EC:2.7.11.13 - FACTA Search

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)

Vasopressin and bradykinin bind to receptors coupled to GTP-binding proteins and rapidly induce polyphosphoinositide breakdown leading to Ca2+ mobilization and activation of protein kinase C. Both peptides are known to induce mitogenesis in the presence of growth factors that act through receptors with intrinsic tyrosine kinase activity. Surprisingly, addition of a combination of vasopressin and bradykinin to Swiss 3T3 cells synergistically stimulates DNA synthesis in the absence of any other growth factors. This effect is induced at nanomolar concentrations of the peptides and could be inhibited by addition of specific receptor antagonists or broad spectrum neuropeptide antagonists. Bradykinin, which stimulates transient activation of protein kinase C, induces DNA synthesis in synergy with substances that cause long-term activation of protein kinase C, like vasopressin or phorbol 12,13-dibutyrate. Down-regulation of protein kinase C inhibited the induction of mitogenesis by the combination of vasopressin and bradykinin, thus demonstrating the importance of long-term activation of this enzyme for DNA synthesis. Analysis of tyrosine phosphorylated proteins of M(r) = 110,000-130,000 and M(r) = 70,000-80,000 revealed a biphasic response after stimulation with bradykinin, whereas the response induced by vasopressin declined after the initial maximum. The combination of bradykinin with vasopressin caused an enhanced and prolonged increase in tyrosine phosphorylation of these proteins as compared with the individual peptides. Inhibition of tyrosine phosphorylation by tyrphostin was paralleled by inhibition of DNA synthesis. Together, these results demonstrate synergistic stimulation of DNA synthesis by bradykinin and vasopressin via prolonged stimulation of multiple signaling pathways and imply that the interactive effects of Ca(2+)-mobilizing peptides on mitogenesis may be more general than previously thought.
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PMID:Synergistic stimulation of DNA synthesis by bradykinin and vasopressin in Swiss 3T3 cells. 807 88

To investigate whether hepatobiliary transport of organic cations is under regulatory control, we studied transport of tri-n-butylmethylammonium in the isolated perfused rat liver and in isolated rat hepatocytes. Transport was investigated in the presence of modulators of the protein kinase C and the cyclic AMP second-messenger system. In the isolated perfused rat liver, it was observed that compounds modulating protein kinase C activity clearly affected the biliary excretion process of the cation tri-n-butylmethylammonium. Phorbol 12-myristate 13-acetate, a compound that directly stimulates protein kinase C, elevated the biliary excretion rate of tri-n-butylmethylammonium in a concentration-dependent manner, reaching a twofold increase at 60 nmol/L of the phorbol ester. The inactive derivative 4 alpha-phorbol 12, 13-didecanoate (60 nmol/L) did not show any effect. Vasopressin (48 nmol/L), a receptor-mediated activator of protein kinase C, stimulated the excretion rate of the cation by about 50%. Staurosporin (1 mumol/L), an inhibitor of protein kinase C, clearly decreased the biliary excretion rate of the cation and also blocked its stimulation by phorbol 12-myristate 13-acetate. Neither phorbol 12-myristate 13-acetate nor vasopressin (at concentrations ranging from 10(-9) to 10(-6) mol/L) affected the initial uptake velocity of tri-n-butylmethylammonium in isolated hepatocytes and isolated perfused livers, whereas staurosporin (1 mumol/L) showed only a modest inhibition of the uptake of the cation. It is inferred that the effect of protein kinase C modulators on hepatobiliary transport of organic cations occurs at the level of carrier-mediated transport in the canalicular membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulators of the protein kinase C system influence biliary excretion of cationic drugs. 822 27

