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)

Neuropeptide-stimulated tyrosine phosphorylation of specific components in Swiss 3T3 cells was investigated using monoclonal antibodies directed against the src transformation-associated substrates p125 focal adhesion kinase (FAK), a novel type of cytosolic tyrosine kinase, and p130. Treatment of Swiss 3T3 cells with the mitogenic peptides bombesin, vasopressin, and endothelin caused a striking increase in the tyrosine phosphorylation of p125FAK, as judged either by anti-phosphotyrosine (anti-Tyr(P)) Western blots of anti-p125FAK immunoprecipitates, or by anti-p125FAK immunoblots of anti-Tyr(P) immunoprecipitates. Bombesin-stimulated tyrosine phosphorylation of p125FAK was detectable within seconds and concentration-dependent (half-maximum effect of 0.3 nM). Neuropeptides also stimulated the tyrosine phosphorylation of a second component of M(r) 130,000, previously identified as the major p130 phosphotyrosyl protein in src-transformed cells. Bombesin stimulated p130 tyrosine phosphorylation with kinetics and concentration dependence similar to those observed for p125FAK. This is the first report to identify substrates for neuropeptide-stimulated tyrosine phosphorylation; the finding that one of these substrates is a tyrosine kinase suggests the existence of a novel signal transduction pathway in the action of mitogenic neuropeptides.
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PMID:Bombesin, vasopressin, and endothelin stimulation of tyrosine phosphorylation in Swiss 3T3 cells. Identification of a novel tyrosine kinase as a major substrate. 138 65

Addition of 1-oleoyl-lysophosphatidic acid (LPA) induces tyrosine phosphorylation of multiple substrates in Swiss 3T3 cells including bands of M(r) 110,000-130,000 and M(r) 70,000-80,000. An increase in tyrosine phosphorylation of the M(r) 110,000-130,000 cluster of bands was detected as soon as 30 s after LPA stimulation reaching a maximum within 1 min. LPA stimulated tyrosine phosphorylation of all bands in a concentration-dependent fashion; a half-maximal effect occurred at 30 nM. Immunoprecipitation of lysates of LPA-treated cells with monoclonal antibodies that specifically recognize focal adhesion kinase (p125FAK), paxillin, and p130 revealed that these proteins are prominent substrates for LPA-stimulated tyrosine phosphorylation. Down-regulation of protein kinase C (PKC) by prolonged pretreatment with phorbol 12,13-dibutyrate, selective inhibition of PKC by GF109203X, or depletion of the intracellular Ca2+ pool by thapsigargin had no effect on LPA-stimulated tyrosine phosphorylation. Thus, protein tyrosine phosphorylation by LPA is largely independent of either the PKC or Ca2+ pathways. In contrast, pretreatment of the cells with cytochalasin D, which selectively disrupts the network of the actin filaments, completely inhibited LPA-induced tyrosine phosphorylation. Furthermore, tyrosine phosphorylation of p125FAK induced by LPA was completely prevented when cells were stimulated in the presence of platelet-derived growth factor at a concentration (30 ng/ml) that causes disruption of actin stress fibers. This suggests that the integrity of the actin cytoskeleton is essential for LPA-induced tyrosine phosphorylation and reveals a novel cross-talk between LPA and platelet-derived growth factor on p125FAK tyrosine phosphorylation.
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PMID:Lysophosphatidic acid stimulates tyrosine phosphorylation of focal adhesion kinase, paxillin, and p130. Signaling pathways and cross-talk with platelet-derived growth factor. 751 Jul 8

In human B cells, interleukin 4 (IL4) acts in regulating proliferation, antigen expression, isotype switching and differentiation. These different effects are mediated through the IL4R complex including the IL2R gamma chain (gamma c) and a specific p130/140 binding unit referred below as human Interleukin 4 Receptor (IL4-R). Here, we studied the signal transduction events following IL4R activation and leading to CD23 expression on resting B cells. We demonstrate that IL4R triggering induced the tyrosine phosphorylation of JAK3 and of a p170 protein. Coimmunoprecipitation of JAK3 with the IL4R suggests a physical association which exists prior to IL4R complex stimulation. Orthovanadate treatment, while having no effect on IL4-induced p130 phosphorylation, leads to the hyperphosphorylation of the p170 and inhibits IL4-induced CD23 expression. These suggest that two mandatory steps exist in early IL4 signaling: one controlled by JAK3 activation and the other by the p170 phosphoprotein.
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PMID:JAK3 associates with the human interleukin 4 receptor and is tyrosine phosphorylated following receptor triggering. 753 55

