Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Salmosin, a disintegrin purified from a Korean snake (Agkistrodon halys brevicaudus) venom, interacts with integrin alpha(v)beta(3) and inhibits the proliferation of bovine capillary endothelial (BCE) cells induced by basic fibroblast growth factor (bFGF). We investigated salmosin's mechanism of inhibition of BCE cell proliferation by examining changes in the cytoskeleton and activation of integrin-mediated signaling molecules. Salmosin disassembled cortical actins at focal adhesions and induced cells to be rounded and detached, but it did not alter microtubule structures in the early stage of cells being rounded. Immunolocalization of paxillin also demonstrated that focal adhesions were disassembled by salmosin. In salmosin-treated BCE cells, focal adhesion kinase (FAK) was dephosphorylated and expression of paxillin and p130(CAS) was decreased, but PI3 kinase, ILK, and beta-catenin were not expressed in decreased amounts or modified, suggesting that salmosin inactivated FAK-dependent integrin signaling pathways. While BCE cells proliferated normally on plates coated with salmosin, cells treated with salmosin eventually underwent apoptosis. These observations strongly suggest that salmosin disorganizes focal contacts to detach cells by competing with the extracellular matrix (ECM) for direct binding to integrin alpha(v)beta(3) on the cell surface, eventually leading to apoptosis.
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PMID:The snake venom disintegrin salmosin induces apoptosis by disassembly of focal adhesions in bovine capillary endothelial cells. 1261 62

During spermatogenesis, the movement of developing germ cells across the seminiferous epithelium associates with extensive restructuring of cell-cell actin-based adherens junctions (AJs), such as ectoplasmic specialization (ES, a testis-specific AJ junction), between Sertoli and germ cells. Although this event of germ cell movement is essential to the completion of spermatogenesis, the mechanism(s) that regulates AJ restructuring is largely unknown. Using Sertoli-germ cells cocultured in vitro to study the regulation of AJ assembly, it was shown that this event associated with a transient induction of beta 1-integrin, vinculin, p-FAK-Tyr(397), and phosphatidylinositol 3-kinase (PI3K) but not the nonphosphorylated form of focal adhesion kinase (FAK), paxillin, and p130 Cas. Furthermore, p-FAK-Tyr(397) was shown to coimmunoprecipitate with beta 1-integrin, vinculin, and c-Src both in vitro and in vivo using Sertoli-germ cell cocultures and seminiferous tubules, respectively. These results seemingly suggest that the testis is using constituent proteins of the focal adhesion complex (FAC) found in other epithelia between cell and extracellular matrix to regulate AJ dynamics. To further confirm that p-FAK, a putative FAC protein in other epithelia, is indeed present at the site of ES, immunohistochemistry and immunofluorescent microscopy were used. The p-FAK-Tyr(397) and p-FAK-Tyr(576) were found to localize almost exclusively at the site of apical ES with weak staining at the basal ES in the seminiferous epithelium in a stage-specific manner, being highest at stages VI-VIII. In contrast, FAK was largely restricted to the basal compartment but with weak staining at the apical compartment. When rats were treated with 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide (AF-2364) to perturb Sertoli-germ cell AJs, an induction of beta 1-integrin, vinculin, p-FAK-Tyr(397), PI3K, and p130 Cas but not the nonphosphorylated form of FAK and paxillin was also detected in the testis, coinciding with the time spermatids began to deplete from the epithelium, indicating their involvement in AJ disassembly. Thereafter, the levels of vinculin, p-FAK-Tyr(397), PI3K, and p130 Cas in the testis plunged, coinciding with the declining events of AJ disruption when virtually all spermatids were depleted from the epithelium. Taken collectively, these results suggest a bifunctional role of p-FAK, being involved in the events of Sertoli-germ cell AJ assembly and disassembly. In summary, the events of AJ dynamics in the testis, in particular at the site of ES, are regulated, at least in part, by proteins that are found in the FAC in other epithelia, such as beta1-integrin, vinculin, and FAK utilizing the integrin/pFAK/PI3K/p130 Cas signaling pathway.
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PMID:Adhering junction dynamics in the testis are regulated by an interplay of beta 1-integrin and focal adhesion complex-associated proteins. 1269 23

