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)

IRS-1 has been found to relay the signals from the receptors for insulin, insulin-like growth factor-1, growth hormone, and many cytokines for the downstream effects in the various cell types tested. For interleukin 4 signaling, most studies were performed on hematopoietic cells and cell lines transfected with rat liver IRS-1 cDNA. In a liver cell lineage, IRS-1 expression has been found to be increased in hepatoma cells and hepatocytes in regenerating liver. To elucidate the possible function and the signal transduction pathway for interleukin 4, in comparison with insulin, in liver cells, we used the Hep 3B hepatoma cell line as a model system. Following insulin and interleukin 4 stimulation, rapid tyrosyl phosphorylation of IRS-1 occurred. Interleukin 4, but not insulin, stimulated the tyrosine phosphorylation of JAK1 and, to a lesser extent, JAK2. In contrast to the other cell types, the association of IRS-1 and Grb2 through the SH2 of Grb2 was demonstrated after IL-4 and insulin stimulation of the Hep3B hepatoma cells. Both insulin and interleukin 4 stimulated tyrosine phosphorylation and the enzyme activity of Erk1 kinase. Our results indicate that interleukin 4 and insulin might modulate hepatic cell growth and differentiation through many different or common pathways for the activation of JAK kinases and the usage of IRS-1 as a docking protein. The binding of IRS-1 with Grb2 after IL-4 as well as insulin stimulation may lead to MAP kinase activation, probably through the Grb2/sos/p21ras pathway.
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PMID:Signal transduction pathways for interleukin 4 and insulin in human hepatoma cells. 886 52

Growth hormone (GH) has long been known to stimulate linear growth and regulate metabolism. The cellular mechanism by which GH elicits these effects has only recently begun to be understood. This review provides an overview of a current model of GH signaling. Briefly, binding of GH to GH receptor induces receptor dimerization and activation of the tyrosine kinase JAK2. Tyrosyl phosphorylation of GH receptor and JAK2 recruits and activates signaling molecules such as Stat transcription factors, SHC, and insulin receptor substrates 1 and 2 that lead to the release of second messengers such as diacylglycerol, calcium, and nitric oxide and the activation of enzymes such as mitogen-activated protein kinase, protein kinase C, phospholipase A2, and phosphatidylinositol 3'-kinase. These pathways regulate cellular function including gene transcription, metabolite transport, and enzymatic activity that result in the ability of GH to control body growth and metabolism.
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PMID:Mechanism of signaling by growth hormone receptor. 887 95

JAK2, a member of the Janus kinase superfamily was found to interact functionally with Raf-1, a central component of the ras/mitogen-activated protein kinase signal transduction pathway. Interferon-gamma and several other cytokines that are known to activate JAK2 kinase were also found to stimulate Raf-1 kinase activity toward MEK-1 in mammalian cells. In the baculovirus coexpression system, Raf-1 was activated by JAK2 in the presence of p21ras. Under these conditions, a ternary complex of p21ras, JAK2, and Raf-1 was observed. In contrast, in the absence of p21ras, coexpression of JAK2 and Raf-1 resulted in an overall decrease in the Raf-1 kinase activity. In addition, JAK2 phosphorylated Raf-1 at sites different from those phosphorylated by pp60v-src. In mammalian cells treated with either erythropoietin or interferon-gamma, a small fraction of Raf-1 coimmunoprecipitated with JAK2 in lysates of cells in which JAK2 was activated as judged by its state of tyrosine phosphorylation. Taken together, these data suggest that JAK2 and p21ras cooperate to activate Raf-1.
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PMID:The cytokine-activated tyrosine kinase JAK2 activates Raf-1 in a p21ras-dependent manner. 887 96

