Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (Ang II) is a potent regulator of proximal tubule functions, including transport, metabolism, and cell proliferation. The opossum kidney (OK) cell line is a useful model of renal proximal tubule. Mitogen-activated protein (MAP) kinases are rapidly phosphorylated and activated in response to various agonists. We investigated Ang II effects on serine/threonine kinase cascades in OK cells. The major findings of the present study are that Ang II stimulated MAP kinase kinase (MAPKK), MAP kinase (MAPK), and S6 kinase activities, and that it increased phosphorylation of Raf-1 kinase and p42 MAP kinase in OK cells. These stimulations of kinases were dose-dependent (from 10(-6) to 10(-11) M). The time course of activation was sequential; the peak stimulation was reached at 5 to 10 minutes for Raf-1 kinase, MAPKK and MAPK, and at 20 minutes for S6 kinase. The activation of MAPK was inhibited by approximately 70% with prolonged 24-hour PMA pretreatment or in the presence of calphostin C or H-7. Tyrosine kinase inhibitors (genistein and herbimycin) did not inhibit AngII-induced MAPK activity. This activation of MAPK was also inhibited via AT1 receptor antagonist, Dup753 and pertussis toxin. This evidence suggests that the activation of serine/threonine cascades by Ang II is largely dependent on PMA-sensitive PKC, and is not dependent on tyrosine kinase and pertussis toxin.
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PMID:Sequential activation of MAP kinase cascade by angiotensin II in opossum kidney cells. 858 39

Raf-1 is a key protein involved in the transmission of developmental and proliferative signals generated by receptor and nonreceptor tyrosine kinases. Biochemical and genetic studies have demonstrated that Raf-1 functions downstream of activated tyrosine kinases and Ras and upstream of mitogen-activated protein kinase (MAPK) and MAPK kinase (MKK or MEK) in many signaling pathways. A major objective of our laboratory has been to determine how Raf-1 becomes activated in response to signaling events. Using mammalian, baculovirus, and Xenopus systems, we have examined the roles that phosphorylation and protein-protein interactions play in regulating the biological and biochemical activity of Raf-1. Our studies have provided evidence that the activity of Raf-1 can be modulated by both Ras-dependent and Ras-independent pathways. Recently, we reported that Arg89 of Raf-1 is a residue required for the association of Raf-1 and Ras. Mutation of this residue disrupted interaction with Ras and prevented Ras-mediated, but not protein kinase C-or tyrosine kinase-mediated, enzymatic activation of Raf-1 in the baculovirus expression system. Further analysis of this mutant demonstrated that kinase-defective Raf-1 proteins interfere with the propagation of proliferative and developmental signals by binding to Ras and blocking Ras function. Our findings have also shown that phosphorylation events play a role in regulating Raf-1. We have identified sites of in vivo phosphorylation that positively and negatively alter the biological and enzymatic activity of Raf-1. In addition, we have found that some of these phosphorylation sites are involved in mediating the interaction of Raf-1 with potential activators (Fyn and Src) and with other cellular proteins (14-3-3). Results from our work suggest that Raf-1 is regulated at multiple levels by several distinct mechanisms.
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PMID:Mechanisms regulating Raf-1 activity in signal transduction pathways. 860 83

Elevated glucose concentrations have been reported to inhibit insulin receptor kinase activity. We studied the effects of high glucose on insulin action in Rat1 fibroblasts transfected with wild-type human insulin receptor (HIRcB) and a truncated receptor lacking the COOH-terminal 43 amino acids (delta CT). In both cell lines, 25 mM glucose impaired receptor and insulin receptor substrate-1 phosphorylation by 34%, but IGF-1 receptor phosphorylation was unaffected. Phosphatidylinositol 3-kinase activity and bromodeoxyuridine uptake were decreased by 85 and 35%, respectively. This was reversed by coincubation with a protein kinase C (PKC) inhibitor or microinjection of a PKC inhibitor peptide. Phosphopeptide mapping revealed that high glucose or PMA led to serine/threonine phosphorylation of similar peptides. Inhibition of the microtubule-associated protein (MAP) kinase cascade by the MAP kinase kinase inhibitor PD98059 did not reverse the impaired phosphorylation. We conclude that high glucose inhibits insulin action by inducing serine phosphorylation through a PKC-mediated mechanism at the level of the receptor at sites proximal to the COOH-terminal 43 amino acids. This effect is independent of activation of the MAP kinase cascade. Proportionately, the impairment of insulin receptor substrate-1 tyrosine phosphorylation is greater than that of the insulin receptor resulting in attenuated phosphatidylinositol 3-kinase activation and mitogenic signaling.
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PMID:Glucose-induced phosphorylation of the insulin receptor. Functional effects and characterization of phosphorylation sites. 860 15

