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)

Focal adhesion kinase, FAK, is a unique protein tyrosine kinase found in cellular focal adhesions. It is widely expressed and highly phosphorylated during embryogenesis. To examine the function of FAK in cell differentiation, we made FAK-deficient embryonic stem (ES) cells by homologous recombination. However, FAK-deficiency did not interfere with differentiation of the ES cells into cells of three germ layers when implanted subcutaneously into nude mice or when treated with retinoic acid in vitro, nor was there any evidence of defects in hematopoiesis in vitro.
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PMID:Focal adhesion kinase is not essential for in vitro and in vivo differentiation of ES cells. 772 50

Insulin treatment of Chinese hamster ovary cells expressing high levels of the human insulin receptor resulted in the tyrosine dephosphorylation of the 125-kDa focal adhesion kinase (pp125FAK). The decrease in pp125FAK tyrosine phosphorylation paralleled a decrease in the cellular content of actin stress fibers, and these changes were independent of the extracellular matrix on which the cells were grown. The reduction in both pp125FAK tyrosine phosphorylation and actin stress fibers occurred in an insulin concentration-dependent manner, with significant effects at approximately 0.3 nM and a maximal effect at 3 nM. However, in the continuous presence of insulin, the decreases in the tyrosine phosphorylation state of pp125FAK and actin stress fiber content were transient. Maximal reduction of pp125FAK tyrosine phosphorylation was observed following 15 min of insulin treatment, with a return to unstimulated control levels by 60 min. Similarly, actin stress fiber content was maximally reduced by 15 min of insulin treatment and fully recovered by 60 min. In contrast to insulin, platelet-derived growth factor stimulation increased actin stress fiber content and enhanced pp125FAK tyrosine phosphorylation. These data demonstrate a novel signaling role for insulin in inducing the tyrosine dephosphorylation of pp125FAK and a concomitant reorganization of actin stress fibers, which underlies at least one aspect of signaling divergence between the insulin and platelet-derived growth factor receptor tyrosine kinases.
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PMID:Divergent insulin and platelet-derived growth factor regulation of focal adhesion kinase (pp125FAK) tyrosine phosphorylation, and rearrangement of actin stress fibers. 773 Mar 24

A number of cellular processes, such as proliferation, differentiation, and transformation, are regulated by cell-extracellular matrix interactions. Previous studies have identified a novel tyrosine kinase, the focal adhesion kinase p125FAK, as a component of cell adhesion plaques. p125FAK was identified as a 125-kDa tyrosine-phosphorylated protein in cells transformed by the v-src oncogene. p125FAK is an intracellular protein composed of three domains: a central domain with homology to protein tyrosine kinases, flanked by two noncatalytic domains of 400 amino acids which bear no significant homology to previously cloned proteins. p125FAK is believed to play an important regulatory role in cell adhesion because it localizes to cell adhesion plaques and because its phosphorylation on tyrosine residues is regulated by binding of cell surface integrins to the extracellular matrix. Recent studies have shown that Src, through its SH2 domain, stably associates with pp125FAK and that this association prevents dephosphorylation of pp125FAK in vitro by protein tyrosine phosphatases. In this report, we identify Tyr-397 as the primary in vivo and in vitro site of p125FAK tyrosine phosphorylation and association with Src. Substituting phenylalanine for tyrosine at position 397 significantly reduces p125FAK tyrosine phosphorylation and association with Src but does not abolish p125FAK kinase activity. In addition, p125FAK kinase is able to trans-phosphorylate Tyr-397 in vitro in a kinase-deficient p125FAK variant. Phosphorylation of Tyr-397 provides a site [Y(P)AEI] that fits the consensus sequence for the binding of Src.
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PMID:Identification of Tyr-397 as the primary site of tyrosine phosphorylation and pp60src association in the focal adhesion kinase, pp125FAK. 773 63

