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)

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

Signaling by the T-cell antigen receptor (TCR) involves both phospholipase C (PLC)-gamma 1 and p21ras activation. While failing to induce Shc/Grb2 association, ligation of the TCR/CD3 receptor in Jurkat T-cells induced hSos1-Grb2 complexes. In addition to hSos1, Grb2 participates in the formation of a tyrosine phosphoprotein complex that includes 145-, 95-, 70-, 54-, and 36-38-kDa proteins. p145 was identified as PLC-gamma 1 and p70 as the protein tyrosine kinase, ZAP-70. Although of the same molecular weight, p95 was not recognized by an anti-serum to p95 Vav. The SH2 domains of Grb2 and PLC-gamma 1 were required for the formation of this protein complex. In anti-CD3-treated cells, Grb2 redistributed from the cytosol to a particulate cell compartment along with p36/p38, ZAP-70, and PLC-gamma 1. Part of the Grb2 complex associated with the particulate compartment could be extracted with Nonidet P-40, while the rest was Nonidet P-40 insoluble. In both the detergent-soluble and -insoluble fractions, Grb2 coimmunoprecipitated with the zeta-chain of the TCR. Taken together, these results indicate that anti-CD3 induces Grb2-hSos1-PLC-gamma 1-p36/p38-ZAP70 complexes, which localize in the vicinity of TCR-zeta.
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PMID:Ligation of the T-cell antigen receptor (TCR) induces association of hSos1, ZAP-70, phospholipase C-gamma 1, and other phosphoproteins with Grb2 and the zeta-chain of the TCR. 762 68

The cytoplasmic protein tyrosine kinase p56lck has been implicated as an effector of interleukin-2-induced cell division in T-lymphocytes, but little is known about physiological substrates for p56lck during these events. We have used p56lck fusion proteins to identify potential cytoplasmic signal transduction proteins that bind to p56lck in mitotically activated human peripheral blood lymphocytes and in constitutively dividing leukemic T-cell lines. In peripheral blood lymphocytes, we have observed an interleukin-2-dependent tyrosine phosphorylation of a 70-kDa protein and binding of tyrosine phosphorylated p70 to the SH2 domain of p56lck. A 70-kDa phosphoprotein was also observed to constitutively bind p56lck in leukemic T-cells. Affinity purification of p56lck-associated p70 and sequencing of proteolytic fragments revealed identity to a 62-kDa protein that has been identified as a ras-GTPase activating protein. These results demonstrate a stimulation-dependent tyrosine phosphorylation of p70 and its interaction with p56lck and may provide a link between p56lck and GTPase-mediated signal transduction pathways in activated T-lymphocytes.
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PMID:p70 phosphorylation and binding to p56lck is an early event in interleukin-2-induced onset of cell cycle progression in T-lymphocytes. 785 12

Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
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PMID:Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. 852 13

Interaction of the cell surface integrin receptors with extracellular matrix proteins results in the activation of intracellular signaling pathways, including activation of the p42/p44 mitogen-activated protein kinases. The protein tyrosine kinase focal adhesion kinase, or FAK, is linked to integrin signaling and interacts with several molecules involved in signal transduction. Here we report that exposure of fibroblast cells to extracellular matrix proteins activates the p70/p85 ribosomal S6 kinase (S6K) pathway in a ligand dependent manner. Treatment of cells with inhibitors of phosphatidylinositol 3-kinase, or FRAP (FKBP 12/rapamycin-associated protein) blocks integrin-mediated activation of S6K. In contrast to the integrin-directed activation of the mitogen-activated protein kinases, cytochalasin D treatment does not inhibit S6K activation. Treatment with the protein tyrosine kinase inhibitors herbimycin A and genistein completely blocks S6K activation, indicating a requirement for tyrosine kinase activity. Overexpression of the COOH-terminal noncatalytic domain of FAK, FRNK (FAK-related non-kinase) in chick embryo cells results in a significant reduction in the integrin-mediated activation of S6K and a concomitant reduction in FAK tyrosine phosphorylation. These results indicate at least a partial requirement for FAK in the S6K activation pathway.
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PMID:Integrin-dependent activation of the p70 ribosomal S6 kinase signaling pathway. 893 16