Hepatocyte growth factor (HGF) stimulated mitogen-activated protein (MAP) kinases and MAP kinase kinase in primary cultured rat hepatocytes. Inhibitors for protein kinase C (PKC), Ro31-8425, H-7, and calphostin C, reduced HGF-induced MAP kinase activity. A PKC activator, phorbol myristate acetate (PMA), induced MAP kinase activation in a concentration-dependent manner. Protein tyrosine kinase (PTK) inhibitors, genistein, and ST638 also inhibited HGF-induced MAP kinase activation. Furthermore, HGF increased formation of Ras guanosine triphosphate (GTP) complex, indicating Ras activation. Genistein inhibited HGF-induced Ras activation, but Ro31-8425 was without effect. On the other hand, Ro31-8425 decreased HGF-induced [3H]arachidonic acid (AA) release and [3H]thymidine incorporation. Genistein also prevented [3H]AA release and [3H]-thymidine incorporation. Moreover, a commonly used phospholipase A2 (PLA2) inhibitor, quinacrine, decreased HGF-induced [3H]AA release and [3H]thymidine incorporation. The inhibitory profile of [3H]AA release was well correlated with that of [3H]thymidine incorporation in Ro31-8425-, genistein-, and quinacrine-treated cells. A cyclooxygenase inhibitor, indomethacin, which suppressed HGF-induced DNA synthesis, had minimal effect on MAP kinase activation. In contrast, prostaglandin (PG) E1, E2, or F2 alpha, which stimulate [3H]thymidine incorporation to the same level as that caused by HGF in hepatocytes, caused very weak activation of MAP kinases. These results suggest that PTK, Ras, and PKC play roles in MAP kinase activation induced by HGF and that MAP kinase activation resulting in AA release is involved in DNA synthesis in rat hepatocytes.
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PMID:Mitogen-activated protein kinase activation in hepatocyte growth factor-stimulated rat hepatocytes: involvement of protein tyrosine kinase and protein kinase C. 862 Nov 60

We report that recombinant glia maturation factor (GMF), a 17-kDa brain protein, inhibits the activity of mitogen-activated protein (MAP) kinase in the test tube assay, in particular the ERK1/ERK2 isoforms. A preliminary phosphorylation of GMF by protein kinase A (PKA) dramatically increases its inhibitory effect by over 600-fold (Ki approximately 3 nM), making it the most potent MAP kinase inhibitor ever reported. Immunoprecipitation of GMF from cell extracts using its specific antibody coprecipitates ERK (and vice versa), suggesting the association of the two proteins in the cell. The inhibitory effect of PKA-phosphorylated GMF is specific, as it does not suppress the activity of cdc2 kinase, another proline-directed kinase. Nor does it inhibit MAP kinase kinase (MEK) and MAP kinase-activated protein (MAPKAP) kinase-2, the two enzymes immediately upstream and downstream, respectively, of ERK. Of the other three enzymes that can phosphorylate GMF, only p90 ribosomal S6 kinase (RSK) enhances the inhibitory function of GMF on ERK; protein kinase C (PKC) and casein kinase II (CKII) are without effect. The inhibition of ERK by PKA-phosphorylated GMF suggests that GMF could be one of the mediators of the suppressive effect of the PKA pathway on the MAP kinase pathway. On the other hand, that RSK-phosphorylated GMF also inhibits ERK implies a negative feedback loop in the regulation of MAP kinase activity.
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PMID:In vitro inhibition of MAP kinase (ERK1/ERK2) activity by phosphorylated glia maturation factor (GMF). 863 70