Treatment of Swiss 3T3 cells with bombesin caused a striking increase (21-fold) in the tyrosine phosphorylation of the cytoskeleton-associated protein paxillin, as judged by anti-phosphotyrosine Western blots of anti-paxillin immunoprecipitates. Vasopressin and endothelin also stimulated paxillin tyrosine phosphorylation. Bombesin-stimulated tyrosine phosphorylation of paxillin was detectable within 1 min and was concentration-dependent (half-maximum effect at 0.09 nM). Bombesin stimulation of paxillin tyrosine phosphorylation could be dissociated from both protein kinase C (PKC) activation and the mobilization of Ca2+ from intracellular stores. Activation of PKC in quiescent Swiss 3T3 cells using the tumor promoter phorbol 12,13-dibutyrate (PDB) increased the tyrosine phosphorylation of paxillin in a time-dependent manner but was less effective than bombesin and stimulated detectable phosphorylation only within 5 min, considerably slower than bombesin-induced tyrosine phosphorylation of paxillin. Furthermore, the selective PKC inhibitor, GF109203X, or down-regulation of PKC using prolonged treatment with PDB markedly inhibited the stimulation of paxillin tyrosine phosphorylation by PDB but had little effect on the response to bombesin. In contrast, cytochalasin D, an agent that selectively disrupts the network of actin microfilaments, completely inhibited bombesin- and PDB-induced paxillin tyrosine phosphorylation. This is the first report to identify paxillin as a substrate for neuropeptide-stimulated tyrosine phosphorylation.
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PMID:Bombesin, vasopressin, and endothelin rapidly stimulate tyrosine phosphorylation of the focal adhesion-associated protein paxillin in Swiss 3T3 cells. 840 63

Vasopressin stimulated GSH efflux from Hep G2 cells. The maximal effect was observed at 10nM. Pretreatment with pertussis toxin or cholera toxin for 18 hr increased GSH efflux. Vasopressin-mediated GSH efflux was observed even in the cells pretreated with those compounds. Dibutyryl-cAMP or dibutyryl-cGMP enhanced GSH efflux although an additive effect of vasopressin was not observed. Glucagon and a phorbol ester independently increased GSH efflux while both compounds decreased the effect of vasopressin. Staurosporine, an inhibitor of protein kinase C, inhibited vasopressin-mediated GSH efflux. The effect of vasopressin was observed even in the absence of extracellular Ca2+. Vasopressin stimulates GSH efflux from Hep G2 cells and protein kinase C-dependent pathway may play a significant role in vasopressin-mediated GSH efflux.
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PMID:Characterization of vasopressin-mediated GSH efflux from Hep G2 cells: significance of protein kinase C. 845 Jul 14

In principal cells of rat cortical collecting ducts (CCD) cellular pH (pHi) is regulated by basolateral Na+/H+ exchange. The influence of various agonists on pHi and cellular Ca2+ activity ([Ca2+]i) in freshly isolated CCD cells was examined with BCECF and fura-2 fluorescence ratios. The recovery of pHi per minute (delta pH/min) after an acid load was 0.26 +/- 0.03 (N = 53) in control conditions and was increased by the diadenosine polyphosphates Ap4A, Ap5A, Ap6A, the phorbol ester phorbol 12-myristat 13-acetate (PMA) (each 5 mumol/L) and angiotensin II (100 nmol/L) by 0.05 +/- 0.02 (N = 10), 0.11 +/- 0.05 (N = 13), 0.09 +/- 0.02 (N = 24), 0.10 +/- 0.03 (N = 7), and 0.09 +/- 0.03 (N = 8), respectively. Vasopressin (10 nmol/L) decreased delta pH/min by 0.11 +/- 0.03 (N = 9); ATP and Ap3A (each 5 mumol/L) had no significant effect. The increase in delta pH/min with Ap6A was abolished in the presence of an inhibitor of protein kinase C, calphostin C (0.1 mumol/l, N = 8). Fura-2 fluorescence ratio was not significantly changed with angiotensin II, Ap3A, or Ap4A but increased with vasopressin, ATP, Ap5A, and Ap6A by 0.08 +/- 0.02 (N = 13), 0.04 +/- 0.02 (N = 13), 0.03 +/- 0.01 (N = 14), and 0.03 +/- 0.01 (N = 10), respectively. These data indicate that Na+/H+ exchange in rat CCD is activated by the stimulation of a Ca(2+)-independent protein kinase C and inhibited by protein kinase A.
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PMID:Regulation of Na+/H+ exchange by diadenosine polyphosphates, angiotensin II, and vasopressin in rat cortical collecting duct. 858 90

