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)

We examined the signaling pathways regulating glycogen synthase (GS) in primary cultures of rat hepatocytes. The activation of GS by insulin and glucose was completely reversed by the phosphatidylinositol 3-kinase inhibitor wortmannin. Wortmannin also inhibited insulin-induced phosphorylation and activation of protein kinase B/Akt (PKB/Akt) as well as insulin-induced inactivation of GS kinase-3 (GSK-3), consistent with a role for the phosphatidylinositol 3-kinase/PKB-Akt/GSK-3 axis in insulin-induced GS activation. Although wortmannin completely inhibited the significantly greater level of GS activation produced by the insulin-mimetic bisperoxovanadium 1,10-phenanthroline (bpV(phen)), there was only minimal accompanying inhibition of bpV(phen)-induced phosphorylation and activation of PKB/Akt, and inactivation of GSK-3. Thus, PKB/Akt activation and GSK-3 inactivation may be necessary but are not sufficient to induce GS activation in rat hepatocytes. Rapamycin partially inhibited the GS activation induced by bpV(phen) but not that effected by insulin. Both insulin- and bpV(phen)-induced activation of the atypical protein kinase C (zeta/lambda) (PKC (zeta/lambda)) was reversed by wortmannin. Inhibition of PKC (zeta/lambda) with a pseudosubstrate peptide had no effect on GS activation by insulin, but substantially reversed GS activation by bpV(phen). The combination of this inhibitor with rapamycin produced an additive inhibitory effect on bpV(phen)-mediated GS activation. Taken together, our results indicate that the signaling components mammalian target of rapamycin and PKC (zeta/lambda) as well as other yet to be defined effector(s) contribute to the modulation of GS in rat hepatocytes.
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PMID:Regulation of glycogen synthase in rat hepatocytes. Evidence for multiple signaling pathways. 1049 84

Engagement of integrins and other adhesion receptors can induce tyrosine phosphorylation of focal adhesion kinase (FAK), a tyrosine kinase present in focal adhesions. Furthermore, in addition to adhesion receptors, a surprising variety of stimuli, acting either on specific surface receptors or on intracellular molecules, such as PKC or Rho, can induce also tyrosine phosphorylation of FAK. I suggest that a potential mechanism by which such distinct factors may modulate the tyrosine phosphorylation of FAK is the promotion of integrin or other adhesion receptor clustering at focal adhesions.
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PMID:Why do so many stimuli induce tyrosine phosphorylation of FAK? 1058 Sep 94

Murine mast cells adhere spontaneously to plate-bound vitronectin (VNPB) via alphav-containing integrins, and this adhesive interaction results in an augmented interleukin-3 (IL-3)-dependent mast-cell proliferation. In this report we demonstrate that the activation of murine mast cells through alphav-integrin, as well as through the high affinity immunoglobulin E (IgE) receptor (FcepsilonRI), results in enhanced tyrosine phosphorylation of focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase involved in mitogenic and oncogenic signal transduction. While mast cell adhesion to VNPB resulted in enhanced FAK phosphorylation, treatment with soluble vitronectin (VNSOL) failed to do so. Spontaneous mast cell adhesion to entactin (EN) did not induce tyrosine phosphorylation of FAK, demonstrating that not all adhesive interactions lead to the same sequence of biochemical events. Because FAK has intrinsic tyrosine kinase activity, we examined whether activating mast cells via alphav-integrins, or via FcepsilonRI-cross-linking stimulated the in vitro kinase activity of FAK. Both pathways were found independently to activate FAK in mast cells and together appeared additive. Protein kinase C depletion in mast cells and calcium depletion in the medium caused decreased tyrosine phosphorylation of FAK, indicating that optimal tyrosine phosphorylation of FAK is regulated by both pathways. These data are consistent with the conclusion that the tyrosine phosphorylation of FAK represents at least one example of a point of convergence in the intracellular tyrosine phosphorylation cascades induced by alphav integrin-and FcepsilonRI-mediated signal transduction pathways in mast cells.
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PMID:Both adhesion to immobilized vitronectin and FcepsilonRI cross-linking cause enhanced focal adhesion kinase phosphorylation in murine mast cells. 1058 94