Adhesion of cells to the extracellular matrix leads to an increase in the tyrosine phosphorylation of a specific set of proteins, three of which have now been identified as the focal adhesion proteins pp125FAK, paxillin and tensin. In addition, we have previously noted the adhesion-induced tyrosine phosphorylation of a fourth protein, with an apparent molecular mass of 130. As in the case of FAK, paxillin and tensin, a 130 kDa protein is also found to be highly tyrosine phosphorylated in Rous sarcoma virus (RSV)-transformed cells. This protein forms a stable complex with pp60src and is directly phosphorylated by activated forms of c-src. Using a monoclonal antibody (mAb 4F4) specific for the src-associated p130 we show that p130 is also phosphorylated in response to cell adhesion. Immunoprecipitation of p130 followed by an anti-phosphotyrosine immunoblot revealed that adhesion of rat embryo fibroblasts (REF52) to fibronectin (FN) led to a significant increase in the phosphotyrosine content of p130. Furthermore, a comparison of cell lysates before and after immunoprecipitation confirmed the absence of tyrosine phosphorylated p130 from lysates immunoprecipitated with mAb 4F4. Immunofluorescence staining of REF52s revealed that p130 is found in focal adhesions as well as along stress fibers in a pattern reminiscent of that exhibited by alpha-actinin. In addition, in many cells, we found significant staining in the nucleus, but evidence is presented that the nuclear staining is not due to tyrosine phosphorylated p130. Finally, unlike pp125FAK, p130 does not appear to be itself a kinase as evidence by immune-complex kinase assays carried out in the presence or absence of exogenous substrates.
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PMID:Adhesion-induced tyrosine phosphorylation of the p130 src substrate. 754 55

As cells adhere to extracellular matrix proteins, several focal adhesion proteins become tyrosine phosphorylated. One of the most prominent of these has been identified as the tyrosine kinase p125FAK (focal adhesion kinase, FAK). An interaction between FAK and members of the Src family tyrosine kinases p59fyn, pp60v-src, and activated pp60c-src (527F) has been demonstrated, raising the possibility that these kinases may regulate FAK activity. To explore the role of Src family kinases in focal adhesions and in the regulation of FAK activity, we isolated fibroblasts from transgenic mice that lack either pp60c-src, p59fyn, or pp62c-yes. These primary fibroblasts, and those of a control mouse, were passaged numerous times and resulted in spontaneously immortalized cell lines without the addition of transforming agents. After confirming the absence of the appropriate nonreceptor tyrosine kinases in the fyn-, src- and yes- fibroblasts, the ability of these fibroblasts to form focal adhesions and stress fibers was assessed by immunofluorescence microscopy and found to be comparable to that of normal fibroblasts. We investigated phosphotyrosine levels in response to adhesion to fibronectin and identified the pp60src substrate p130 as the one major protein with reduced levels of tyrosine phosphorylation in the cells lacking p59fyn and pp62c-yes, and particularly in those lacking pp60c-src. We examined FAK phosphorylation and kinase activity and found that there were no significant differences between these cells.
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PMID:An examination of focal adhesion formation and tyrosine phosphorylation in fibroblasts isolated from src-, fyn-, and yes- mice. 758 9