The proto-oncogene c-eyk, the cellular counterpart of a transforming oncogene, v-eyk, encodes a receptor protein tyrosine kinase with a distinctive extracellular region. We now demonstrate that c-Eyk can be constitutively activated through dimerization, and that the active Eyk displays a unique signaling pattern. When the kinase domain of c-Eyk was fused to the extracellular and transmembrane domains of CD8, the resulting chimera showed elevated kinase activity and caused cellular transformation. We found that the activated Eyk kinases, both v- and c-Eyk, constitutively stimulate the JAK-STAT pathway, while exerting little effect on other signaling routes such as the Ras-MAP kinase and the JNK pathways. The activated Eyk kinases specifically stimulate tyrosine phosphorylation of STAT1, STAT3 and JAK1. These downstream molecules also co-immunoprecipitate with the constitutively dimerized form of Eyk. The Eyk kinase activity is required for STAT1 stimulation. We found that the activation of STAT1 but not STAT3 correlates well with cellular transformation. In constitutively stimulating the JAK-STAT pathway, particularly STAT1, Eyk is unique in its downstream signaling and may be dependent on this pathway for cellular transformation.
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PMID:Unique signal transduction of Eyk: constitutive stimulation of the JAK-STAT pathway by an oncogenic receptor-type tyrosine kinase. 888 43

The novel substance P (SP) analogue, [D-Arg1,D-Trp5,7,9,Leu11]SP like [D-Arg1,D-Phe5,D-Trp7,9,Leu11]SP inhibited DNA synthesis induced by bombesin, vasopressin, and bradykinin, but did not interfere with the mitogenic response induced by other growth factors or pharmacological agents in Swiss 3T3 cells. [D-Arg1,D-Trp5, 7,9,Leu11]SP reversibly inhibited bombesin-induced DNA synthesis, causing a 6-fold greater rightward shift in the bombesin dose response than [D-Arg1,D-Phe5,D-Trp7,9,Leu11]SP at identical concentrations (10 microM). We found that the new, more potent, SP analogue coordinately and reversibly inhibited bombesin-induced Ca2+ mobilization and protein kinase C (PKC) and mitogen-activated protein (MAP) kinase activation. The dose-response curves for bombesin-induced Ca2+ mobilization and MAP kinase activation were similarly displaced (51- and 40-fold, respectively) by [D-Arg1, D-Trp5,7,9,Leu11]SP. In addition, [D-Arg1,D-Trp5,7,9,Leu11]SP reversibly inhibited bombesin-induced tyrosine phosphorylation of Mr 110,000-130,000 and 70,000-80,000 bands as well as p125 focal adhesion kinase. [D-Arg1,D-Trp5,7,9,Leu11]SP also reversibly and coordinately inhibited vasopressin-induced Ca2+ mobilization, PKC stimulation, MAP kinase activation, tyrosine phosphorylation, and DNA synthesis in Swiss 3T3 cells. Surprisingly, deletion of the terminal Leu of [D-Arg1,D-Phe5,D-Trp7,9,Leu11]SP to yield [D-Arg1, D-Phe5,D-Trp7,9]SP1-10 resulted in a selective loss of inhibitory activity of this analogue against bombesin- but not vasopressin-stimulated DNA synthesis, Ca2+ mobilization, and MAP kinase activation. Collectively, these results suggest that SP analogues act at the receptor level to coordinately and reversibly antagonize bombesin- or vasopressin-induced signal transduction in Swiss 3T3 cells.
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PMID:[D-Arg1,D-Trp5,7,9,Leu11]Substance P coordinately and reversibly inhibits bombesin- and vasopressin-induced signal transduction pathways in Swiss 3T3 cells. 891 Jun 12

