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)

We examined the effect of basic fibroblast growth factor (bFGF) on the activation of phosphatidylcholine-hydrolyzing phospholipase D in osteoblast-like MC3T3-E1 cells. bFGF stimulated both the formations of choline (EC50 was 30 ng/ml) and inositol phosphates (EC50 was 10 ng/ml). Calphostin C, an inhibitor of protein kinase C (PKC), had little effect on the bFGF-induced formation of choline. bFGF stimulated the formation of choline also in PKC down regulated cells. Genistein and methyl 2,5-dihydroxycinnamate, inhibitors of protein tyrosine kinases, significantly suppressed the bFGF-induced formation of choline. Sodium orthovanadate, an inhibitor of protein tyrosine phosphatases, enhanced the bFGF-induced formation of choline. In vitro kinase assay for FGF receptors revealed that FGF receptor 1 and 2 were autophosphorylated after FGF stimulation. bFGF dose-dependently stimulated DNA synthesis of these cells. These results strongly suggest that bFGF activates phosphatidylcholine-hydrolyzing phospholipase D through the activation of tyrosine kinase, but independently of PKC activated by phosphoinositide hydrolysis in osteoblast-like cells.
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PMID:Basic fibroblast growth factor stimulates phosphatidylcholine-hydrolyzing phospholipase D in osteoblast-like cells. 897 64

The involvement of protein kinase C (PKC) and protein tyrosine kinase (PTK) in hypercapnia-induced cerebral vasodilation in newborn pigs was investigated with closed cranial windows using the PKC stimulator phorbol 12-myristate 13-acetate (PMA), and the PTK inhibitors, genistein and herbimycin A. The influence of prostaglandin I2 was eliminated using the prostaglandin cyclooxygenase inhibitor, indomethacin. Changes in pial arteriolar diameters in response to hypercapnia [partial pressure of arterial CO2 approximately 9.3 kPa (70 torr)] were analyzed. Genistein (40 micrograms/mL), herbimycin A (10 microM), or PMA (1 microM) did not affect cerebral vasodilation to hypercapnia when applied topically. Indomethacin (5 mg/kg i.v.) treatment blocked the dilation to hypercapnia and attenuated hypercapnia-induced increase in cortical cAMP. Genistein and herbimycin A restored the response to hypercapnia to indomethacin-treated piglets. PMA also restored the pial arteriolar dilation and the cAMP response to hypercapnia to indomethacin-treated piglets. One-hour exposure to 10 microM PMA, to down-regulate PKC, blocked vasodilation to hypercapnia but did not inhibit vasodilation to sodium nitroprusside. After prolonged (2 h) topical exposure of indomethacin-treated piglets to 10 microM PMA, neither genistein nor iloprost could restore dilation to hypercapnia. These results indicate that PKC stimulation and/or PTK inhibition may permit hypercapnia-induced vasodilation. These data further suggest that PKC is downstream from PTK in the regulatory pathway. Because previous data showed prostaglandin I2 at subdilator concentrations can also return dilation to hypercapnia to piglets treated with indomethacin, prostaglandin I2 could provide its permissive input by activating PKC and/or inhibiting PTK.
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PMID:Protein kinase Cs and tyrosine kinases in permissive action of prostacyclin on cerebrovascular regulation in newborn pigs. 897 94

We have previously shown a direct stimulatory effect of insulin on NaCl absorption in the medullary thick ascending limb of Henle's loop (mTAL). To further investigate the signal transduction involved, we determined whether tyrosine kinase, phosphatidylinositol 3-kinase (PI3-kinase), and/or protein kinase C (PKC) regulate insulin-stimulated NaCl absorption in the mTAL by in vitro microperfusion methods. In control experiments, insulin increased transepithelial voltage (V(te)) and net lumen-to-bath Cl- flux (J(Cl)). Genistein and methyl 2,5-dihydroxycinnamate, two specific tyrosine kinase inhibitors, abolished the effects of insulin. Wortmannin, a specific PI3-kinase inhibitor, inhibited the action of insulin. The effects of insulin also were inhibited by staurosporin and calphostin C, which are dissimilar inhibitors of PKC. These results indicate that insulin stimulates NaCl absorption in the mTAL through tyrosine kinase, PI3-kinase, and PKC-mediated mechanisms. Moreover, because we have reported previously that insulin causes no detectable change in cytosolic free Ca2+ in the mTAL cells, the present results also suggest that insulin-induced PKC activation is not related to inositol 1,4,5-triphosphate (IP3) production.
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PMID:Tyrosine kinase, phosphatidylinositol 3-kinase, and protein kinase C regulate insulin-stimulated NaCl absorption in the thick ascending limb. 908 68