To understand the mechanism for resistance of primary cultures of rat embryo fibroblasts (REFs) to oncogene-induced transformation, we studied the transforming ability of a recombinant retrovirus, ZSV, containing v-src and neo genes in REFs and in the rat cell line F2408. The susceptibility of REFs to p60v-src transformation was markedly reduced when compared with that of F2408 cells, despite high levels of expression of functional p60v-src tyrosine kinase in the two systems. In hybrid cells obtained by somatic cell fusion between F2408 cells transformed by v-src and uninfected REFs, the transformed phenotype was suppressed despite persistent expression of p60v-src tyrosine kinase. On the other hand, hybrid cells between v-src transformed F2408 cells and uninfected F2408 cells retained the transformed phenotypes. These results indicate that primary cells possess an intracellular function(s) that cause suppression of the transformed phenotype induced by the v-src gene. In ZSV-infected REFs, tyrosine phosphorylation of cellular proteins, including p125 focal adhesion kinase, p70 paxillin and p130 was similar to that in the ZSV-infected F2408 cells, indicating that tyrosine phosphorylation of these proteins is not sufficient for the expression of transformed phenotype. On the other hand, cellular fibronectin and one of integrin receptors were downregulated in the ZSV-transformed F2408 cells but not in ZSV-infected REFs, suggesting that fibronectin and/or its receptor might play a role in suppressing v-src transformation in primary rat cells.
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PMID:Suppression of v-Src transformation in primary rat embryo fibroblasts. 762 40

p130(Cas) (crk associated substrate) has the structural characteristics of an adapter protein, containing multiple consensus SH2 binding sites, an SH3 domain, and a proline-rich domain. The structure of p130(Cas) suggests that it may act to provide a framework for protein-protein interactions; however, as yet, its functional role in cells is unknown. In this report we show that p130(Cas) is localized to focal adhesions. We demonstrate that p130(Cas) associates both in vitro and in vivo with pp125(FAK) (focal adhesion kinase), a kinase implicated in signaling by the integrin family of cell adhesion receptors. p130(Cas) also associates with pp41/43(FRNK) (pp125(FAK)-related, non-kinase), an autonomously expressed form of pp125(FAK) composed of only the C-terminal noncatalytic domain. We show that the association of p130(Cas) with pp125(Fak) and pp41/43(FRNK) is direct, and is mediated by the binding of the SH3 domain of p130(Cas) to a proline-rich sequence present in both the C terminus of pp125(FAK) and in pp41/43(FRNK). In agreement with recent studies we show that p130(Cas) is tyrosine-phosphorylated upon integrin mediated cell adhesion. The association of p130(Cas) with pp125(FAK), a kinase which is activated upon cell adhesion, is likely to be functionally important in integrin mediated signal transduction.
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PMID:p130Cas, a substrate associated with v-Src and v-Crk, localizes to focal adhesions and binds to focal adhesion kinase. 866 21

The intracellular effects of bradykinin are mediated through the recently cloned B2 kinin receptor which belongs to the superfamily of receptors with seven transmembrane domains. The molecular events which transduce the bradykinin signal on the post-receptor level are not understood in detail. We studied whether in human foreskin fibroblasts bradykinin treatment induces tyrosine phosphorylation of cellular proteins. Using phosphotyrosine antibodies we detected a bradykinin-dependent phosphorylation of a group of proteins of about 130 kDa and an additional signal around 70kDa after starvation of cells. The effect evoked by 10 nM bradykinin was rapid (2 min) and it was partially reduced by the B2-kinin-receptor antagonist Hoe 140 which was shown to be a weak inducer of tyrosine phosphorylation. The bradykinin-mediated tyrosine phosphorylation events were reproduced in human embryonal kidney 293 fibroblasts which were transiently transfected with the rat B2 kinin receptor, but they were not observed in untransfected 293 control cells. These data suggest that the B2 kinin-receptor subtype is involved. Upon fractionation of cells the 130kDa protein group was recovered both in the membrane and the cytosolic protein fraction. To assess the specificity of this bradykinin effect we stimulated human foreskin fibroblasts with epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-I) and insulin. While IGF-I, insulin and EGF were almost ineffective, PDGF stimulated the tyrosine phosphorylation of 130-kDa bands with a similar pattern to that produced by bradykinin. Immunoprecipitation experiments with specific antibodies against potential candidate proteins in the molecular-mass range around 130kDa revealed positive results for the focal adhesion kinase FAK and the p130 Src substrate while negative results were obtained for the GTPase-activating protein GAP, the phospholipase C-gamma1, the Janus kinase JAK-1 and vinculin. The data suggest that the tyrosine phosphorylation of FAK and the pl30 Src substrate might be involved in the B2-kinin-receptor signalling cascade.
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PMID:Bradykinin induces tyrosine phosphorylation in human foreskin fibroblasts and 293 cells transfected with rat B2 kinin receptor. 866 18