Many G protein-coupled receptors (e.g. that of angiotensin II) activate phospholipase Cbeta, initially increasing intracellular calcium and activating protein kinase C. In the WB and GN4 rat liver epithelial cell lines, agonist-induced calcium signals also stimulate tyrosine phosphorylation and subsequently increase the activity of c-Jun N-terminal kinase (JNK). We have now purified the major calcium-dependent tyrosine kinase (CADTK), and by peptide and nucleic acid sequencing identified it as a rat homologue of human PYK2. CADTK/PYK2 is most closely related to p125(FAK) and both enzymes are expressed in WB and GN4 cells. Angiotensin II, which only slightly increases p125(FAK) tyrosine phosphorylation in GN4 cells, substantially increased CADTK tyrosine autophosphorylation and kinase activity. Agonists for other G protein-coupled receptors (e.g. LPA), or those increasing intracellular calcium (thapsigargin), also stimulated CADTK. In comparing the two rat liver cell lines, GN4 cells exhibited approximately 5-fold greater angiotensin II- and thapsigargin-dependent CADTK activation than WB cells. Although maximal JNK activation by stress-dependent pathways (e.g. UV and anisomycin) was equivalent in the two cell lines, calcium-dependent JNK activation was 5-fold greater in GN4, correlating with CADTK activation. In contrast to JNK, the thapsigargin-dependent calcium signal did not activate mitogen-activated protein kinase and Ang II-dependent mitogen-activated protein kinase activation was not correlated with CADTK activation. Finally, while some stress-dependent activators of the JNK pathway (NaCl and sorbitol) stimulated CADTK, others (anisomycin, UV, and TNFalpha) did not. In summary, cells expressing CADTK/PYK2 appear to have two alternative JNK activation pathways: one stress-activated and the other calcium-dependent.
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PMID:Activation of a novel calcium-dependent protein-tyrosine kinase. Correlation with c-Jun N-terminal kinase but not mitogen-activated protein kinase activation. 893 45

We previously demonstrated that in white fat cell precursors alpha2-adrenoceptor stimulation lead to the phosphorylation of p44 and p42 mitogen-activated protein kinases and an increase in cell number. Regulation of cell adhesion and cell cytoskeleton plays a crucial role in the control of cell growth by various growth factors. Here, we report that in mouse 3T3F442A preadipocytes expressing 2500 fmol/mg protein of the human alpha2C10-adrenoceptor (alpha2AF2 cells), alpha2-adrenergic stimulation rapidly restored the spreading of cells previously retracted by serum withdrawal. This effect was pertussis toxin sensitive and was blocked by pretreatment of the cells with dihydrocytochalasin B (a blocker of actin polymerization), genistein (a tyrosine kinase inhibitor), or agents that increase cell cAMP content. Spreading was accompanied by cell membrane ruffling, formation of lamelipodia and filipodia, appearance of focal adhesion plaques, and induction of actin stress fibers. alpha2-Adrenergic stimulation also lead to a rapid Gi- and actin-dependent tyrosine phosphorylation of the pp125 focal adhesion kinase (FAK) as well as of the p42 and p44 mitogen-activated protein kinases. alpha2-Adrenergic-dependent spreading and FAK and mitogen-activated protein kinase phosphorylation were also observed in 3T3F442A preadipocytes permanently expressing 20 fmol/mg protein of the human alpha2C10-adrenoceptor (alpha2AF3 cells) as well as in BFC-1beta preadipocytes, which constitutively express 25 fmol/mg protein of mouse alpha2A-adrenoceptors. In BFC-1beta preadipocytes, alpha2-adrenergic-dependent spreading and pp125FAK phosphorylation were counteracted by beta-adrenergic stimulation. Our results suggest that alpha2-adrenergic control of actin polymerization and focal adhesion assembly could play a crucial role in the regulation of preadipocyte growth by the sympathetic nervous system.
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PMID:alpha2-Adrenoceptor stimulation promotes actin polymerization and focal adhesion in 3T3F442A and BFC-1beta preadipocytes. 894 Mar 38

Using a temperature-sensitive mutant of the p210 BCR-ABL gene, transfected into a growth factor-dependent cell line (BaF3), we show that transient BCR-ABL kinase expression increases single cell and clonogenic resistance to apoptosis arising from genotoxic damage induced by ionizing radiation and VP-16/etoposide. This effect is achieved in the absence of any detectable changes in the levels of BCL-2, BAX or BCL-x proteins and is independent of proliferative, MAP kinase-dependent effects of BCR-ABL kinase. In contrast to parental cells that transiently arrest in G2 and then apoptose, p210 BaF3 cells show a pronounced and sustained G2 arrest following radiation coupled with enhanced phosphorylation of cdc2. A cell cycle block in early M phase induced by the mitotic spindle poison, nocodazole, does not provide protection from apoptosis. Reversal of G2 arrest by caffeine abolishes the protective effect of BCR-ABL kinase. These data provide further insight into the transforming properties of BCR-ABL and are relevant to the clinical intransigence of Ph-positive leukaemias.
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PMID:ts BCR-ABL kinase activation confers increased resistance to genotoxic damage via cell cycle block. 895 Sep 90