PGF2alpha stimulates the proliferation of clonal osteoblastic MC3T3-E1 cells via PGF2alpha receptor linked to phospholipase C activation. To elucidate intracellular events elicited by this receptor, we examined the effects of PGF2alpha on tyrosine phosphorylation and mitogen-activated protein kinase (MAPK) activity in MC3T3-E1 cells. PGF2alpha rapidly raised the level of phosphotyrosine of cellular proteins with Mr values of 62, 68, 72, 76, 82, 125, and 150 kDa. This PGF2alpha-induced tyrosine phosphorylation of proteins (except for pp62) was blocked by down-regulating protein kinase C (PKC) by 12-O-tetradecanoylphorbol 13-acetate pretreatment and by GF 109203X, a potent specific PKC inhibitor. The addition of PGF2alpha also transiently activated MAPK in the same range of concentrations that stimulated tyrosine phosphorylation. In addition, PGF2alpha augmented the MAPK kinase kinase activity of Raf-1, whereas basal activity of MAPK/extracellular signal-regulated protein kinase kinase was less than that of Raf-1 and was little affected by PGF2alpha. Like the tyrosine phosphorylation, these activations of Raf-1 and MAPK activities were reduced by inhibition and down-regulation of PKC. Genistein, a potent inhibitor of tyrosine kinases, did not block the Raf-1 induced by PGF2alpha, indicating a tyrosine kinase-independent pathway for Raf-1 activation. However, the tyrosine kinase inhibitor partially inhibited the MAPK activity, suggesting an involvement of another Raf-1-independent kinase cascade for activation of MAPK by PGF2alpha. Fluprostenol, a specific agonist of PGF2alpha receptor, mimicked the actions of PGF2alpha consistent with a PGF2alpha receptor pathway. Thus, the action of PGF2alpha on osteoblastic MC3T3-E1 cells appears to involve a single receptor that uses diverse interacting signal transduction systems.
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PMID:Prostaglandin F2alpha stimulates tyrosine phosphorylation and mitogen-activated protein kinase in osteoblastic MC3T3-E1 cells via protein kinase C activation. 911 74

The prenylated isoflavone warangalone from the insecticidal plant Derris scandens is a selective and potent inhibitor of rat liver cyclic AMP-dependent protein kinase catalytic subunit (cAK) (IC50 3.5 microM). The inhibition of rat liver cAK by warangalone is non-competitive with respect to both ATP and the synthetic peptide substrate (LRRASLG) employed in this study. Warangalone is a poor inhibitor of avian calmodulin-dependent myosin light chain kinase (MLCK), rat brain Ca(2+)- and phospholipid-dependent protein kinase C (PKC) and wheat embryo Ca(2+)-dependent protein kinase (CDPK). The related plant derived prenylisoflavones are also potent cAK inhibitors. Thus, 8-gamma-gamma-dimethylallylwighteone, 3' -gamma-gamma-dimethlallylwighteone and nallanin are inhibitors of cAK with IC50 values in the range 20-33 microM. The prenyl-substituted isoflavones tested in this study are ineffective or poor as inhibitors of PKC. Thus nallanin is a poor PKC inhibitor (IC50 value of 120 microM). The related isoflavones biochanin A and genistein are poor inhibitors of cAK (IC50 values 100 microM and 126 microM, respectively). Genistein inhibits MLCK (IC50 value 14 microM) but biochanin A is a poor MLCK inhibitor (IC50 value 300 microM). The D. scandens prenyl-isoflavones and related isoflavones are ineffective inhibitors of wheat embryo Ca(2+)-dependent protein kinase (CDPK). The 4-methoxy-3-phenyl-coumarin robustic acid is a potent inhibitor of rat liver cAK (IC50 value 10 microM) but is a poor inhibitor of rat brain PKC, avian MLCK and wheat embryo CDPK. The coumarins 5-methoxypsoralen and 4,4'-di-O-methyl scandenin are poor cAK inhibitors (IC50 values 240 and 248 microM, respectively). All of the non-prenylated coumarins examined are ineffective as inhibitors of the eukaryote signal-regulated protein kinases cAK, MLCK, PKC and CDPK. The selective, high affinity interaction of warangalone and robustic acid with cAK may contribute to their biological effects in vivo and to the insecticidal activity of the plant D. scandens.
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PMID:Specific inhibition of cyclic AMP-dependent protein kinase by warangalone and robustic acid. 911 91