We and others have recently cloned a non-receptor, calcium-dependent tyrosine kinase (CADTK; also known as PYK2, CAKbeta, and RAFTK) that shares both overall domain structure and 45% amino acid identity with p125(FAK). We have studied the signaling, activation, and potential function of these related enzymes in GN4 rat liver epithelial cells that express CADTK and p125(FAK) at roughly similar levels. p125(FAK) is nearly fully tyrosine-phosphorylated in resting GN4 cells. In contrast, while CADTK is not tyrosine-autophosphorylated in untreated cells, angiotensin II increases CADTK Tyr(P) by 5-10-fold. With regard to signaling, CADTK activation is correlated with stimulation of c-Jun N-terminal kinase and p70(S6K) pathways but not with the stimulation of mitogen-activated protein kinase or p90(RSK). In this report we assessed the contribution of CADTK and p125(FAK) to tyrosine phosphorylation of focal contact proteins. In adherent GN4 cells, the constitutive activity of p125(FAK) was correlated with basal paxillin, tensin, and p130(CAS) tyrosine phosphorylation. A rapid increase in the tyrosine phosphorylation of each protein was detected after treatment with angiotensin II or other agonists that stimulate CADTK; the prolonged 3-4-fold increase in paxillin tyrosine phosphorylation was the most substantial change. In the WB cell line that expresses 3-fold less CADTK than GN4 cell line agonist-dependent paxillin tyrosine phosphorylation is similarly reduced. Immunoprecipitation of CADTK from GN4 cells revealed CADTK. paxillin complexes that persisted in 500 mM NaCl but not in 0.1% SDS cell lysis buffer. The complexes were largely independent of the tyrosine phosphorylation state of either protein. Surprisingly, we did not detect p125(FAK).paxillin complexes in immunoprecipitates using either of two p125(FAK) antibodies. When CADTK and p125(FAK) were transiently overexpressed in 293(T) cells, both enzymes associated with paxillin, but the avidity of CADTK appeared to be greater. In addition, in transfected 293(T) cells, complexes between CADTK and another potential substrate, p130(CAS), were detected. In summary, in GN4 rat liver epithelial cells stimulation of CADTK was highly correlated with paxillin tyrosine phosphorylation; in addition, CADTK but not p125(FAK) was complexed to paxillin at detectable levels. This suggests that agonist-dependent cytoskeletal changes in epithelial cells might proceed, in part, by CADTK-dependent mechanisms.
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PMID:Paxillin is tyrosine-phosphorylated by and preferentially associates with the calcium-dependent tyrosine kinase in rat liver epithelial cells. 916 70

p70 S6 kinase (p70 S6k) is important in regulating a variety of cellular functions including mRNA translation and cell cycle progression and is activated by mitogens and hormones. Unexpectedly, we have found that, in adult rat cardiomyocytes, arsenite, which generally induces stress responses, markedly and rapidly activates p70 S6k. This activation of p70 S6k is completely blocked by rapamycin but only partially prevented by inhibitors of phosphatidylinositol 3-kinase. In trying to delineate the mechanism underlying this effect, we found that arsenite did not activate protein kinase B, JNK or MAP kinase, but did activate p38 MAP kinase in cardiac myocytes. A specific inhibitor of p38 MAP kinase (SB203580) partially attenuated the stimulation of p70 S6k by arsenite. These data indicate that the activation of p70 S6k by arsenite involves p38 MAP kinase and phosphatidylinositol 3-kinase but not PKB.
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PMID:p70 S6 kinase is activated by sodium arsenite in adult rat cardiomyocytes: roles for phosphatidylinositol 3-kinase and p38 MAP kinase. 929 80