The Philadelphia chromosome (Ph) translocation generates a chimeric tyrosine kinase oncogene, BCR/ABL, which causes chronic myelogenous leukemia (CML) and a type of acute lymphoblastic leukemia (ALL). In primary samples from virtually all patients with CML or Ph+ALL, the CRKL adapter protein is tyrosine phosphorylated and physically associated with p210(BCR/ABL). CRKL has one SH2 domain and two SH3 domains and is structurally related to c-CRK-II (CRK) and the v-Crk oncoprotein. We have previously shown that CRKL, but not the related adapter protein c-CRK, is tyrosine phosphorylated in cell lines transformed by BCR/ABL, and that CRKL binds to BCR/ABL through the CRKL-SH3 domains. Furthermore, the CRKL-SH2 domain has been shown to bind one or more cellular proteins, one of which is p120(CBL). Here we demonstrate that another cellular protein linked to BCR/ABL through the CRKL-SH2 domain is p130(CAS). p130(CAS) was found to be tyrosine phosphorylated and associated with CRKL in BCR/ABL expressing cell lines and in samples obtained from CML and ALL patients, but not in samples from controls. In both normal and BCR/ABL transformed cells, p130(CAS) was detected in focal adhesion-like structures, as was BCR/ABL. In normal cells, the focal adhesion proteins tensin, p125(FAK), and paxillin constitutively associated with p130(CAS). However, in BCR/ABL transformed cells, the interaction between p130(CAS) and tensin was disrupted, while the associations between p130(CAS), p125(FAK), and paxillin were unaffected. These results suggest that the BCR/ABL oncogene could alter the function of p130(CAS) in at least three ways: tyrosine phosphorylation, inducing constitutive binding of CRKL to a domain in p130(CAS) containing Tyr-X-X-Pro motifs (substrate domain), and disrupting the normal interaction of p130(CAS) with the focal adhesion protein tensin. These alterations in the structure of signaling proteins in focal adhesion like structures could contribute to the known adhesion abnormalities in CML cells.
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PMID:p130CAS forms a signaling complex with the adapter protein CRKL in hematopoietic cells transformed by the BCR/ABL oncogene. 881 Feb 78

Endothelin-1 (ET-1) binding to ETB receptors increases the activity of the apical membrane Na+/H+ antiporter (NHE3) of renal proximal tubule and cultured OKP cells. In OKPETB6 cells, a clonal cell line of OKP cells that overexpresses ETB receptors, ET-1-induced increases in Na+/H+ antiporter activity are mediated 50% by Ca2(+)-dependent pathways and 50% by tyrosine kinase pathways. ET-1 induces tyrosine phosphorylation of proteins of 68, 110, 125, 130, and 210 kDa. ET-1-induced tyrosine phosphorylation is mediated by the ETB receptor and is not dependent on increases in cell Ca2+ or protein kinase C. The 68-, 110-, 125-, and 130-kDa phosphoproteins are cytosolic, whereas the 210-kDa phosphoprotein is an integral membrane protein. Immunoprecipitation studies showed that the 68-kDa protein is paxillin and the 125-kDa protein is p125FAK (focal adhesion kinase). Cytochalasin D, which disrupts focal adhesions, prevented ET-1-induced tyrosine phosphorylation of paxillin, p110, p125FAK, and p130 but did not prevent tyrosine phosphorylation of p210 and did not prevent ET-1-induced increases in Na+/H+ antiporter activity. Thus 50% of ETB receptor-induced Na+/H+ antiporter activation is mediated by tyrosine kinase pathways, possibly involving p210. ETB receptor activation also induces tyrosine phosphorylation of focal adhesion proteins, but this is not required for antiporter activation.
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PMID:Role of tyrosine kinase pathways in ETB receptor activation of NHE3. 884 5


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