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)

Chornic exogenous administration of cholecystokinin octapeptide (CCK8) to rats led to a reduced sensitivity of pancreatic acinar cells to both CCK8 and carbachol stimulation without changes in affinity or number of CCK or muscarinic receptors. In addition, repeated feeding of camostate, a synthetic protease inhibitor which stimulates endogenous CCK release, desensitized the response of the acini to caerulein. This study investigates whether an altered postreceptor signal transduction mechanism is responsible for the reduced amylase secretion. Four days of camostate treatment significantly increased pancreatic weight, protein and amylase, but not DNA content, indicating organ hypertrophy, CCK8 and carbachol stimulated amylase release from acini, isolated from camostate-treated rats, was significantly reduced without shifting the dose response curve compared to controls. There was no difference in total phosphoinositide turnover between the groups. In addition, CCK8 and carbachol stimulated 45Ca efflux and calcium ionophore stimulated amylase release were similar in both groups. These results indicate that the release of calcium from intracellular stores and the utilization of intracellular calcium to drive amylase secretion is not affected in the hypertrophied pancreas. In contrast, incubation of acini from camostate-treated rats with TPA (a phorbol ester which directly stimulates protein kinase C) showed a 48% reduction in amylase secretion. This suggests that a regulatory mechanism is present at the level of protein kinase C or beyond, which is responsible for the decrease in amylase release in the hypertrophied pancreas.
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PMID:Intracellular mechanism responsible for reduced enzyme secretion from camostate-induced hypertrophied pancreas. 170 70

The role played by protein kinase C (PKC) in TH gene regulation was investigated at transcriptional and post-transcriptional levels using PC12 cells. The cells were treated with the phorbol ester TPA, which not only activates PKC but also causes down-regulation. PKC levels were monitored by [3H]PDBU binding assay and by using an anti-PKC antibody that detected intact PKC (79 kd) as well as its catalytic and regulatory domains. The [3H]PDBU binding to the membrane-associated PKC increased within 15-30 min of TPA treatment; thereafter total cellular [3H]PDBU binding decreased to a minimum of 20% of the control at 8 h. The rate of decrease in binding was greater than the decrease in the intensity of the staining of PKC holo enzyme visualized by anti-PKC antibody. TH mRNA levels, measured over the same time period, rose within 15 min of TPA treatment to peak at 4 h and subsequently declined below control level, paralleling the depletion of PKC. If cells depleted of PKC were reincubated in the normal medium, a recovery in PKC level was seen and, in parallel, TH mRNA levels increased to above control level. Furthermore, if down-regulation of PKC was prevented by incubating the cells with the protease inhibitor leupeptin, a decrease beyond control level in TH mRNA was not observed. TPA rapidly induced TH gene transcription; a maximal increase of two-fold was observed at 15 min, but the transcriptional rate then declined although it did not decrease beyond control values after 8 and 24 h of TPA treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transcriptional and post-transcriptional regulation of tyrosine hydroxylase gene by protein kinase C. 197 13

Synaptic plasma membranes from rat brain cortex possess intrinsic ability to dephosphorylate the endogenous protein B-50. At low concentrations of [gamma-32P]ATP, B-50 phosphorylation in synaptic membranes is maximal at 30 seconds, followed by dephosphorylation for an additional 60 minutes. The dephosphorylation of 32P-labeled B-50 is not sensitive to the protease inhibitor leupeptin and not correlated with a loss of the B-50 content of synaptic membranes as measured with immunoblot analysis. Dephosphorylation of membrane-associated B-50 is stimulated to a small extent by Mg2+ but not by Ca2+. Heat-stable protein phosphatase inhibitors prevent dephosphorylation of 32P-labeled B-50. Dephosphorylation of B-50 in synaptic membranes is stimulated by ATP, ADP, or adenosine 5'-O-thiotriphosphate, but not by adenine, adenosine, other adenine or guanine nucleotides, nonhydrolyzable analogs of ATP or GTP, nor by adenosine 5'-O-(2-thiodiphosphate). B-50, phosphorylated by exogenous protein kinase C and purified to homogeneity, has been used as a substrate to follow the purification of B-50 phosphatase activity. B-50 phosphatase activity can be solubilized from synaptic membranes with 0.5% Triton X-100 and 75 mM KCl. Chromatography of the extract on DEAE-cellulose yields enhanced B-50 phosphatase activity.
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PMID:Dephosphorylation of B-50 in synaptic plasma membranes. 215 32