Prolin-rich kinase 2 (PYK2) is a nonreceptor tyrosine kinase related to the focal adhesion kinase (FAK) p125(FAK). PYK2 is rapidly phosphorylated on tyrosine residues in response to various stimuli, such as tumor necrosis factor-alpha (TNF-alpha), changes in osmolarity, elevation in intracellular calcium concentration, angiotensin, and UV irradiation. PYK2 has ligand sequences for Src homology 2 and 3 (SH-2 and SH-3), and has binding sites for paxillin and p130(cas). Activation of PYK2 leads to modulation of ion channel function, phosphorylation of tyrosine residues, and activation of the MAP kinase signaling pathways. Immunocytochemistry shows that PYK2 is present in mouse germinal and Sertoli cells (ser). Northern blot and immunoprecipitation analysis demonstrate that, among germinal cells, PYK2 is more abundant in spermatocytes (spc) and spermatids (spt); in addition, immunofluorescence analysis clearly shows that the diffuse cytoplasmic localization of PYK2 changes in a specific cellular compartment in spt and spermatozoa.
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PMID:Prolin-rich tyrosine kinase 2 (PYK2) expression and localization in mouse testis. 1278 55

CrkII belongs to a family of adaptor proteins that become tyrosine phosphorylated after various stimuli. We examined the role of CrkII tyrosine phosphorylation in fibronectin-induced cell migration. Overexpression of CrkII inhibited dephosphorylation of focal adhesion components such as p130 Crk-associated substrate (p130cas) and paxillin by protein tyrosine phosphatase 1B (PTP1B). Tyrosine-phosphorylated CrkII was dephosphorylated by PTP1B both in vitro and in vivo, showing for the first time that PTP1B directly dephosphorylates CrkII. A CrkII mutant in which tyrosine residue 221 was substituted by phenylalanine (CrkII-Y221F) could not be tyrosine phosphorylated, and it showed significantly increased binding to p130cas and paxillin. Enhanced binding of CrkII to p130cas has been reported to promote cell migration. Nonphosphorylated CrkII-Y221F promoted HT1080 cell migration on fibronectin, whereas wild-type CrkII did not at moderate expression levels. Moreover, co-expression of CrkII and PTP1B promoted HT1080 cell migration on fibronectin and retained tyrosine phosphorylation and binding of p130cas to CrkII, whereas paxillin tyrosine phosphorylation was reduced. These findings support the concepts that CrkII binding activity is regulated by tyrosine kinases and phosphatases, and that tyrosine phosphorylation of CrkII can downmodulate cell migration mediated by the focal adhesion kinase/p130cas pathway.
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PMID:Tyrosine phosphorylation of the CrkII adaptor protein modulates cell migration. 1279 22

Our previous work indicates intestinal epithelial cell ERK activation by collagen IV, a major component of the intestinal epithelial basement membrane, requires focal adhesion kinase (FAK) and suggests FAK and ERK may have important roles in regulating intestinal epithelial cell migration. We therefore sought to identify FAK downstream targets regulating intestinal epithelial cell spreading, migration, and ERK activation on collagen IV and the integrins involved. Both dominant-negative Src and Src inhibitor PP2 strongly inhibited collagen IV ERK activation in Caco-2 intestinal epithelial cells. Collagen IV stimulated Grb2 binding site FAK Y925 phosphorylation, which was inhibited by PP2 and required FAK Y397 autophosphorylation. Additionally, FAK Y925F expression blocked collagen IV ERK activation. alpha(1)beta(1)- Or alpha(2)beta(1)-integrin blockade with alpha(1)- or alpha(2)-integrin subunit antibodies indicated that either integrin can mediate adhesion, cell spreading, and FAK, Src, and ERK activation on collagen IV. Both dominant-negative Src and PP2 inhibited Caco-2 spreading on collagen IV. PP2 inhibited p130(Cas) tyrosine phosphorylation, but dominant-negative p130(Cas) did not inhibit cell spreading. PP2 inhibited Caco-2 migration on collagen IV much more strongly than the mitogen-activated protein kinase kinase inhibitor PD-98059, which completely inhibited collagen IV ERK activation. These results suggest a pathway for collagen IV ERK activation requiring Src phosphorylation of FAK Y925 not previously described for this matrix protein and suggest either alpha(1)beta(1)- or alpha(2)beta(1)-integrins can regulate Caco-2 spreading and ERK activation on collagen IV via Src. Additionally, these results suggest Src regulates Caco-2 migration on collagen IV primarily through ERK-independent pathways.
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PMID:Collagen IV regulates Caco-2 migration and ERK activation via alpha1beta1- and alpha2beta1-integrin-dependent Src kinase activation. 1460 60