The involvement of protein kinase C (PKC) in vasopressin-induced effects on renal water reabsorption is still unresolved. Activation of PKC can be detected by its translocation from the cytosol (C) to the plasma membrane (PM). In LLC-PK1 cells, the redistribution of PKC alpha, a predominant isoform of PKC detected, was studied utilizing western blotting after stimulation with vasopressin. Vasopressin (100 mU/ml) failed to induce a translocation of PKC alpha from the C to the PM. By contrast, phorbol myristate acetate (PMA, 200 nM), a potent activator of PKC, induced a relocalization of PKC alpha from the C to the PM. After 2 hours of treatment of cells with PMA, PKC alpha was predominantly detected in the PM and absent from the C. These results suggest that the signal transduction pathway of vasopressin in LLC-PK1 cells does not involve PKC alpha activation and translocation.
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PMID:Is protein kinase C alpha (PKC alpha) involved in vasopressin-induced effects on LLC-PK1 pig kidney cells? 882 10

In isolated hamster hepatocytes, the Ca2+ ionophore A-23187 immediately decreased the uptake rate of taurocholic acid (TCA) by 60-70%, whereas it slowly inhibited that of ursodeoxycholic acid (UDCA) by a maximum of 35-45%, with an inhibition constant (Ki) of 0.36 and 1.93 microM, respectively. In contrast to ionomycin, which mimicked the effect of A-23187, vasopressin inhibited the bile acid uptake rate by 40 and 45%, respectively, only after a 5- to 10-min preincubation. The Na(+)-dependent bile acid transport was exclusively inhibited by these agents, and this inhibition was independent of extracellular Ca2+. However, intracellular Ca2+ depletion with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid or chelation with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid resulted in 40-50% inhibition of the uptake rate of both bile acids. The exogenous protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), but not the nonactive 4 alpha-phorbol, significantly inhibited TCA uptake rate. Although both A-23187 and ionomycin immediately increased and decreased the cellular Na+ and K+ concentration, respectively, neither vasopressin nor PMA had a significant effect on the cellular concentration of these cations, even after a 10-min incubation. Furthermore, the effect of A-23187 and ionomycin on TCA uptake and Na+ flux, respectively, disappeared after a 40-min preincubation, and additional ionophore remained without effect. However, after a 40-min incubation with A-23187, PMA was still able to inhibit TCA uptake. Therefore, A-23187 and ionomycin transiently inhibited Na(+)-dependent uptake of both TCA and UDCA, in part because of transient alteration of the cellular Na+ and K+ concentration. Vasopressin and PMA inhibited Na(+)-dependent bile acid uptake, at least in part, through protein kinase C activation.
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PMID:Regulation of taurocholate and ursodeoxycholate uptake in hamster hepatocytes by Ca(2+)-mobilizing agents. 899 53

We previously demonstrated that the antiprogestogen RU 486, when superfused on myometrial strips, induces a rapid decrease in spontaneous uterine contractile frequency, an increase in amplitude and duration of contractions, and a concomitant decrease in 6-keto PGF(1alpha) release. In this study, we present further work on the role of calcium transients and the involvement of the PLC/PKC pathway in mediating RU 486 effects. We found no clear causal relationship between the spontaneous contractility controlled by external Ca++ concentration and 6-keto PGF(1alpha) release depending mostly on intracellular Ca++ mobilization. We show that RU 486 strengthened the inhibitory effect of TMB8, a potent inhibitor of internal calcium, on both spontaneous contractility and 6-keto PGF(1alpha), release and antagonized the stimulatory action of thapsigargin, a toxin blocking the endoplasmic reticulum calcium pump (ER Ca++ ATPase). These data indicate that RU 486 could act as an inhibitor of intracellular Ca++ mobilization. A slight but significant decrease of the prostanoid liberation was observed in the presence of U73122, an inhibitor of PLC, but not in the presence of neomycin, another PLC inhibitory compound. PKC inhibitors, staurosporine and H7 did not significantly affect spontaneous 6-keto PGF1alpha release, showing that PIP2 hydrolysis and PKC pathway were not involved in the basal release of the prostacyclin metabolite. Vasopressin (AVP), an agent known to induce contractility of the non-pregnant human uterus, markedly increased 6-keto PGF(1alpha) release in a dose-dependent manner. Stimulation of GTP-regulated proteins (G proteins) by ALF4 was accompanied by a rise in 6-keto PGF(1alpha) liberation and a high contractile activity. The effects of both vasopressin and ALF4- were not significantly opposed by RU 486, indicating that other sources of Ca++, not controlled by the steroid, were involved in the agonist-stimulated prostanoid release. Studies with structurally related RU 486 analogues showed that the steroid effects were not dependent on their antihormonal activity, but rather on a specific 11beta arylsubstitution and a 17beta-hydroxy-13beta-methyl configuration of the 4,9-estradien-3-one molecule.
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PMID:RU 38486 inhibits intracellular calcium mobilization and PGI2 release from human myometrium: mechanisms of action. 900 39