Fluid shear stress modulates vascular function and structure by stimulating mechanosensitive endothelial cell signal events. Cell adhesion, mediated by integrin-matrix interactions, also regulates intracellular signaling by mechanosensitive events. To gain insight into the role of integrin-matrix interactions, we compared tyrosine phosphorylation and extracellular signal-regulated kinase (ERK1/2) activation in adhesion- and shear stress-stimulated human umbilical vein endothelial cells (HUVEC). Adhesion of HUVEC to fibronectin, but not to poly-L-lysine, rapidly activated ERK1/2. Fluid shear stress (12 dyn/cm2) enhanced ERK1/2 activation stimulated by adhesion, suggesting the presence of a separate pathway. Two differences in signal transduction were identified: focal adhesion kinase phosphorylation was increased rapidly by adhesion but not by shear stress; and ERK1/2 activation in response to adhesion was inhibited to a significantly greater extent when actin filaments were disrupted by cytochalasin D. Two similarities in activation of ERK1/2 were observed: protein kinase C (PKC) activity was necessary as shown by complete inhibition when PKC was downregulated; and an herbimycin-sensitive (genistein- and tyrphostin-insensitive) tyrosine kinase was required. c-Src was identified as a candidate tyrosine kinase as it was activated by both shear stress and adhesion. These findings suggest that adhesion and shear stress activate ERK1/2 via a shared pathway that involves an herbimycin-sensitive tyrosine kinase and PKC. In addition, shear stress activates ERK1/2 through another pathway that is partially independent of cytoskeletal integrity.
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PMID:Mitogen-activated protein kinase (ERK1/2) activation by shear stress and adhesion in endothelial cells. Essential role for a herbimycin-sensitive kinase. 895 27

The experiments presented here were designed to examine the contribution of p125 focal adhesion kinase (p125FAK) tyrosine phosphorylation to the activation of the mitogen-activated protein kinase cascade induced by bombesin, lysophosphatidic acid (LPA), and platelet-derived growth factor (PDGF) in Swiss 3T3 cells. We found that tyrosine phosphorylation of p125FAK in response to these growth factors is completely abolished in cells treated with cytochalasin D or in cells that were suspended in serum-free medium for 30 min. In marked contrast, the activation of p42mapk by these factors was independent of the integrity of the actin cytoskeleton and of the interaction of the cells with the extracellular matrix. The protein kinase C inhibitor GF 109203X and down-regulation of protein kinase C by prolonged pretreatment of cells with phorbol esters blocked bombesin-stimulated activation of p42mapk, p90rsk, and MAPK kinase-1 but did not prevent bombesin-induced tyrosine phosphorylation of p125FAK. Furthermore, LPA-induced p42mapk activation involved a pertussis toxin-sensitive guanylate nucleotide-binding protein, whereas tyrosine phosphorylation of p125FAK in response to LPA was not prevented by pretreatment with pertussis toxin. Finally, PDGF induced maximum p42mapk activation at concentrations (30 ng/ml) that failed to induce tyrosine phosphorylation of p125FAK. Thus, our results demonstrate that p42mapk activation in response to bombesin, LPA, and PDGF can be dissociated from p125FAK tyrosine phosphorylation in Swiss 3T3 cells.
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PMID:Dissociation of mitogen-activated protein kinase activation from p125 focal adhesion kinase tyrosine phosphorylation in Swiss 3T3 cells stimulated by bombesin, lysophosphatidic acid, and platelet-derived growth factor. 897 Jan 51


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