In determining the mechanism of the chemokinetic action of the thiol protease inhibitor, E-64, in endothelial cell monolayers subjected to wounding, we synthesized succinyl-leucyl-agmatine (SLA), an analogue of E-64 that lacked the epoxy group and protease inhibitory effect. We observed that this analogue retained its chemokinetic effect on wounded endothelial cells. Its stimulatory action on endothelial cell polarization response to wounding was rapid and associated with directed cell migration. Furthermore, its effect on cellular polarization was blocked by protein kinase C (PKC) inhibitors and mimicked by pharmacologic agents that stimulated PKC activity. To determine if SLA's chemokinetic action was mediated by protein kinase C activation, we compared the effects of SLA and the tumor promoter phorbol myristate acetate (PMA) on the translocation of PKC activity in endothelial cells. We observed that both SLA and PMA induced the translocation of PKC activity from the cytosolic to the particulate fraction of the cells. We also observed that both SLA and PMA induced the phosphorylation of two proteins (Mr 23.4 and 36.5 kDa) in intact 32P-labeled cells. Thus, SLA stimulates the endothelial cell locomotor response to wounding by stimulating PKC activity.
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PMID:A novel succinyl dipeptide stimulates directed cell migration by modulating protein kinase C activity. 230 31

The protease inhibitor, phenylmethylsulfonyl fluoride inhibits granule enzyme release and, above 1 mM, superoxide production from rabbit peritoneal neutrophils induced by the chemotactic peptide, fMet-Leu-Phe. At concentrations below 1 mM, it enhances superoxide production. Superoxide generation stimulated by phorbol 12-myristate-13-acetate is increased by phenylmethylsulfonyl fluoride at all concentrations studied. Phenylmethylsulfonyl fluoride has no effect on the rise in intracellular calcium or the depolarization induced by fMet-Leu-Phe but does decrease the extent of repolarization and abolishes hyperpolarization. It depresses actin polymerization and abolishes cytoplasmic alkalinization caused by fMet-Leu-Phe. The increased phosphorylation induced by phorbol 12-myristate-13-acetate in four of the five proteins studied was not affected by phenylmethylsulfonyl fluoride, but the increased phosphorylation of the fifth, a 21-kD protein was enhanced. We conclude that phenylmethylsulfonyl fluoride acts on inhibitory and enhancing processes or steps induced by fMet-Leu-Phe which are subsequent to or independent of calcium mobilization and protein kinase C activity.
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PMID:Actions of the protease inhibitor phenylmethylsulfonyl fluoride on neutrophil granule enzyme secretion and superoxide production induced by fMet-Leu-Phe and phorbol 12-myristate-13-acetate. 255 25

Production of cAMP- and Ca2+-independent protein kinase was stimulated when rat liver plasma membrane was incubated with increasing concentrations of NaCl. This protein kinase release was diminished by addition of protease inhibitor. The molecular mass of this enzyme was approx. 50 kDa and a high concentration of Mg2+ was required for whole histone phosphorylation. These properties are similar to those of the protease-activated form of protein kinase C. The NaCl effect could be replaced by other salts such as LiCl and NaHCO3. These results suggest that membrane-bound protein kinase C is activated by limited proteolysis corresponding to an increase in ionic strength.
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PMID:Effect of ionic strength on production of cAMP- and Ca2+-independent protein kinase from rat liver plasma membrane. 300 29

Protein kinase C prepared from rat brain was used to phosphorylate a calcium-activated neutral protease, purified from bovine cardiac muscle. Attempts to phosphorylate the enzyme in the presence of calcium were unsuccessful, unless the protease inhibitor leupeptin was also present. Phosphorylation of the 74K subunit of the protease was completely inhibited in the absence of phosphatidylserine and diolein, indicating that phosphorylation of the enzyme was catalysed by the calcium and phospholipid-dependent protein kinase C.
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PMID:Phosphorylation of bovine cardiac calcium-activated neutral protease by protein kinase-C. 301 95