Platelet-activating factor (PAF), a phospholipid second messenger, has diverse physiological functions, including responses in differentiated endothelial cells to external stimuli. We used human umbilical vein endothelial cells (HUVECs) as a model system. We show that PAF activated pertussis toxin-insensitive G alpha(q) protein upon binding to its seven transmembrane receptor. Elevated cAMP levels were observed via activation of adenylate cyclase, which activated protein kinase A (PKA) and was attenuated by a PAF receptor antagonist, blocking downstream activity. Phosphorylation of Src by PAF required G alpha(q) protein and adenylate cyclase activation; there was an absolute requirement of PKA for PAF-induced Src phosphorylation. Immediate (1 min) PAF-induced STAT-3 phosphorylation required the activation of G alpha(q) protein, adenylate cyclase, and PKA, and was independent of these intermediates at delayed (30 min) and prolonged (60 min) PAF exposure. PAF activated PLC beta 3 through its G alpha(q) protein-coupled receptor, whereas activation of phospholipase C gamma 1 (PLC gamma 1) by PAF was independent of G proteins but required the involvement of Src at prolonged PAF exposure (60 min). We demonstrate for the first time in vascular endothelial cells: (i) the involvement of signaling intermediates in the PAF-PAF receptor system in the induction of TIMP2 and MT1-MMP expression, resulting in the coordinated proteolytic activation of MMP2, and (ii) a receptor-mediated signal transduction cascade for the tyrosine phosphorylation of FAK by PAF. PAF exposure induced binding of p130(Cas), Src, SHC, and paxillin to FAK. Clearly, PAF-mediated signaling in differentiated endothelial cells is critical to endothelial cell functions, including cell migration and proteolytic activation of MMP2.
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PMID:Activation of platelet-activating factor receptor-coupled G alpha q leads to stimulation of Src and focal adhesion kinase via two separate pathways in human umbilical vein endothelial cells. 1461 36

Although the expression of CCK(2) receptors is widely reported in human colorectal cancers, little is known on its role in mediating the proliferative effects of mature amidated gastrin (G17 amide) on colorectal cancers. The purpose of the present study was to determine the effects of G17 amide on tyrosine phosphorylation of focal adhesion kinase (FAK), paxillin, and p130 Crk-associated substrate (p130(Cas)) in Colo 320 cells, a human colorectal cancer cell line which expresses CCK(2) receptors. By immunoprecipitation and immunoblotting, an increase in tyrosine phosphorylation of FAK (tyrosine-397), paxillin (tyrosine-31), and p130(Cas) was detected in a time- and dose-dependent manner. Overexpression of CCK(2) receptors in Colo 320 cells (Colo 320 WT) by stable transfection with the human CCK(2) receptor cDNA resulted in an increased tyrosine phosphorylation of FAK, paxillin, and p130(Cas). After incubation with 1 microM L-365,260, a specific CCK(2) receptor antagonist, this increase was completely inhibited. Our results demonstrate that in human colon cancer cells, gastrin caused a rapid tyrosine phosphorylation of FAK, paxillin, and p130(Cas) by activation of CCK(2) receptor. The phosphorylation of these proteins might be important in mediating gastrin effects on proliferation, apoptosis, and metastasis.
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PMID:Rapid tyrosine phosphorylation of focal adhesion kinase, paxillin, and p130Cas by gastrin in human colon cancer cells. 1466 36

