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

Spreading of HeLa cells on a gelatin substratum is initiated by the activation of protein kinase C epsilon (PKC epsilon) upon contact of the cells with the matrix. In this study, we examined the functional role of PKC epsilon in the activation of mitogen-activated protein kinase (MAP kinase) and its relationship to cell spreading. MAP kinase isoforms, Erk-1 and -2, are activated upon attachment of HeLa cells to gelatin. Inhibition of PKC with calphostin C blocked cell spreading without any effect on MAP kinase activation. In contrast, inhibition of MAP kinase kinase blocked adhesion-induced MAP kinase activation, but showed no effect on either translocation of PKC epsilon or cell spreading. Thus, activation of PKC epsilon that occurs upon HeLa cell attachment to gelatin is related to cell spreading but not to the activation of MAP kinase, and MAP kinase is activated upon HeLa cell attachment in the absence of cell spreading.
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PMID:Integrin-mediated activation of mitogen-activated protein kinase is independent of the activation of protein kinase C epsilon during the spreading of HeLa cells on a gelatin substratum. 938 44

The GT1-1 GnRH neuronal cell lines exhibit highly differentiated properties of GnRH neurons. We have used GT1-1 cells to study the roles of norepinephrine (NE), membrane depolarization, calcium influx, and phorbol esters in the regulation of mitogen-activated protein (MAP) kinase. NE, which is known to stimulate the release of GnRH, induced MAP kinase activity, the tyrosine phosphorylation of MAP kinase, and MAP kinase kinase activity. Forskolin led to activation of MAP kinase comparable with that induced by NE, and a selective inhibitor of cAMP-dependent protein kinase, H8, attenuated the NE-induced activation of MAP kinase. On the other hand, elimination of extracellular calcium by EGTA completely blocked NE-induced tyrosine phosphorylation of MAP kinase, and a selective inhibitor of calcium/calmodulin-dependent protein kinase, KN-62, attenuated the NE-induced activation of MAP kinase. Furthermore, depolarization of GT1-1 cells with 75 mM KCl, 10 microM BayK 8644, or 1 microM calcium ionophore (A23187) induced rapid tyrosine phosphorylation of MAP kinase. The omission of calcium from the extracellular medium completely abolished these effects of tyrosine phosphorylation of MAP kinase. Phorbol 12-myristate 13-acetate (PMA) also induced MAP kinase activity, but pretreatment of the cultured cells with PMA to down-regulate protein kinase C did not abolish the activation of MAP kinase by NE. In addition, although phosphorylation of Raf-1 kinase was stimulated by PMA, this phosphorylation was not induced by either NE or A23187. These results demonstrate that NE activates MAP kinase directly in GT1-1 cells, and that the effect of NE is mediated by increase in the cAMP level and by calcium influx, but not by PMA-sensitive protein kinase C or Raf-1 kinase.
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PMID:Norepinephrine stimulates mitogen-activated protein kinase activity in GT1-1 gonadotropin-releasing hormone neuronal cell lines. 938 11

The signaling pathway involved in low density lipoprotein (LDL) receptor gene expression induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was investigated in the human hepatoma HepG2 cell line. Treatment of HepG2 cells with 100 nM TPA resulted in an approximately 20-fold increase in LDL receptor mRNA level, as determined by RT-PCR, which peaked at 2-4 h of treatment and subsequently declined. The protein kinase C (PKC) inhibitors calphostin C and staurosporine prevented TPA-mediated LDL receptor mRNA induction. In contrast, TPA did not affect squalene synthase mRNA expression. Immunoblotting of cell extracts with isozyme-specific PKC antibodies revealed that HepG2 cells expressed PKC alpha, which was mainly cytosolic, and PKC beta, PK epsilon, and PKC zeta, all of which were present in both the cytosolic and particulate fractions. Treatment of HepG2 cells with 100 nM TPA resulted in translocation of cytosolic PKC alpha to the particulate fraction, with a maximum at 30 min-2 h of treatment, but was without effect on the subcellular distribution of the other isozymes. TPA treatment also led to activation of the mitogen-activated protein kinase (MAPK) ERK cascade. The specific MAPK pathway inhibitor PD98059 blocked TPA-induced ERK activation. Furthermore, pretreatment of cells with PD98059 inhibited TPA-induced LDL receptor mRNA induction. Moreover, pretreatment of cells with calphostin C inhibited TPA-mediated ERK activation and LDL receptor mRNA induction in a dose-dependent fashion. Based on a close kinetic correlation between PKC alpha translocation and ERK activation, and the effects of specific inhibitors, these findings suggest that translocation/activation of PKC alpha, and subsequent activation of the Raf-1/MEK/ERK MAPK cascade, represent key events in the transcriptional induction of LDL receptor gene by TPA in HepG2 cells.
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PMID:Phorbol ester-induced low density lipoprotein receptor gene expression in HepG2 cells involves protein kinase C-mediated p42/44 MAP kinase activation. 939 22