Exposure of quiescent density arrested BALB/c-3T3 cells (clone A31) to platelet-derived growth factor (PDGF; 6-12 ng/ml) results in a rapid, reversible, time- and dose-dependent removal of vinculin from adhesion plaques (Herman and Pledger, 1985). Potential cellular mechanisms involved in PDGF-induced removal of vinculin from adhesion plaques were examined. Removal of vinculin from adhesion plaques following exposure of cells to PDGF was temperature dependent, occurred in many fibroblast cell lines, and could be mimicked by 12-tetradecanoyl phorbol-13-acetate (TPA; 5-125 nM) or melittin (0.35 microM). Unlike the effect of PDGF, TPA- or melittin-induced vinculin disruption was not reversible. The removal of vinculin from adhesion plaques was inhibited by trifluoroperazine (TFP; 2.5 microM). 8-(N,N-diethylamino) octyl-3,4,5-trimethoxy benzoate (TMB-8; 1.0 microM), mepacrine (220 microM), n-alpha-p-tosyl-L-lysine chloromethylketone (TLCK; 100 microM), phenylmethoxysulphonylfluoride (PMSF; 500 microM), and epsilon-aminocaproic acid (epsilon-ACA; 100 microM); however, amiloride (100 microM), A23187 (20 microM), and chloroquine (1 mM) were unable to inhibit this effect. Melittin disruption of vinculin was inhibited by (in order of decreasing effectiveness) mepacrine greater than TMB-8 greater than TFP greater than leupeptin greater than PMSF, whereas A23187 and amiloride had no effect. The return of vinculin to adhesion plaques following PDGF treatment required de novo mRNA transcription and protein synthesis and was associated with PDGF-stimulated synthesis of vinculin. The observation that both PDGF- and melittin-induced removal of vinculin from adhesion plaques is inhibited by mepacrine suggests that phospholipase activation may be an early and important step in PDGF-induced disruption of vinculin from adhesion plaques. In addition, TFP, TMB-8 and protease inhibitor inhibition of both the PDGF and melittin effects on vinculin distribution, coupled with the finding that TPA can mimic the PDGF or melittin response, suggests that Ca2+, calmodulin, protein kinase C, and/or proteolysis may play an important role(s) in the removal of vinculin from adhesion plaques following PDGF addition. The lack of effect of A23187 addition on vinculin distribution suggests that alterations in cellular Ca2+ is necessary but not sufficient for vinculin removal from adhesion plaques.
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PMID:Identification of the cellular mechanisms responsible for platelet-derived growth factor induced alterations in cytoplasmic vinculin distribution. 308 Apr 38

To clarify the role of proteases and protease inhibitors in the initiation and execution of endothelial cell movement, we observed the effect of several protease inhibitors on the polarization and locomotor responses of an endothelial cell monolayer subjected to experimental wounding. We found that the thiol protease inhibitor, E-64 (L-transepoxysuccinyl-leucylamido-[4-guanidino]butane) stimulated both cellular processes. The stimulatory effect of E-64 on the polarization response of cells to wounding required a preincubation period of at least 1 hr, calcium-calmodulin interaction, protein kinase C activation, and was blocked by cyclic AMP analogs. The chemokinetic action of E-64 appears to be unique among the protease inhibitors tested and may represent a novel role for this cysteine protease inhibitor or its endogenous counterpart in the modulation of cell locomotion.
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PMID:The cysteine protease inhibitor, E-64, stimulates the polarization and locomotor responses of endothelial cells to wounding. 312 49

Hexamethylenebisacetamide (HMBA) is a potent inducer of murine erythroleukemia (MEL) cell differentiation. The mechanism of action of HMBA is not known. In this study we provide evidence that protein kinase C has a role in inducer-mediated MEL cell differentiation: (i) HMBA induces the formation of a soluble, proteolytically activated form of protein kinase C that is catalytically active in the absence of Ca2+ and phospholipid; (ii) the protease inhibitor leupeptin blocks formation of this activated form of the kinase and inhibits HMBA-induced MEL cell hemoglobin accumulation; (iii) phorbol 12-myristate 13-acetate (PMA) inhibits HMBA-induced MEL differentiation and causes depletion of total protein kinase C activity; (iv) MEL cells depleted in protein kinase C activity by culture with PMA are resistant to induction by HMBA; (v) upon removal of PMA, restoration of MEL cell sensitivity to HMBA is correlated with reaccumulation of protein kinase C activity; and (vi) MEL cells grown to density arrest are both depleted of protein kinase C activity and resistant to HMBA. Together, these results suggest that HMBA-mediated MEL cell differentiation involves a protein kinase C-related mechanism and the proteolytically activated form of the kinase, which does not require Ca2+ or phospholipid for its catalytic activity.
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PMID:Protein kinase C activity and hexamethylenebisacetamide-induced erythroleukemia cell differentiation. 347 54


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