Lysophosphatidic acid (LPA) induces actin rearrangement, focal adhesion assembly, and cell migration through the activation of small G protein Rho and its downstream effectors. These diverse cellular responses are mediated by its associated G protein-coupled receptors. However, the mechanisms and specificity by which these LPA receptors mediate LPA actions are still poorly understood. Here we show that LPA stimulation promotes the interaction of the LPA(2) receptor with a focal adhesion molecule, TRIP6 (thyroid receptor interacting protein 6)/ZRP-1 (zyxin-related protein 1). TRIP6 directly binds to the carboxyl-terminal tail of the LPA(2) receptor through its LIM domains. LPA-dependent recruitment of TRIP6 to the plasma membrane promotes its targeting to focal adhesions and co-localization with actin stress fibers. In addition, TRIP6 associates with the components of focal complexes including paxillin, focal adhesion kinase, c-Src, and p130(cas) in an agonist-dependent manner. Overexpression of TRIP6 augments LPA-induced cell migration; in contrast, suppression of endogenous TRIP6 expression by a TRIP6-specific small interfering RNA reduces it in SKOV3 ovarian cancer cells. Strikingly, the association with TRIP6 is specific to the LPA(2) receptor but not LPA(1) or LPA(3) receptor, indicating a specific role for TRIP6 in regulating LPA(2) receptor-mediated signaling. Taken together, our results suggest that TRIP6 functions at a point of convergence between the activated LPA(2) receptor and downstream signals involved in cell adhesion and migration.
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PMID:TRIP6 enhances lysophosphatidic acid-induced cell migration by interacting with the lysophosphatidic acid 2 receptor. 1468 63

Histone acetylase and histone deacetylase are two crucial enzymes that determine the structure of chromatin, regulating gene expression. In this study, we observed that trichostatin A (TSA), a specific histone deacetylase inhibitor, could effectively inhibit the growth of v-Src-transformed (IV5) cells and abrogate their ability to form colonies in soft agar. Further analysis demonstrated that, although TSA reduced the expression of Eps8 in a dose- and time-dependent manner, both the protein expression and kinase activity of v-Src remained constant, and the abundance and phosphotyrosine levels of Src substrates, including cortactin, focal adhesion kinase, p130(Cas), paxillin, and Shc, were not altered. Notably, removal of TSA from the medium restored not only the expression of Eps8, but also cellular growth. Northern and reverse transcription-PCR analyses revealed the significant reduction of eps8 transcripts in TSA-treated IV5 cells relative to control cells. When active Src-expressing chicken embryonic cells were forced to overexpress p97(Eps8), they became resistant to TSA-mediated anti-proliferation. Furthermore, using small interference RNA of eps8, we demonstrated the requirement for Eps8 in IV5 cell proliferation. Thus, our results highlight a critical role for p97(Eps8) in TSA-exerted growth inhibition of v-Src-transformed cells.
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PMID:Participation of p97Eps8 in Src-mediated transformation. 1469 56

Retinoids have shown clinical efficacy in cancer chemoprevention and therapy presumably by modulating the growth, differentiation, and apoptosis of normal, premalignant, and malignant cells. To better understand the mechanisms by which retinoids exert their effects, we used a high-throughput Western blotting method (Becton-Dickinson PowerBlot) to evaluate changes in the levels of cellular signaling proteins in head and neck squamous cell carcinoma cells treated with the cytostatic all-trans-retinoic acid or with the proapoptotic retinoids 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid or N-(4-hydroxyphenyl)retinamide. Treatments of the head and neck squamous cell carcinoma cells with these retinoids for 24 h resulted in increased levels of 14, 22, and 22 proteins and decreased levels of 5, 10, and 7 proteins, respectively. The changes in the levels of the following proteins were confirmed by conventional western immunoblotting: all-trans-retinoic acid increased ELF3, topoisomerase II alpha, RB2/p130, RIG-G, and EMAPII and decreased MEF2D and cathepsin L. N-(4-Hydroxyphenyl)retinamide up-regulated ELF3, c-Jun, Rb2/p130, JAK1, p67phox, Grb2, O(6)-methylguanine-DNA methyltransferase, and Ercc-1. 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid increased Rb2/p130, c-Jun, Sp1, Sin, and tomosyn and decreased cathepsin L, Mre11, and topoisomerase II alpha. Some of these proteins were also modulated by these retinoids in other human cancer cell lines. A subset of the proteins were modulated similarly by the different retinoids, whereas changes in other proteins were unique for each retinoid. These results suggest that the mechanisms by which these retinoids modulate proteins are distinct but may overlap. Some of the retinoid-modulated proteins identified in this study may be novel candidates for mediating different responses to retinoids.
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PMID:Identification of retinoid-modulated proteins in squamous carcinoma cells using high-throughput immunoblotting. 1505 97


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