The use of bisindolylmaleimide derivatives of staurosporine as selective inhibitors of protein kinase C (PKC) is in doubt following the report by Alessi [FEBS Lett. 402 (1997) 121-123] that Ro31-8220 and GF109203X are potent in vitro inhibitors of p70 S6 kinase and mitogen-activated protein kinase-activated protein kinase-1beta, as well as of PKC. Here we show that the phorbol ester-stimulated release of choline- and ethanolamine-metabolites from C6 glioma cells due to phospholipid hydrolysis by phospholipase D (PLD) is not inhibited by rapamycin or PD98059, specific inhibitors respectively of p70 S6 kinase and MAPKK (MEK) and thus of MAPKAP kinase-1beta but is still completely blocked by Ro31-8220. We conclude therefore that p70S6k and MAPKAP kinase-1beta as well as MAPK are not involved in signalling pathways downstream of PKC that regulate phorbol ester-stimulated phospholipid turnover and that the inhibitory action of Ro31-8220 occurs by blocking PKC which regulates at least one pathway to PLD activation. The PI-3 kinase inhibitor, wortmannin, inhibits the phorbol ester-stimulated release of ethanolamine- but not choline-metabolites from C6 cells suggesting that different PLD isoforms regulate the turnover of PtdEth and PtdCho in C6 cells. Both PLD isoforms are activated via PKC but the PtdEth-PLD is also regulated via a wortmannin-sensitive pathway.
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PMID:Ro31-8220 inhibits protein kinase C to block the phorbol ester-stimulated release of choline- and ethanolamine-metabolites from C6 glioma cells: p70 S6 kinase and MAPKAP kinase-1beta do not function downstream of PKC in activating PLD. 939 70

Oligodendrocytes, the myelin-producing cells of the central nervous system, express muscarinic acetylcholine receptors (mAChR). Activation of this neurotransmitter receptor by the stable acetylcholine analog carbachol (CCh) triggers transducing events, modulating c-fos expression and cellular proliferation. To elucidate the signal transduction pathways involved in the transmission of these cellular events, we examined the ability of CCh to activate mitogen-activated protein kinase (MAPK) in primary cultures of oligodendrocyte progenitors prepared from newborn rat brain. CCh produced a concentration- and time-dependent increase in MAPK activity (predominantly the p42mapk or ERK2) as determined by in-gel MBP kinase assays. Using the non-selective muscarinic antagonist atropine we determined that MAPK-activation by CCH is mediated by muscarinic receptors. In the presence of PD098059, a specific inhibitor of MAPK kinase (MEK), MAPK activity was blocked. Similarly, the presence of extracellular calcium was required for CCh-mediated MAPK activation. To further elucidate the mechanisms involved in MAPK activation by CCh, the role of PKC was studied. In cells in which protein kinase had been downregulated by chronic treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA), the effect of carbachol on MAPK activation was maintained. In contrast, the response to CCh was blocked by the PKC inhibitors H7 and bisindolylmaleimide GF109203X. Our results suggest that MAPK is implicated in the transmission of the signal for mACh receptors and involves a TPA-insensitive PKC pathway. Further work is required to define the upstream and downstream events which result in CCh-mediated MAPK activation and proliferation of oligodendrocyte progenitors.
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PMID:Acetylcholine agonists stimulate mitogen-activated protein kinase in oligodendrocyte progenitors by muscarinic receptors. 941 62