In the endothelial cell line EAhy 926, 1-oleoyl-lysophosphatidic acid (LPA) stimulated the tyrosine phosphorylation of the pp42 isoform of mitogen-activated protein (MAP) kinase. Maximum phosphorylation was observed within 5 min of LPA addition, but the response was sustained for up to 120 min. Re-addition of LPA after 60 min stimulated a further sustained increase in the tyrosine phosphorylation of MAP kinase. In cells pretreated with phorbol 12-myristate 13-acetate (PMA; 24 h) or preincubated with the protein kinase C inhibitor Ro-318220, LPA-induced tyrosine phosphorylation of pp42 MAP kinase was substantially reduced at 2 min but potentiated at 60 min. Ro-318220 in combination with either PMA or pertussis toxin pretreatment abolished the LPA response at all time points, suggesting an involvement of protein kinase C in the pertussis toxin-sensitive part of the pathway. Agents which raised intracellular cyclic AMP levels did not affect the initial phase of LPA-stimulated MAP kinase activation, but abolished the late phase. However, this effect was prevented by Ro-318220, implicating a greater role for protein kinase C than protein kinase A in the regulation of sustained MAP kinase responses. LPA stimulated an increase in the tyrosine phosphorylation of focal adhesion kinase pp125 (pp125FAK) in EAhy 926 cells which was both protein kinase C- and pertussis toxin-independent. These results are discussed in terms of the pathways regulating both MAP kinase and pp125FAK in response to LPA in the EAhy 926 endothelial cells line.
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PMID:Regulation of lysophosphatidic acid-stimulated tyrosine phosphorylation of mitogen-activated protein kinase by protein kinase C- and pertussis toxin-dependent pathways in the endothelial cell line EAhy 926. 774 5

The focal adhesion kinase, pp125FAK, is a novel non-receptor protein tyrosine kinase expressed in different cells including mast cells. Here we report that a 77-kDa protein associates with pp125FAK in the mast cell analog, rat basophilic leukemia (RBL-2H3) cells. When pp125FAK immunoprecipitates were subjected to an in vitro kinase assay, there was prominent phosphorylation on tyrosine of pp125FAK and of a 77-kDa protein. By V8 protease digestion mapping and by immunoblotting with two different anti-pp125FAK antibodies, the 77-kDa protein was distinct from pp125FAK. This Fak Associated Protein or FAP was detected in RBL-2H3 cells but not in fibroblasts. The aggregation of the high affinity IgE receptor, Fc epsilon RI, induced the in vivo tyrosine phosphorylation of FAP. However, there was a marked decrease in the in vitro phosphorylation of FAP in the immunoprecipitates from Fc epsilon RI aggregated cells. Both of these Fc epsilon RI-mediated effects were enhanced by cell adhesion. There was strong association of FAP with non-tyrosine-phosphorylated pp125FAK. Thus this interaction does not appear to be mediated by the Src homology 2 domain. Together the data indicate that FAP associates with pp125FAK and suggest that FAP may play a role in Fc epsilon RI signaling.
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PMID:A 77-kDa protein associates with pp125FAK in mast cells and becomes tyrosine-phosphorylated by high affinity IgE receptor aggregation. 774 83

Focal adhesion kinase (pp125FAK or FAK) is a cytoplasmic protein-tyrosine kinase stimulated in response to cell interactions with extracellular matrix components and by exposure to a variety of agonists, including neuropeptides. FAK lacks Src-homology SH2 and SH3 domains, is highly conserved across species, and may represent the prototype for a tyrosine kinase family involved in novel signal transduction pathways. We have identified sequence variants in the 3' untranslated regions of the focal adhesion kinase gene in mice and used a PCR-based oligonucleotide hybridization assay to map the mouse gene (Fadk) to Chromosome (Chr) 15 distal to the myelocytomatosis protooncogene (Myc). The human homolog (PTK2) has been assigned to human Chr 8 on a panel of somatic hybrid cell lines. On the basis of synteny of mouse and human chromosomal maps, the position of the human PTK2 gene probably corresponds to human Chr 8q24-qter.
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PMID:Mapping of the focal adhesion kinase (Fadk) gene to mouse chromosome 15 and human chromosome 8. 776 95

Morphological transformation of cells by the v-Src tyrosine kinase is incompletely understood. However, it is independent of nuclear functions and probably involves phosphorylation of targets associated with the cytoskeleton and focal adhesions, structures which tether the cytoskeleton to the points of cell attachment. v-Src activity both stimulates tyrosine phosphorylation of a tyrosine kinase present in focal adhesions (focal adhesion kinase or pp125FAK) and disrupts focal adhesions, leading to cell rounding and detachment. However, pp125FAK is also phosphorylated on tyrosine as a result of integrin stimulation which induces quite different biological consequences including the organisation of focal adhesions when cells spread on fibronectin (reviewed in Schaller and Parsons, 1993). To address this paradox, we examined changes in pp125FAK during activation and shut-off of temperature sensitive mutant v-Src proteins that induce varying degrees of transformation in chick embryo fibroblasts. An efficiently transforming v-Src mutant initially stimulated pp125FAK tyrosine phosphorylation, but induced subsequent pp125FAK degradation prior to the onset of cell rounding and detachment. v-Src mutants which are impaired in their ability to induce morphological transformation were much less efficient at inducing degradation of pp125FAK. Moreover, cell spreading during restitution of normal morphology did not require detectable tyrosine phosphorylation of pp125FAK, or its potential substrate paxillin, suggesting that pp125FAK may function more in the turnover of focal adhesions than in their assembly.
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PMID:v-Src-induced degradation of focal adhesion kinase during morphological transformation of chicken embryo fibroblasts. 778 71

