Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, we have shown that okadaic acid (OA), isolated from black sponge (Halichondria okadai) causes contraction even in the absence of Ca++ in the saponin-permealized taenia isolated from guinea pig cecum. In the present study, mechanism of action of OA was examined using native actomyosin extracted from chicken gizzard smooth muscle. In the absence of Ca++, OA (0.1-1 microM) induced superprecipitation and increased the Mg++-adenosine triphosphatase activity. The OA-induced superprecipitation was enhanced by Ca++ at a concentration (greater than 0.1 microM) which did not activate the calmodulin-dependent myosin light chain (MLC) kinase. The effect of OA was not affected by the calmodulin inhibitor, trifluoperazine, at a concentration (100 microM) needed to inhibit the Ca++-induced response, but was inhibited markedly by the nonselective kinase inhibitors, amiloride (1 mM) and K-252a (5 microM). The OA-induced superprecipitation in the absence of Ca++ was accompanied by phosphorylation of the 20 K dalton MLC, which also was enhanced by low concentration of Ca++ (greater than 0.1 microM). OA did not change the phosphatase activity which dephosphorylates the phosphorylated MLC. An activator of Ca++- and phospholipid-dependent protein kinase, 12-O-tetradecanoylphorbol 13-acetate (1 microM), did not modulate superprecipitation or phosphorylation of MLC in the presence and absence of OA. Furthermore, inhibitors of Ca++ and phospholipid-dependent protein kinase, 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine dihydrochloride (400 microM) and polymyxin B (100 micrograms/ml), affected neither superprecipitation nor phosphorylation of MLC induced by OA. With a reconstituted system containing purified myosin and MLC kinase, OA induced only slight phosphorylation of MLC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcium-independent phosphorylation of smooth muscle myosin light chain by okadaic acid isolated from black sponge (Halichondria okadai). 282 58

The present study was undertaken to determine whether a cAMP pathway mediates the mobility of CD3, CD4, and CD8 within the membrane. Crosslinking CD3, CD4, and CD8 with monoclonal antibody and anti-antibody induced rapid accumulation of intracellular cAMP, occupancy of cAMP receptors, and was temporally associated with the mobilization and directed movement of these molecules to a pole of the cell. This capping process could be partially inhibited in a dose-dependent manner by treatment of T cells with 2',5'-dideoxyadenosine, a ribose-modified adenosine analogue that binds to the P site of the catalytic subunit of adenylate cyclase and reduces adenylate cyclase activity. Furthermore, inhibition of cAMP-dependent endogenous phosphorylation of 17.5-kDa, 23/25-kDa, and 33.5-kDa bands in intact T cells by N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide, a cell-permeable inhibitor of cyclic nucleotide-dependent protein kinase, blocked the capping event. Data support the conclusion that crosslinking of CD3, CD4, and CD8 activates a cAMP-dependent pathway that mediates the mobilization and directed movement of these molecules. cAMP-dependent protein phosphorylation is an integral step leading to the capping process.
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PMID:Mobility of the human T lymphocyte surface molecules CD3, CD4, and CD8: regulation by a cAMP-dependent pathway. 282 2

Cyclic AMP-stimulated mRNA levels in cultured rat hepatocytes were inhibited by three different inhibitors of cAMP-dependent protein kinase activity: (i) Rp-cAMPS, a cAMP analog with a sulfur substitution at the equatorial oxygen of the cyclic monophosphate; (ii) H8, an isoquinoline sulfonamide derivative; and (iii) PKI, a 20-amino acid synthetic peptide of the Walsh protein kinase inhibitor. These inhibitors specifically blocked the cAMP-stimulated increase in mRNA for tyrosine aminotransferase and phosphoenolpyruvate carboxykinase; they had no effect on the level of albumin mRNA which is not cAMP regulated. These results provide functional evidence that kinase activity involving protein phosphorylation is required in cAMP-mediated gene expression in mammalian cells.
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PMID:Catalytic subunit of cAMP-dependent protein kinase is essential for cAMP-mediated mammalian gene expression. 283 Jan 34