Intestinal trefoil factor (ITF), a small, compact protease-resistant peptide, is abundantly expressed in goblet cells of large and small intestine. Although several biological activities of ITF have been identified, including promotion of wound healing, stimulation of epithelial cell migration, and protection of intestinal epithelial barrier, little is known about signaling events through which ITF mediates its physiological function. In this study, the effects of exogenous ITF on mitogen-activated protein kinase (MAPK) signaling cascades were examined in IEC-6 cells, a nontransformed intestinal epithelial cell line that does not express endogenous trefoil peptides. Stimulation with ITF resulted in rapid decrease in extracellular signal-related protein kinase (ERK) activity and concomitant reduced ERK tyrosine phosphorylation. ITF also decreased activation of ERK activity induced by either transforming growth factor-alpha, which links extracellular stimuli to the Ras/Raf/MEK/ERK pathway via the epidermal growth factor receptor, or phorbol 12-myristate 13-acetate, which activates Raf through protein kinase C. ITF-induced inhibition of ERK activity was blocked by an inhibitor of tyrosine and dual-specific phosphatases, sodium orthovanadate. In summary, ITF leads to inhibition of ERK and the MAPK pathway through activation of tyrosine or dual-specific phosphatase.
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PMID:Intestinal trefoil factor induces inactivation of extracellular signal-regulated protein kinase in intestinal epithelial cells. 941 49

Mitogen-activated protein (MAP) kinases are activated by the sequential activation of Ras, Raf, and MEK (MAP kinase kinase) and regulate a wide variety of cell functions. To determine the kinase cascade for granulocyte-macrophage colony-stimulating factor (GM-CSF)- and IL-5-induced MAP kinase activation in eosinophils, we studied the effect of inhibitors of Jak2 kinase, tyrosine kinases, phosphatidylinositol 3-kinase, and protein kinase C on GM-CSF- and IL-5-induced MAP kinase activation in human eosinophils. GM-CSF and IL-5 activated 40, 42, and 44 kilodalton MAP kinase isoforms in eosinophils. This was indicated by the electrophoretic mobility shift of the three isoforms of MAP kinase in immunoblotting with anti-MAP kinase antibody and also by in-gel MAP kinase assay. MAP kinase activation was time- and dose-dependent, becoming maximal 3 to 15 minutes after stimulation. A Jak2 kinase inhibitor AG-490, a tyrosine kinase inhibitor genistein, and a phosphatidylinositol 3-kinase inhibitor wortmannin inhibited GM-CSF- and IL-5-induced MAP kinase activation in eosinophils, whereas a protein kinase C inhibitor staurosporine had a weak inhibitory effect. Furthermore, AG-490 and genistein prevented GM-CSF-induced tyrosine phosphorylation of Jak2 kinase in eosinophils. Taken together, these results indicate that GM-CSF and IL-5 activate MAP kinases through the signaling pathway of Jak2 kinase-tyrosine phosphorylated beta chain-phosphatidylinositol 3-kinase-Ras in eosinophils.
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PMID:Granulocyte-macrophage colony-stimulating factor and IL-5 activate mitogen-activated protein kinase through Jak2 kinase and phosphatidylinositol 3-kinase in human eosinophils. 944 May 44

