158},"obj":"Protein"}],"relations":[{"id":"R13941","pred":"causeOf","subj":"T20867","obj":"T20868"},{"id":"R13942","pred":"causeOf","subj":"T20867","obj":"T20869"},{"id":"R13943","pred":"themeOf","subj":"T20869","obj":"T20868"},{"id":"R13944","pred":"themeOf","subj":"T20870","obj":"T20869"},{"id":"R13945","pred":"themeOf","subj":"T20882","obj":"T20883"}],"text":"Our results raise some important mechanistic questions relevant to the specific regulation of Akt during necroptosis. First, what is the mechanism of the RIP1-dependent increase in Akt Thr308 phosphorylation? One possibility is that RIP1 kinase inhibits a phosphatase that targets Thr308. To our knowledge, PP2A is the only enzyme established to specifically dephosphorylate this residue [45]. However, we did not observe any effect of the PP2A inhibitor, okadaic acid, on Thr308 phosphorylation or activation of necroptosis in L929 cells. Another possibility is that the increase in Thr308 results from RIP1 kinase targeting PDK1, Akt or scaffolding factors that bring these two kinases together. Interestingly, we observed phosphorylation of Akt by recombinant RIP1 kinase in vitro on Thr146, 195/197, and 435 and Ser381 residues. Furthermore, mutating these residues to Ala in Myr-Akt leads to the loss of its ability to promote necroptosis. However, we were not able to confirm phosphorylation of these residues on endogenous Akt in L929 cells using either mass spectrometry or western blotting with a phospho-specific antibody raised against Thr435 peptide, suggesting that direct phosphorylation of Akt by RIP1 likely represents an in vitro artifact and does not reflect endogenous regulation. Second, what are the key substrates of Akt that promote necrotic death and TNFα synthesis? On the one hand, our data suggest new roles for Akt effector pathways mediated by mTORC1 in necroptotic control. On the other hand, we have observed only modest changes in mTORC1 activity under necroptotic conditions, suggesting that additional Akt substrates are likely to be involved. This warrants a re-evaluation of the roles of additional Akt substrates in necroptotic death, since no such connections have been established. Similarly, the mechanisms connecting mTORC1 to JNK remain to be elucidated. While there are some recent examples of mTORC1-dependent regulation of JNK, e.g. following ER stress [46], the exact mechanisms during necroptosis remain to be established. Given the activation of JNK by TNFα and the importance of mTORC1-dependent translational control in necroptosis, one possibility is that mTORC1 contributes to the translation of TNFα and forms a positive feed forward loop with JNK."}