PMC:546208 / 2266-8038 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/546208","sourcedb":"PMC","sourceid":"546208","source_url":"http://www.ncbi.nlm.nih.gov/pmc/546208","text":"Background\nAt the heart of structural and functional integrity of multicellular entities is the ability of each and every cell of it to successfully integrate signals arising from soluble factors, cell-substratum adhesion and cell-cell adhesion [1]. Correct processing of these signals allows appropriate cellular growth, differentiation, and tissue morphogenesis, but malfunctions often lie at the basis of pathologies such as tumor growth and metastasis. At sites of cell adhesion, more and more proteins are being identified that not only play a role in maintaining cell shape and motility but that, in addition to these structural functions, are also implicated in signaling events. Because of this dual function, these proteins have to interact, via multiple binding motifs, with components of both the actin cytoskeleton and signaling pathways that regulate e.g. gene expression.\nA protein that may play a role in these processes is the LPP (Lipoma Preferred Partner) protein [2]. LPP is a member of the zyxin family of LIM domain proteins, which consists of five members: zyxin [3], TRIP6 (Thyroid Receptor Interacting Protein 6) [4], LPP [2], ajuba [5] and LIMD1 (LIM Domain containing 1) [6]. LPP has three LIM domains (zinc-finger protein interaction domains) at its carboxy-terminus, which are preceded by a proline-rich pre-LIM region containing a number of protein interaction domains (Fig. 1A). LPP has been shown to localize at sites of cell adhesion, such as focal contacts, which are membrane attachment sites to the extracellular matrix, and cell-cell contacts. However, apart from its localization in cell adhesion sites, this protein has also been shown to localize transiently in the nucleus. Because of its structural features and its characteristic to shuttle between the nucleus and the cytoplasm, LPP has been proposed to be a scaffolding protein involved in signal transduction from sites of cell adhesion to the nucleus.\nFigure 1 Schematic representation of human LPP and Scrib proteins. (A) Schematic representation of the human LPP protein. Human LPP contains a proline-rich pre-LIM region followed by three tandem LIM domains. In its pre-LIM region, LPP harbors one nuclear export signal, two VASP binding sites and one α-actinin binding site. Furthermore, LPP has two regions in common with its family member TRIP6 and one region with its family members zyxin, TRIP6 and LIMD1. At its carboxy-terminus, LPP has a binding site for Scrib. (B) Schematic representation of the human Scrib protein human Scrib is a 1630 amino acid protein that contains 16 leucine-rich repeats (LRR) followed by 2 domains that are specific for the LAP family of proteins (LAP-specific domain (LAPSD) a and b), and 4 PDZ domains. The corresponding position of the mouse Scrib prey clone that was isolated in a yeast-two hybrid screen using LPP as bait is indicated. The amino acid sequence of the PDZ domains of mouse Scrib was compared to that of human Scrib, and percentage identity is indicated for each PDZ domain. Originally, we identified the LPP gene, as being the preferred translocation partner of the HMGA2 gene in a subgroup of lipomas, which are benign tumors of adipose tissue [2]. In these tumors, HMGA2/LPP fusion transcripts are expressed and identical fusion transcripts have also been found in a subgroup of pulmonary chondroid hamartomas [7], in a parosteal lipoma [8], and in a soft tissue chondroma [9]. In a case of acute monoblastic leukemia, the LPP gene acts as translocation partner of the MLL gene and the tumor expresses MLL/LPP fusion transcripts [10]. All tumor-specific fusion transcripts that are expressed in the above mentioned tumors encode similar LPP fusion proteins containing AT-hooks (DNA binding domains) of the HMGA2 or MLL proteins followed by LIM domains of LPP. These fusion proteins are mainly expressed in the nucleus [11].\nAt cell adhesions, the LPP protein interacts with α-actinin and VASP (vasodilator-stimulated phosphoprotein) via its pre-LIM region that contains an α-actinin binding site located near its N-terminus and two VASP-binding (\"FP4\")-motifs (Fig. 1A) [11,12]. In the nucleus, LPP has transcriptional activation capacity in reporter gene assays suggesting that it is involved in the regulation of gene expression [11]. The nucleocytoplasmic distribution of this protein involves a nuclear export signal (NES) that also resides in the pre-LIM region (Fig. 1A) [11]. Recently, we have shown that the LIM domains of LPP cooperate to target the protein to focal adhesions, and that the linker between LIM domains 1 and 2 plays a pivotal role in this targeting [13]. When overexpressed in the cytoplasm of cells, these LIM domains deplete endogenous LPP and vinculin from focal adhesions suggesting a role for LPP in focal adhesion assembly [13]. Recently, LPP was found to be highly expressed in smooth muscle [14,15], and a role for LPP in regulating cell motility was proposed [14].