Telomerase, a specialized RNA-directed DNA polymerase that extends telomeres of eukaryotic chromosomes, is repressed in normal human somatic cells but is activated during development and upon neoplasia. Whereas activation is involved in immortalization of neoplastic cells, repression of telomerase permits consecutive shortening of telomeres in a chromosome replication-dependent fashion. This cell cycle-dependent, unidirectional catabolism of telomeres constitutes a mechanism for cells to record the extent of DNA loss and cell division number; when telomeres become critically short, the cells terminate chromosome replication and enter cellular senescence. Although neither the telomere signaling mechanisms nor the mechanisms whereby telomerase is repressed in normal cells and activated in neoplastic cells have been established, inhibition of telomerase has been shown to compromise the growth of cancer cells in culture; conversely, forced expression of the enzyme in senescent human cells extends their life span to one typical of young cells. Thus, to switch telomerase on and off has potentially important implications in anti-aging and anti-cancer therapy. There is abundant evidence that the regulation of telomerase is multifactorial in mammalian cells, involving telomerase gene expression, post-translational protein-protein interactions, and protein phosphorylation. Several proto-oncogenes and tumor suppressor genes have been implicated in the regulation of telomerase activity, both directly and indirectly; these include c-Myc, Bcl-2, p21(WAF1), Rb, p53, PKC, Akt/PKB, and protein phosphatase 2A. These findings are evidence for the complexity of telomerase control mechanisms and constitute a point of departure for piecing together an integrated picture of telomerase structure, function, and regulation in aging and tumor development-Liu, J.-P. Studies of the molecular mechanisms in the regulation of telomerase activity.
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PMID:Studies of the molecular mechanisms in the regulation of telomerase activity. 1059 57

This study was initiated to identify signaling proteins used by the receptors for vascular endothelial cell growth factor KDR/Flk1, and Flt1. Two-hybrid cloning and immunoprecipitation from human umbilical vein endothelial cells (HUVEC) showed that KDR binds to and promotes the tyrosine phosphorylation of phospholipase Cgamma (PLCgamma). Neither placental growth factor, which activates Flt1, epidermal growth factor (EGF), or fibroblast growth factor (FGF) induced tyrosine phosphorylation of PLCgamma, indicating that KDR is uniquely important to PLCgamma activation in HUVEC. By signaling through KDR, VEGF promoted the tyrosine phosphorylation of focal adhesion kinase, induced activation of Akt, protein kinase Cepsilon (PKCepsilon), mitogen-activated protein kinase (MAPK), and promoted thymidine incorporation into DNA. VEGF activates PLCgamma, PKCepsilon, and phosphatidylinositol 3-kinase independently of one another. MEK, PLCgamma, and to a lesser extent PKC, are in the pathway through which KDR activates MAPK. PLCgamma or PKC inhibitors did not affect FGF- or EGF-mediated MAPK activation. MAPK/ERK kinase inhibition diminished VEGF-, FGF-, and EGF-promoted thymidine incorporation into DNA. However, blockade of PKC diminished thymidine incorporation into DNA induced by VEGF but not FGF or EGF. Signaling through KDR/Flk1 activates signaling pathways not utilized by other mitogens to induce proliferation of HUVEC.
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PMID:Utilization of distinct signaling pathways by receptors for vascular endothelial cell growth factor and other mitogens in the induction of endothelial cell proliferation. 1067 53

Insulin exerts wide variety of biological effects through interaction with its specific receptor, which belongs to a large family of receptor tyrosine kinases. The activated insulin receptor phosphorylates the intracellular substrate IRS protains, which then bind various signalling molecules that contain Src homology 2 domains. The first downstram molecule that was shown to associate with IRS protains is PI3-kinase. PI3-kinase contributes to a wide variety of biological actions. Both Akt(PKB), a serine-threonine kinase with a PH domain, and atypical PKC(PKC zeta, PKC lambda) have been implicated as downstream effectors of PI3-kinase. Insulin resistance contributes to the pathogenesis of NIDDM. Both primary, genetically, and secondary, environmentally factors are important for insulin resistance. The secondary factors include hyperglycemia, hyperlipidemia, obesity, TNF alpha, FFA(free fatty acid).
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PMID:[Insulin signalling system and mechanism of insulin resistance]. 1070 48

The role of the phosphatidylinositol 3-kinase (PI3K) pathway in the hyperphosphorylation of tau was investigated in SY5Y human neuroblastoma cells. Wortmannin, an inhibitor of PI3K, induced transient (after 1 h) activation of glycogen synthase kinase-3 (GSK-3), hyperphosphorylation of tau and dose-dependent cytotoxicity. However, continuous inactivation of protein kinase (PK) B was observed from 1 to 24 h, suggesting the involvement of protein kinase(s) other than PKB in the phosphorylation and inactivation of GSK-3 after 3 h. In cells treated with wortmannin, PKC delta fragments were observed, and the PKC activity increased after 3 h, whereas treatment of cells with z-DEVD-fmk, an inhibitor of caspase 3, also inhibited fragmentation of PKC delta and induced continuous activation of GSK-3. It is suggested that fragmentation of PKC delta during the process of apoptosis results in the phosphorylation and inactivation of GSK-3 and consequently inhibition of the phosphorylation of tau.
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PMID:Inactivation of glycogen synthase kinase-3 by protein kinase C delta: implications for regulation of tau phosphorylation. 1070 67