Fluoride is known to increase bone mass in vivo, probably through stimulation of osteoblast proliferation; however, the mechanisms of fluoroaluminate action in osteoblasts have not yet been elucidated. We have previously shown that in osteoblastic MC3T3-E1 cells, fluoroaluminate stimulates G protein-mediated protein tyrosine phosphorylation (Scaronuscarona, M., Standke, G. J. R., Jeschke, M., and Rohner, D. (1997) Biochem. Biophys. Res. Commun. 235, 680-684). Although the Ser/Thr kinases Erk1, Erk2, and p70(S6K) were activated in response to fluoroaluminate, the identity of fluoroaluminate-activated tyrosine kinase(s) remained elusive. In this study, we show that in MC3T3-E1 cells, fluoroaluminate induces a 110-kDa tyrosine-phosphorylated protein that we identify as Pyk2, a cytoplasmic tyrosine kinase related to Fak (focal adhesion kinase). The tyrosine phosphorylation of Pyk2 increased in a dose- and time-dependent manner. The autophosphorylation activity of Pyk2 increased 3-fold and reached its maximum within 10 min of fluoroaluminate treatment. Fluoroaluminate also induced activation of Src and the association of Pyk2 with Src. The phosphorylation of Src-associated Pyk2 increased >20-fold in in vitro kinase assays, suggesting that Pyk2 is phosphorylated by Src. Although MC3T3-E1 cells express much more Fak than Pyk2, Src preferentially associated with Pyk2. In vitro, Pyk2 bound to the Src SH2 domain, suggesting that this interaction mediates the Src-Pyk2 association in cells. These data indicate that osteoblastic cells express Pyk2, which is tyrosine-phosphorylated and activated in response to G protein activation by fluoroaluminate, and that the mechanism of Pyk2 activation most likely involves Src. Thus, Src and Pyk2 are tyrosine kinases involved in G protein-mediated tyrosine phosphorylation in osteoblastic cells and may be important for the osteogenic action of fluoroaluminate.
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PMID:Fluoroaluminate induces activation and association of Src and Pyk2 tyrosine kinases in osteoblastic MC3T3-E1 cells. 955 30

Polyoma middle T antigen (PMT) was originally identified as the tumorigenic component of the polyomavirus genome. To investigate whether the serine/ threonine kinase Akt/PKB, which is the proto-oncogene transduced by the transforming AKT8 retrovirus, is activated by PMT, 3T3-L1 fibroblasts were stably transfected with wild type PMT. PMT expression accelerated glucose transport and increased phosphorylation of p70 S6-kinase and MAPK. PMT expression also stimulated Akt kinase activity 7 fold as compared to untreated, mock infected cells. This stimulation rivaled that obtained following insulin treatment of both mock and PMT infected cells. Akt activation and phosphorylation were eliminated in a PMT mutant incapable of interacting with PI3-kinase, but not one which does not interact with Shc, and correlated closely to the amount of PI3-kinase activity in anti-phosphotyrosine immunoprecipitates. These results indicate that the PI3-kinase pathway is requisite, but the Shc pathway is dispensable, for Akt activation. The studies further suggest that Akt may participate in PMT and PI3-kinase's regulation of cellular transformation and tumorigenesis.
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PMID:Polyoma middle T antigen activates the Ser/Thr kinase Akt in a PI3-kinase-dependent manner. 960 71

In mouse embryo NIH 3T3 fibroblasts, ethanol (60-80 mM) was found to enhance the stimulatory effects of sphingosine 1-phosphate (S1P) on both DNA synthesis and cell proliferation. Well-detectable potentiating effects of ethanol on S1P-induced mitogenesis required the presence of calcium (>1 mM) and zinc (20-40 microM) in the incubation medium. The amphibian tetrapeptide bombesin, which is known to mobilize intracellular calcium in fibroblasts, had no effect alone, but it approximately doubled the combined stimulatory effects of ethanol and S1P on DNA synthesis. The synergistic mitogenic effects of ethanol and S1P were also slightly enhanced, rather than inhibited, by the alcohol dehydrogenase inhibitor 4-methylpyrazole (5 mM). Of the various growth regulatory enzymes examined, ethanol detectably enhanced the stimulatory effects of S1P on the phosphosphorylation (activation) of p42/p44 mitogen-activated protein (MAP) kinases, but not of p38 MAP kinase. Cotreatment of fibroblasts with ethanol for 10 min also enhanced the stimulatory effects of S1P on the activities of c-Raf-1 kinase and p70 S6 kinase, but neither S1P nor ethanol had effects on phosphatidylinositol 3'-kinase and Akt/PKB kinase activities. Ethanol-plus-S1P-induced DNA synthesis was partially inhibited by both PD 98059 (50 microM) and rapamycin (10 nM), inhibitors of p42/p44 MAP kinase kinase and mTOR/p70 S6 kinases, respectively. The results indicate that in NIH 3T3 fibroblasts, ethanol can enhance the mitogenic effects of S1P by a zinc- and calcium-dependent mechanism involving both the rapamycin-sensitive p70 S6 kinase-dependent and the c-Raf-1/MAP kinase-dependent growth regulatory pathways.
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PMID:Ethanol potentiates the mitogenic effects of sphingosine 1-phosphate by a zinc- and calcium-dependent mechanism in fibroblasts. 1033 73


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