Mitogen activated protein kinase in extracts of U-937 macrophage-like cells was stimulated by LDL and oxLDL. A maximum value (161% of the basal phosphotransferase activity) was obtained after 6 min exposure to oxidized LDL (27 microgram/ml) using APRTPGGRR peptide substrate. The activatory effect was more pronounced (LDL 181%, oxLDL 201%) when MAPK of stimulated cells was immunoprecipitated with anti-p42MAPK antibodies and phosphotransferase activity was assayed in immune complexes. Stimulation produced by oxLDL was inhibited by poly I, fucoidan, dextran sulfate and by the MAPKK inhibitor PD 098059 but not by PMA-mediated depletion of PKC or by pre-treatment with chloroquine or with pertussis toxin. These results suggest a direct mitogenic effect of LDL which, in the case of oxLDL, is dependent on scavenger receptor ligation but not on G-protein mediated or PKC-dependent signal transduction.
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PMID:Stimulation of mitogen activated protein kinase by LDL and oxLDL in human U-937 macrophage-like cells. 864 40

Ligation of the B cell Ag receptor (BCR) activates a protein-tyrosine kinase (PTK) and CD45 protein-tyrosine phosphatase (PTPase)-dependent signaling cascade that results in the activation of Ras. This pathway of Ras activation can operate independently of protein kinase C (PKC) activity. Activation of Ras may lead to two distinct Ras-dependent pathways involving either a Raf1/MEK/MAPK module or a MEKK/SEK/SAPK module; however, it is unclear as to how Ras controls the independent activation of either of these pathways. We have used genistein and phenylarsine oxide (PAO) as inhibitors of PTK and PTPase, respectively, to investigate whether they regulate the BCR- and Ca2+/PKC-dependent activation of the Ras/Raf1/MEK/MAPK module. Assays of phosphotransferase activities conducted with Ag (TNP6-OVA)-specific 7.9 murine B lymphoma cells demonstrated that BCR-mediated stimulation of the Raf1/MEK/MAPK module is controlled by PTK and PTPase activities. An elevation in [Ca2+]i was required to optimally activate Raf1 and MEK through the BCR. However, when signaling through the BCR was bypassed by direct stimulation of the Raf1/MEK/MAPK module via a rise in [Ca2+]i and phorbol ester-induced PKC activation, the phosphotransferase activities of Raf1, MEK and MAPK were still regulated in a PTK-dependent manner that was also partially sensitive to the PTPase inhibitor PAO. Thus, at least two alternate routes, i.e. a BCR/PTK/Ras-dependent route and another PKC/Ca(2+)-dependent route, may converge at the level of Raf1 for activation of the Raf1/MEK/MAPK module in B cells.
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PMID:Regulation of BCR- and PKC/Ca(2+)-mediated activation of the Raf1/MEK/MAPK pathway by protein-tyrosine kinase and -tyrosine phosphatase activities. 864 50