\nIn an effort to learn more about the molecular function of LPP, we performed a yeast two-hybrid screening experiment to identify potential LPP-interacting proteins. Here, we report that LPP interacts with Scrib, a member of the LAP (leucine-rich repeat and PDZ domain) family of proteins [16]. Scrib is a functional homologue [17] of Drosophila Scribble, a tumor suppressor that plays a role in the regulation of cellular adhesion, cell shape and polarity [18,19]. In follow-up of the results of the yeast two-hybrid screening, we have performed various experiments to find out whether the observed interaction also occurs in mammalian cells and have substantiated this interaction in vitro and in vivo. Furthermore, we have studied whether or not the Scrib protein plays a role in the subcellular targeting of LPP.","divisions":[{"label":"Title","span":{"begin":0,"end":10}},{"label":"Figure caption","span":{"begin":1948,"end":3029}}],"tracks":[{"project":"2_test","denotations":[{"id":"15649318-10600702-9187460","span":{"begin":246,"end":247},"obj":"10600702"},{"id":"15649318-8812423-9187461","span":{"begin":983,"end":984},"obj":"8812423"},{"id":"15649318-3536951-9187462","span":{"begin":1086,"end":1087},"obj":"3536951"},{"id":"15649318-9598321-9187463","span":{"begin":1138,"end":1139},"obj":"9598321"},{"id":"15649318-8812423-9187464","span":{"begin":1147,"end":1148},"obj":"8812423"},{"id":"15649318-10330178-9187465","span":{"begin":1158,"end":1159},"obj":"10330178"},{"id":"15649318-10647888-9187466","span":{"begin":1198,"end":1199},"obj":"10647888"},{"id":"15649318-8812423-9187467","span":{"begin":3202,"end":3203},"obj":"8812423"},{"id":"15649318-9598796-9187468","span":{"begin":3369,"end":3370},"obj":"9598796"},{"id":"15649318-9772904-9187469","span":{"begin":3396,"end":3397},"obj":"9772904"},{"id":"15649318-14614053-9187470","span":{"begin":3432,"end":3433},"obj":"14614053"},{"id":"15649318-11433529-9187471","span":{"begin":3588,"end":3590},"obj":"11433529"},{"id":"15649318-10637295-9187472","span":{"begin":3877,"end":3879},"obj":"10637295"},{"id":"15649318-10637295-9187473","span":{"begin":4129,"end":4131},"obj":"10637295"},{"id":"15649318-12615977-9187474","span":{"begin":4132,"end":4134},"obj":"12615977"},{"id":"15649318-10637295-9187475","span":{"begin":4290,"end":4292},"obj":"10637295"},{"id":"15649318-10637295-9187476","span":{"begin":4436,"end":4438},"obj":"10637295"},{"id":"15649318-12441356-9187477","span":{"begin":4633,"end":4635},"obj":"12441356"},{"id":"15649318-12441356-9187478","span":{"begin":4813,"end":4815},"obj":"12441356"},{"id":"15649318-12760907-9187479","span":{"begin":4883,"end":4885},"obj":"12760907"},{"id":"15649318-12869577-9187480","span":{"begin":4886,"end":4888},"obj":"12869577"},{"id":"15649318-12760907-9187481","span":{"begin":4952,"end":4954},"obj":"12760907"},{"id":"15649318-10878817-9187482","span":{"begin":5246,"end":5248},"obj":"10878817"},{"id":"15649318-14681682-9187483","span":{"begin":5284,"end":5286},"obj":"14681682"},{"id":"15649318-10688207-9187484","span":{"begin":5414,"end":5416},"obj":"10688207"},{"id":"15649318-10884224-9187485","span":{"begin":5417,"end":5419},"obj":"10884224"}],"attributes":[{"subj":"15649318-10600702-9187460","pred":"source","obj":"2_test"},{"subj":"15649318-8812423-9187461","pred":"source","obj":"2_test"},{"subj":"15649318-3536951-9187462","pred":"source","obj":"2_test"},{"subj":"15649318-9598321-9187463","pred":"source","obj":"2_test"},{"subj":"15649318-8812423-9187464","pred":"source","obj":"2_test"},{"subj":"15649318-10330178-9187465","pred":"source","obj":"2_test"},{"subj":"15649318-10647888-9187466","pred":"source","obj":"2_test"},{"subj":"15649318-8812423-9187467","pred":"source","obj":"2_test"},{"subj":"15649318-9598796-9187468","pred":"source","obj":"2_test"},{"subj":"15649318-9772904-9187469","pred":"source","obj":"2_test"},{"subj":"15649318-14614053-9187470","pred":"source","obj":"2_test"},{"subj":"15649318-11433529-9187471","pred":"source","obj":"2_test"},{"subj":"15649318-10637295-9187472","pred":"source","obj":"2_test"},{"subj":"15649318-10637295-9187473","pred":"source","obj":"2_test"},{"subj":"15649318-12615977-9187474","pred":"source","obj":"2_test"},{"subj":"15649318-10637295-9187475","pred":"source","obj":"2_test"},{"subj":"15649318-10637295-9187476","pred":"source","obj":"2_test"},{"subj":"15649318-12441356-9187477","pred":"source","obj":"2_test"},{"subj":"15649318-12441356-9187478","pred":"source","obj":"2_test"},{"subj":"15649318-12760907-9187479","pred":"source","obj":"2_test"},{"subj":"15649318-12869577-9187480","pred":"source","obj":"2_test"},{"subj":"15649318-12760907-9187481","pred":"source","obj":"2_test"},{"subj":"15649318-10878817-9187482","pred":"source","obj":"2_test"},{"subj":"15649318-14681682-9187483","pred":"source","obj":"2_test"},{"subj":"15649318-10688207-9187484","pred":"source","obj":"2_test"},{"subj":"15649318-10884224-9187485","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#93ece6","default":true}]}]}}