Immunocytes from the mollusc Mytilus galloprovincialis express corticotropin-releasing hormone (CRH) receptor subtype (CRH-R1 and CRH-R2)-like mRNAs. Using computer-assisted microscopic image analysis, we have found that exogenous CRH provokes changes in the cellular shape of immunocytes, and that this response is extracellular Ca(2+)-dependent. The various inhibitors of transduction signaling pathways, i.e. suramin sodium, 2', 5'-dideoxyadenosine, neomycin sulfate, calphostin C, H-89, and wortmannin, completely or partially inhibit these changes. The present findings demonstrate that PKA, PKC, and PKB/Akt are involved in CRH-induced cell shape changes in immunocytes, and that the cellular effect of CRH needs the synergistic action of the two second messengers, cAMP and IP(3).
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PMID:Synergistic role of cAMP and IP(3) in corticotropin-releasing hormone-induced cell shape changes in invertebrate immunocytes. 1076 42

Tyrosine phosphorylation plays a key role in transmembrane and cytoplasmic signal transduction mechanisms stimulated by oncogenes, integrins, growth factors, neuropeptides, and bioactive lipids. Moreover, recent studies show that stimulation of odd-numbered muscarinic receptors increases the tyrosine phosphorylation of several proteins in different cellular types. The present study was aimed at examining whether activation of m3 muscarinic receptors in rat pancreatic acini evokes tyrosine phosphorylation of p125(FAK), and its substrates, p130(cas) and paxillin. Results show that stimulation of pancreatic acini with carbachol resulted in a rapid and transient increase in tyrosine phosphorylation of p125(FAK), p130(cas), and paxillin. Tyrosine phosphorylation of these proteins occurred in a time- and concentration-dependent manner. Simultaneous blockage of both PKC activation and increases in [Ca(2+)](i) partially decreased p125(FAK), p130(cas), and paxillin tyrosine phosphorylation stimulated by carbachol. Pretreatment of pancreatic acini with Clostridium botulinum C3 transferase, which specifically inactivates p21(rho), partially inhibited carbachol-induced p125(FAK), p130(cas), and paxillin tyrosine phosphorylation. In contrast, this treatment had no effect on amylase release stimulated by carbachol. Cytochalasin D, which disrupts actin microfilaments network, completely inhibited carbachol stimulated tyrosine phosphorylation of these proteins without having significant effects in carbachol-stimulated amylase secretion. These results dissociate tyrosine phosphorylation of p125(FAK), p130(cas), and paxillin from amylase secretion after m3 muscarinic receptors occupation in rat pancreatic acini. Taken together, these data suggest that (a) activation of m3 muscarinic receptors in rat pancreatic acini increases tyrosine phosphorylation of p125(FAK) and its substrates, p130(cas) and paxillin by diacylglycerol-activated PKC- and calcium- dependent, and independent pathways, (b) these responses require activation of p21(rho) and an intact actin cytoskeleton, and (c) p125(FAK), p130(cas), and paxillin are unlikely related to secretion in rat pancreatic acinar cells.
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PMID:Activation of m3 muscarinic receptors induces rapid tyrosine phosphorylation of p125(FAK), p130(cas), and paxillin in rat pancreatic acini. 1077 45

The protein kinase Akt/PKB is activated via a multistep process by a variety of signals. In the early steps of this process, PI-3 kinase-generated D3-phosphorylated phosphoinositides bind the Akt PH domain and induce the translocation of the kinase to the plasma membrane where it co-localizes with phosphoinositide-dependent kinase-1. By binding to the PH domains of both Akt and phosphoinositide-dependent kinase-1, D3-phosphorylated phosphoinositides appear to also induce conformational changes that permit phosphoinositide-dependent kinase-1 to phosphorylate the activation loop of Akt. The paradigm of Akt activation via phosphoinositide-dependent phosphorylation provided a framework for research into the mechanism of activation of other members of the AGC kinase group (p70S6K, PKC, and PKA) and members of the Tec tyrosine kinase family (TecI, TecII, Btk/Atk, Itk/Tsk/Emt, Txk/Rlk, and Bm/Etk). The result was the discovery that these kinases and Akt are activated by overlapping pathways. In this review, we present our current understanding of the regulation and function of the Akt kinase and we discuss the common and unique features of the activation processes of Akt and the AGC and Tec kinase families. In addition, we present an overview of the biosynthesis of phosphoinositides that contribute to the regulation of these kinases.
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PMID:AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. 1087 70


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