Two glial cell populations of the CNS, astrocytes and microglia, were examined for expression of two immunologically important molecules, MHC class II and nitric oxide (NO), following treatment with cytokines. IFN-gamma induced both molecules in microglia at substantially higher levels than astrocytes. The addition of TNF-alpha to IFN-gamma elevated class II expression and NO in both cells. Genistein, an inhibitor of tyrosine kinases, and calphostin, an inhibitor of protein kinase C, diminished cytokine induction of class II MHC and NO in both glial populations. Forskolin was most effective in inhibiting class II MHC expression, but had little inhibitory effect on NO production. These results indicate microglia are more effective than astrocytes in producing cell-associated and secreted immune mediators in response to IFN-gamma and or TNF-alpha and multiple parallel, but distinct, signaling events are required for cytokine induced class II MHC or NO production.
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PMID:Differential regulation of cytokine-induced major histocompatibility complex class II expression and nitric oxide release in rat microglia and astrocytes by effectors of tyrosine kinase, protein kinase C, and cAMP. 911 73

The effect of 2-chloroadenosine (2CA), an adenosine receptor agonist, on the activation status of mouse natural killer (NK) cells was determined. Splenic lymphocytes incubated with 2CA exocytosed an NK cell-associated granzyme with N alpha-CBZ-L-lysine thiobenzyl ester (BLT) esterase activity in a dose- and time-dependent manner. Selective depletion of NK cells by anti-asialoGM1 antibody plus complement pretreatment confirmed that NK cells were the source of the BLT esterase activity. 2CA-induced granule exocytosis was not reduced in the presence of the nucleoside uptake blockers NBTI, dilazep, or dipyridamole, indicating the involvement of an extracellular receptor. However, adenosine or other A1, A2, or A3 cell-surface adenosine receptor agonists failed to trigger the exocytotic process. Furthermore, the nonselective adenosine receptor antagonist theophylline, as well as the selective A1 receptor antagonist DPCPX and the selective A2 receptor antagonist DMPX, did not interfere with 2CA-induced BLT esterase secretion. These data suggest that 2CA acts on NK cells via a novel (non-A1/A2/A3) cell-surface receptor. Genistein, a protein tyrosine kinase inhibitor, and calphostin C, a protein kinase C inhibitor, both interfered with 2CA-induced granule exocytosis. Pertussis toxin, an ADP-ribosylating toxin to which certain GTP-binding proteins are sensitive, also inhibited 2CA-stimulated BLT esterase release. In addition, 2CA-induced granule exocytosis was reduced in the presence of cyclosporin A, an inhibitor of Ca(2+)-dependent signaling pathways, and the Ca(2+)-chelating agent EGTA. We conclude that 2CA, acting through a novel extracellular receptor on mouse NK cells, triggers granule exocytosis via a Ca(2+)-dependent signal transduction pathway that is coupled to GTP-binding proteins and involves protein tyrosine kinase and protein kinase C activation.
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PMID:2-chloroadenosine stimulates granule exocytosis from mouse natural killer cells: evidence for signal transduction through a novel extracellular receptor. 918 87

Zooxanthellatoxin-A (ZT-A), a polyhydroxypolyene isolated from a symbiotic dinoflagellate Symbiodinium sp., caused thromboxane A2-(TXA2) dependent and genistein-sensitive aggregation in rabbit platelets. Our study was performed to clarify the mechanism of the action of ZT-A. ZT-A caused an increase in tyrosine phosphorylation of 42-kDa protein, which is defined as p42 mitogen-activated protein kinase (MAPK) by immunoprecipitation. Although indomethacin (10 microM) completely inhibited ZT-A-induced TXB2 release, it partially inhibited the MAPK activation. The remained MAPK activation was completely inhibited by genistein (50 microM). Genistein (50 microM), by itself, abolished TXB2 release induced by ZT-A. ZT-A (2 microM) stimulated liberation of arachidonic acid and the subsequent metabolites such as TXB2 and 12-hydroperoxyeicosatetraenoic acid. However, ZT-A-stimulated phosphoinositide hydrolysis which was due to an increase in tyrosine phosphorylation of phospholipase C-(PLC)gamma2. The phosphorylation of PLC-gamma2 and the phosphoinositide hydrolysis were also partially inhibited by indomethacin (10 microM), and were abolished by a combined treatment of indomethacin (10 microM) and genistein (50 microM). ZT-A- (2 microM) induced MAPK activation in the presence of indomethacin (10 microM) was concentration-dependently inhibited by staurosporine and calphostin C, protein kinase C inhibitors. PD98059 (50 microM), a MAPK kinase inhibitor, also inhibited ZT-A-induced TXB2 release. Depletion of external Ca++ abolished ZT-A- (2 microM) induced MAPK activation, phosphoinositide hydrolysis, arachidonic acid liberation and TXB2 release. These results suggest that ZT-A stimulates a protein tyrosine kinase in the presence of external Ca++, resulting in the activation of MAPK probably via PLC-gamma2 and protein kinase C. The MAPK stimulated a liberation of arachidonic acid that is rapidly converted to TXA2. The released TXA2 causes aggregation accompanied with second stimulation of MAPK cascade.
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PMID:Involvement of phospholipase C-gamma2 in activation of mitogen-activated protein kinase and phospholipase A2 by zooxanthellatoxin-A in rabbit platelets. 922 92