Activation of human platelets by the peptide YFLLRNP has been shown to induce shape change but not secretion, Ca2+ mobilization, or pleckstrin phosphorylation (Rasmussen, U.B., Gachet, C., Schlesinger, Y., Hanau, D., Ohlmann, P., Van Obberghen-Schilling, E., Pouyssegur, J., Cazenave, J.P., and Pavirani, A. (1993) J. Biol. Chem. 268, 14322-14328). YFLLRNP was added to washed human platelets that had been pretreated with EGTA at 37 degrees C or preincubated with the fibrinogen receptor antagonist RGDS to preclude the activation of the integrin alpha IIb beta 3 (fibrinogen receptor). YFLLRNP induced shape change and stimulated the tyrosine phosphorylation of proteins of 62, 68, and 130 kDa within 7 s. Tyrosine phosphorylation of these proteins reached maximum levels (2-3-fold) 15-30 s after addition of YFLLRNP and decreased subsequently. The chelation of intracellular Ca2+ by BAPTA-AM decreased basal tyrosine protein phosphorylation but did not inhibit the increase of tyrosine phosphorylation of P62, P68, and P130 or the shape change induced by YFLLRNP. Preincubation of platelets with the tyrosine kinase inhibitors genistein or tyrphostin A23 completely inhibited platelet shape change and protein tyrosine phosphorylation induced by YFLLRNP. The inactive structural analogs daidzein and tyrphostin A1 were barely inhibitory. P62, P68, and P130, which exhibited increased tyrosine phosphorylation upon stimulation with YFLLRNP, were found in the cytoskeleton. P130 was not identical to vinculin or the focal adhesion kinase pp125FAK. The results indicate that stimulation of G-protein-coupled thrombin receptors rapidly induces protein tyrosine kinase activation through a Ca(2+)- and integrin-independent mechanism. Protein tyrosine kinase activation and tyrosine phosphorylation of novel protein substrates seem to play an essential role in the induction of platelet shape change.
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PMID:Platelet shape change induced by thrombin receptor activation. Rapid stimulation of tyrosine phosphorylation of novel protein substrates through an integrin- and Ca(2+)-independent mechanism. 783 59

Platelet activation is accompanied by a dramatic increase in tyrosine phosphorylation of many cellular proteins. Phosphorylation of these proteins occurs in successive waves during the activation process, suggesting that several distinct mechanisms, occurring in a temporal order, regulate protein tyrosine kinases and/or phosphatases in activated platelets. Several tyrosine kinases, including Src family kinases, Syk and FAK, have been implicated in these phosphorylation events. These kinases are regulated by distinct receptor-mediated events involving activation of their catalytic activity and alterations in their cellular localization.
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PMID:Regulation of protein tyrosine kinases in platelets. 785 88

Actin reorganization is an early response to many extracellular factors. In Swiss 3T3 fibroblasts, the Ras-related GTP-binding proteins Rho and Rac act as key signal transducers in these responses: Rho is required for growth factor-induced formation of stress fibres and focal adhesions, whereas membrane ruffling is regulated by Rac proteins. Several proteins that act as GTPase activating proteins (GAPs) for Rho-related proteins have been identified, and these could act either as targets or down-regulators of Rho or Rac in cells. In vitro, the GAP domain of p190 has a striking preference for Rho as a substrate, and when microinjected into Swiss 3T3 cells it inhibits stress fibre formation but not membrane ruffling induced by growth factors. BcrGAP acts on Rac but not Rho in vitro, and specifically inhibits membrane ruffling in vivo. Finally, RhoGAP acts preferentially on the Rho-related protein G25K/Cdc42Hs in vitro, but can inhibit Rho-mediated responses in vivo. These results suggest that p190, Bcr and RhoGAP play specific roles in signalling pathways through different Rho family members. The mechanisms underlying Rho-regulated stress fibre formation have been investigated further by analysing the role of other signals known to be activated by lysophosphatidic acid (LPA). Neither activation of PK-C, increased intracellular Ca2+, decreased cAMP levels or Ras activation appear to mediate stress fibre formation. However, LPA stimulates tyrosine phosphorylation of a number of proteins, including the focal adhesion kinase, pp125FAK, and genistein, a tyrosine kinase inhibitor, prevents this increase in tyrosine phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Signal transduction through the GTP-binding proteins Rac and Rho. 788 87


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