Phenylephrine and noradrenaline (alpha-adrenergic agonism) or isoprenaline (beta-adrenergic agonism) stimulated protein synthesis rates, increased the activity of the atrial natriuretic factor gene promoter and activated mitogen-activated protein kinase (MAPK). The EC50 for MAPK activation by noradrenaline was 2-4 microM and that for isoprenaline was 0.2-0.3 microM. Maximal activation of MAPK by isoprenaline was inhibited by the beta-adrenergic antagonist, propranolol, whereas the activation by noradrenaline was inhibited by the alpha1-adrenergic antagonist, prazosin. FPLC on a Mono-Q column separated two peaks of MAPK (p42MAPK and p44MAPK) and two peaks of MAPK-activating activity (MEK) activated by isoprenaline or noradrenaline. Prolonged phorbol ester exposure partially down-regulated the activation of MAPK by noradrenaline but not by isoprenaline. This implies a role for protein kinase C in MAPK activation by noradrenaline but not isoprenaline. A role for cyclic AMP in activation of the MAPK pathway was eliminated when other agonists that elevate cyclic AMP in the cardiac myocyte did not activate MAPK. In contrast, MAPK was activated by exposure to ionomycin, Bay K8644 or thapsigargin that elevate intracellular Ca2+. Furthermore, depletion of extracellular Ca2+ concentrations with bis-(o-aminophenoxy)ethane-NNN'N'-tetra-acetic acid (BAPTA) or blocking of the L-type Ca2+ channel with nifepidine or verapamil inhibited the response to isoprenaline without inhibiting the responses to noradrenaline. We conclude that alpha- and beta-adrenergic agonists can activate the MEK/MAPK pathway in the heart by different signalling pathways. Elevation of intracellular Ca2+ rather than cyclic AMP appears important in the activation of MAPK by isoprenaline in the cardiac myocyte.
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PMID:Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade and cardiac hypertrophy. 866 Feb 71

Treatment of human platelets with phorbol 12-myristate 13-acetate (PMA) and arginine vasopressin (AVP) increase the phosphorylation and activation of mitogen-activated protein kinase (MAPK). Electrophoretic retardation of MAPK mobility on SDS-polyacrylamide gels was used for determination of MAPK phosphorylation. The activity of MAPK was tested in myelin basic protein (MBP)-containing polyacrylamide gels. In this study we compared the PMA and AVP signal transduction pathways leading to the activation of MAPKs and Na+/H+ exchanger (NHE). Both agonists stimulate MAPK and NHE activities in a similar time frame and concentration dependence. The MAPK and NHE activities induced by PMA were inhibited by staurosporine, a potent inhibitor for protein kinase C (PKC), and by MAPK kinase (MEK) inhibitor, PD98059, but were not affected by the tyrosine kinase inhibitor genistein. In contrast, both AVP-induced MAPK and NHE activities were inhibited by genistein and MEK inhibitor but were not affected by staurosporine. Immunoprecipitation studies demonstrate that PMA, but not AVP, enhances the basal phosphorylation of the NHE-1. In this study, MAPKs are suggested to be a part of converging signaling leading to NHE activation by PKC-dependent and AVP-tyrosine kinase-dependent pathways. We propose that the MAPK activation of the NHE-1 does not involve phosphorylation of this exchanger protein. On the other hand, PKC can lead to phosphorylation and to additional activation of the NHE-1 through a MAPK-independent pathway.
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PMID:Stimulation of mitogen-activated protein kinase and Na+/H+ exchanger in human platelets. Differential effect of phorbol ester and vasopressin. 866

A common response of cells to mitogenic and hypertrophic factors is the activation of high rates of protein synthesis. To investigate the molecular basis of this action, we have used the recently developed MAP kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor PD 98059 to examine the involvement of the ERK pathway in the regulation of global protein synthesis by growth factors in rat aortic smooth muscle cells (SMC). Incubation with PD 98059 blocked angiotensin II (AII)-dependent phosphorylation and enzymatic activity of both MEK1 and MEK2 isoforms, leading to inhibition of the phosphorylation and activation of p44(mapk) and p42(mapk). The compound was found to selectively inhibit activation of the ERK pathway by AII, but not the stimulation of p70 S6 kinase, phospholipase C, or tyrosine phosphorylation. Most importantly, treatment of aortic SMC with PD 98059 potently inhibited AII-stimulated protein synthesis with a half-maximal inhibitory concentration of 4.3 microM. The effect of PD 98059 was not restricted to AII, since the compound also blocked to various extent the induction of protein synthesis by growth factors acting through tyrosine kinase receptors, G protein-coupled receptors, or protein kinase C. These results provide strong evidence that activation of ERK isoforms is an obligatory step for growth factor-induced protein synthesis in aortic SMC.
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PMID:Inhibition of growth factor-induced protein synthesis by a selective MEK inhibitor in aortic smooth muscle cells. 866 42


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