Treatment of Swiss 3T3 cells with bombesin rapidly induced tyrosine phosphorylation of the p130 Crk-associated substrate (p130(cas)). Vasopressin, endothelin, bradykinin, lysophosphatidic acid, sphingosylphosphorylcholine, and phorbol 12,13-dibutyrate also stimulated p130(cas) tyrosine phosphorylation. Bombesin-induced p130(cas) tyrosine phosphorylation could be dissociated from both protein kinase C activation and Ca2+ mobilization from intracellular stores. In contrast, cytochalasin D, which disrupts the network of actin microfilaments, completely prevented tyrosine phosphorylation of p130(cas) by bombesin. Platelet-derived growth factor, at low concentrations (1-5 ng/ml), also induced tyrosine phosphorylation of p130(cas) via a pathway that depended on the integrity of the actin cytoskeleton. The phosphatidylinositol 3'-kinase inhibitors wortmannin and LY294002 prevented tyrosine phosphorylation of p130(cas) in response to platelet-derived growth factor but not in response to neuropeptides, lysophosphatidic acid, sphingosylphosphorylcholine, or phorbol 12,13-dibutyrate. All agonists that induced p130(cas) tyrosine phosphorylation also promoted the formation of a p130(cas).Crk complex in intact Swiss 3T3 cells. Thus, our results identified distinct signal transduction pathways that lead to tyrosine phosphorylation of p130(cas) in the same cells and suggest that p130(cas) could play a role in mitogen-mediated signal transduction.
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PMID:Tyrosine phosphorylation of p130(cas) by bombesin, lysophosphatidic acid, phorbol esters, and platelet-derived growth factor. Signaling pathways and formation of a p130(cas)-Crk complex. 908 73

In the present study, we investigated the role of calcium and protein kinase C (PKC) in the activation of mitogen-activated protein kinase (MAPK) in isolated rat hepatocytes. We found that the glycogenolytic hormone norepinephrine (NE), acting through the alpha1-adrenergic receptor and the G protein Gq, was able to induce a dose- and time-dependent activation of MAPK in hepatocytes. Vasopressin, which acts through a different receptor but also through stimulation of the Gq-dependent pathway, also caused a twofold activation of MAPK. Activation of MAPK by both agonists required the presence of free extracellular calcium and was blocked by the specific PKC inhibitor, Ro 31-8220. MAPK activation was also induced by phorbol myristate acetate (PMA), confirming that a PKC-dependent pathway exists for MAPK activation in liver. Furthermore, calcium-mobilizing agents such as thapsigargin and ionomycin were able to induce an activation of MAPK by a PKC-independent pathway that was totally abolished by preincubation of cells with EGTA. A second pathway for MAPK activation that relies solely on calcium may therefore exist. Ro 31-8220 did not affect phosphorylase activation by NE, vasopressin, thapsigargin, and ionomycin, indicating that PKC inhibition did not interfere with the signaling pathway leading to inositol-1,4,5-triphosphate (IP3)-induced calcium mobilization or with changes in calcium fluxes. The role of MAPK activation by NE and vasopressin in the regulation of hepatic carbohydrate metabolism is discussed.
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PMID:Activation of mitogen-activated protein kinase in freshly isolated rat hepatocytes by both a calcium- and a protein kinase C-dependent pathway. 916 Aug 23

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