We have previously reported a delayed or "second window of protection" against infarction 24-72 h after ischemic preconditioning in the rabbit. This phenomenon has also been associated with the protein kinase C signalling pathway. In the present study, we expanded our investigation to ascertain whether protein tyrosine kinase was in any way associated with this phenomenon in the rabbit heart. We found that 48 h after ischemic preconditioning with 4x5 min coronary occlusions the percentage of myocardium infarcting within the risk zone following a 30-min coronary occlusion and 120-min reperfusion (I/R) was reduced from 39. 6+/-3.3% to 18.0+/-3.7% (P<0.01). However, an i.v. bolus administration of genistein (5 mg/kg), a tyrosine kinase inhibitor, 5 min before ischemic preconditioning stimulus, abolished this protection (I/R=39.0+/-3.4%). Genistein per se had no significant effect on infarction 48 h later. Risk zone volume after coronary ligation was not significantly different between intervention groups. There were no differences in hemodynamic parameters between groups throughout the experimental period. We conclude that the second window of protection, 48 h after preconditioning, is mediated by tyrosine kinase activation in the rabbit heart.
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PMID:Genistein, a tyrosine kinase inhibitor, blocks the "second window of protection" 48 h after ischemic preconditioning in the rabbit. 923 42

1. Inhalation of vanadium compounds, particularly vanadate, is a cause of occupational bronchial asthma. We have now studied the action of vanadate on human isolated bronchus. Vanadate (0.1 microM-3 mM) produced concentration-dependent, well-sustained contraction. Its -logEC50 was 3.74 +/- 0.05 (mean +/- s.e.mean) and its maximal effect was equivalent to 97.5 +/- 4.2% of the response to acetylcholine (ACh, 1 mM). 2. Vanadate (200 microM)-induced contraction of human bronchus was epithelium-independent and was not inhibited by indomethacin (2.8 microM), zileuton (10 microM), a mixture of atropine, mepyramine and phentolamine (each at 1 microM), or by mast cell degranulation with compound 48/80. 3. Vanadate (200 microM)-induced contraction was unaltered by tissue exposure to verapamil or nifedipine (each 1 microM) or to a Ca2+-free, EGTA (0.1 mM)-containing physiological salt solution (PSS). However, tissue incubation with ryanodine (10 microM) in Ca2+-free, EGTA (0.1 mM)-containing PSS reduced vanadate-induced contraction. A series of vanadate challenges was made in tissues exposed to Ca2+-free EGTA (0.1 mM)-containing PSS with the object of depleting intracellular Ca2+ stores. In such tissues cyclopiazonic acid (CPA; 10 microM) prevented Ca2+-induced recovery of vanadate-induced contraction. 4. Tissue incubation in K+-rich (80 mM) PSS, K+-free PSS, or PSS containing ouabain (10 microM) did not alter vanadate (200 microM)-induced contraction. Ouabain (10 microM) abolished the K+-induced relaxation of human bronchus bathed in K+-free PSS. This action was not shared by vanadate (200 microM). The tissue content of Na+ was increased and the tissue content of K+ was decreased by ouabain (10 microM). In contrast, vanadate (200 microM) did not alter the tissue content of these ions. Tissue incubation in a Na+-deficient (25 mM) PSS or in PSS containing amiloride (0.1 mM) markedly inhibited the spasmogenic effect of vanadate (200 microM). 5. Vanadate (200 microM)-induced contractions were markedly reduced by tissue treatment with each of the protein kinase C (PKC) inhibitors H-7 (10 microM), staurosporine (1 microM) and calphostin C (1 microM). Genistein (100 microM), an inhibitor of protein tyrosine kinase, also reduced the response to vanadate. 6 Vanadate (0.1-3 mM) and ACh (1 microM- 3 mM) each increased inositol phosphate accumulation in bronchus. Such responses were unaffected by a Ca2+-free medium either alone or in combination with ryanodine (10 microM). 7. In human cultured tracheal smooth muscle cells, histamine (100 microM) and vanadate (200 microM) each produced a transient increase in intracellular Ca2+ concentration ([Ca2+]i). 8. Intracellular microelectrode recording showed that the contractile effect of vanadate (200 microM) in human bronchus was associated with cellular depolarization. 9. It is concluded that vanadate acts directly on human bronchial smooth muscle, promoting the release of Ca2+ from an intracellular store. The Ca2+ release mechanism involves both the production of inositol phosphate second messengers and inhibition of Ca-ATPase. The activation of PKC plays an important role in mediating vanadate-induced contraction at values of [Ca2+]i that are close to basal.
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PMID:The spasmogenic effects of vanadate in human isolated bronchus. 925 12


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