Phorbol ester treatment of quiescent Swiss 3T3 cells leads to cell proliferation, a response thought to be mediated by protein kinase C (PKC), the major cellular receptor for this class of agents. We demonstrate here that this proliferation is dependent on the activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) cascade. It is shown that dominant-negative PKC-alpha inhibits stimulation of the ERK/MAPK pathway by phorbol esters in Cos-7 cells, demonstrating a role for PKC in this activation. To assess the potential specificity of PKC isotypes mediating this process, constitutively active mutants of six PKC isotypes (alpha, beta, delta, epsilon, eta, and zeta) were employed. Transient transfection of these PKC mutants into Cos-7 cells showed that members of all three groups of PKC (conventional, novel, and atypical) are able to activate p42 MAPK as well as its immediate upstream activator, the MAPK/ERK kinase MEK-1. At the level of Raf, the kinase that phosphorylates MEK-1, the activation cascade diverges; while conventional and novel PKCs (isotypes alpha and eta) are potent activators of c-Raf1, atypical PKC-zeta cannot increase c-Raf1 activity, stimulating MEK by an independent mechanism. Stimulation of c-Raf1 by PKC-alpha and PKC-eta was abrogated for RafCAAX, which is a membrane-localized, partially active form of c-Raf1. We further established that activation of Raf is independent of phosphorylation at serine residues 259 and 499. In addition to activation, we describe a novel Raf desensitization induced by PKC-alpha, which acts to prevent further Raf stimulation by growth factors. The results thus demonstrate a necessary role for PKC and p42 MAPK activation in 12-O-tetradecanoylphorbol-13-acetate induced mitogenesis and provide evidence for multiple PKC controls acting on this MAPK cascade.
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PMID:Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. 944 75

Activation of protein kinase C (PKC) regulates the processing of Alzheimer amyloid precursor protein (APP) into its soluble form (sAPP) and amyloid beta-peptide (A beta). However, little is known about the intermediate steps between PKC activation and modulation of APP metabolism. Using a specific inhibitor of mitogen-activated protein (MAP) kinase kinase activation (PD 98059), as well as a dominant negative mutant of MAP kinase kinase, we show in various cell lines that stimulation of PKC by phorbol ester rapidly induces sAPP secretion through a mechanism involving activation of the MAP kinase cascade. In PC12-M1 cells, activation of MAP kinase by nerve growth factor was associated with stimulation of sAPP release. Conversely, M1 muscarinic receptor stimulation, which is known to act in part through a PKC-independent pathway, increased sAPP secretion mainly through a MAP kinase-independent pathway. A beta secretion and its regulation by PKC were not affected by PD 98059, supporting the concept of distinct secretory pathways for A beta and sAPP formation.
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PMID:Regulation of secretion of Alzheimer amyloid precursor protein by the mitogen-activated protein kinase cascade. 945 46

Vasoconstrictors, such as angiotensin II (Ang II), are involved in the regulatory mechanisms of post myocardial infarction (MI) hypertrophy. Arginine vasopressin (AVP), may be another vasoconstrictor that influences the mechanisms that lead to post MI hypertrophy. In these studies we investigated the possible activation of the 42/44 kDa mitogen-activated protein kinases (MAPKs), also referred as extracellular signal regulated kinases (ERKs), in cultured cardiomyocytes. Treatment of rat cardiomyocytes with AVP, Ang II and phorbol 12-myristate 13-acetate (PMA) increases the activation of ERKs. The activity of the 42/44 kDa MAPKs was tested using the phosphorylation of: (1) EGF receptor peptide (EGFR-P); (2) myelin basic protein (MBP) immobilized in poly acrylamide gels; and (3) T183 and Y185 residues of these proteins. The activity of the MAPKs, induced by AVP or PMA was inhibited by downregulation of protein kinase C (PKC), by the tyrosine kinase inhibitor genistein and by MAPK kinase (MEK) inhibitor, PD98059. In addition, the AVP-induced stimulation of MAPKs was shown to be mediated through a V1 receptor. We suggest that AVP activates the 42/44kDa MAPKs through a signal transduction pathway that involves stimulation of AVP-V1 receptor, tyrosine kinase, PKC and MEK. These results suggest that AVP may be involved in ERKs dependent regulatory functions of cardiomyocytes growth.
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PMID:Stimulation of 42/44 kDa mitogen-activated protein kinases by arginine vasopressin in rat cardiomyocytes. 945 90


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