The effects of 1-(5-isoquinoline sulphonyl)-2-methyl piperazine (H-7), a recently described inhibitor of Ca2+/phospholipid-dependent protein kinase (protein kinase C), were studied during under-agarose migration of human polymorphonuclear neutrophils (PMN) stimulated by various chemoattractants, in order to determine whether protein kinase C is involved in PMN locomotion. The effect of H-7 on the oxidative burst induced by phorbol 12-myristate 13-acetate or N-formyl-methionyl-leucyl-phenylalanine (FMLP) was also measured. Pre-incubation of PMN with H-7 concentrations ranging from 50 to 400 microM inhibited: (i) spontaneous PMN migration under agarose; (ii) the directed migration induced by activated serum, leukotriene B4 or FMLP; and (iii) the speed of the migration induced by FMLP. The inhibition by H-7 of FMLP-induced directed migration was less when FMLP was used at high concentrations which, in the absence of H-7, inhibit locomotion. H-7 depressed the oxidative burst induced by phorbol myristate acetate (PMA) but not that induced by FMLP. All the effects of H-7 on the oxidative burst and migration were reversed by washing PMN after H-7 treatment. These findings indicate that protein kinase C, inhibitable by H-7, is involved in a mechanism controlling the speed of PMN locomotion.
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PMID:Negative effect of a protein kinase C inhibitor (H-7) on human polymorphonuclear neutrophil locomotion. 283 13

Rabbit peritoneal neutrophils were stimulated with either the chemotactic factor, fMet-Leu-Phe (10(-8) M, 10 s) or the protein kinase C activator, phorbol-12-myristate-13-acetate (PMA), (0.1 microgram/ml, 3 min) at 37 degrees C, lysed with Triton X-100 at the indicated times and the histone H4 kinase activity of the lysate measured. The histone H4 protein kinase activity was increased severalfold by fMet-Leu-Phe but not PMA. The inclusion of the potent protein kinase C inhibitor, 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine (50 microM) inhibited little if any of the histone H4 protein kinase activity. The effect of fMet-Leu-Phe was transient, maximum stimulation occurring within 10 s and decaying thereafter. The soluble fraction (extract) of the Triton X-100 lysates from control and fMet-Leu-Phe-treated cells was found to contain both histone H4 protein kinase and calcium-phospholipid-activated protein kinase (protein kinase C) activities. The histone H4 protein kinase activity obtained after fMet-Leu-Phe treatment was very little affected by calcium, phospholipid, and PMA and preferred histone H4 but not H1 or H2A as its substrate. In contrast, the calcium-phospholipid-activated protein kinase activity of the extract preferred histones H1 or H2A as substrates and was strongly inhibited by 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine. The histone H4 protein kinase was partially separated from kinase C by DEAE-cellulose and phenyl-Sepharose 4B chromatography. It phosphorylated mostly serine in histone H4. The results indicate that the chemotactic factor, fMet-Leu-Phe, stimulates a protein kinase with substrate specificity and biochemical properties distinct from calcium-phospholipid-activated protein kinase C.
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PMID:Stimulation of a histone H4 protein kinase in Triton X-100 lysates of rabbit peritoneal neutrophils pretreated with chemotactic factors. Effect of fMet-Leu-Phe and partial characterization of the protein kinase. 284 11

Isoquinoline sulfonamides have recently been shown to exert novel inhibitory effects on mammalian protein kinases by competitively binding to the ATP substrate site (Hidaka, H., M. Inagaki, S. Kawamoto, and Y. Sasaki, 1984, Biochemistry, 23: 5036-5041). We synthesized a unique analog of the previously reported compounds, 1-(5-isoquinolinesulfonyl) piperazine (C-I), in order to assess the role of protein kinases in modulating the agonist-stimulated oxidative burst of human polymorphonuclear leukocytes (PMN). Compound C-I, at micromolar concentration, markedly inhibited the release of superoxide anion from human PMN stimulated with phorbol myristate acetate or the synthetic diacylglycerol, 1-oleoyl-2-acetyl glycerol. These data are consonant with previously reported data which indicate that the calcium and phospholipid-dependent protein kinase, protein kinase C, serves as the intracellular receptor for these agonists. In contrast, superoxide anion production stimulated by the complement anaphylatoxin peptide C5a or the synthetic chemotaxin formyl-methionyl-leucyl-phenylalanine were not inhibited by C-I. These data suggest that parallel pathways exist for the agonist-stimulated respiratory burst of human neutrophils, only one of which utilizes the calcium and phospholipid-dependent protein kinase.
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PMID:Role of protein kinases in stimulation of human polymorphonuclear leukocyte oxidative metabolism by various agonists. Differential effects of a novel protein kinase inhibitor. 300 55

To elucidate the biological mechanisms of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced phenotypic changes in HTLV-I virus-infected human T-cell line KH-2Lo cells, inhibitors of TPA-induced ornithine decarboxylase (ODC), protein kinases and calmodulin were examined for their effects on TPA-induced multinucleated cell formation and HTLV-I p19 antigen expression. Among the inhibitors of TPA-induced ODC activity, alpha-difluoromethyl ornithine (DFMO), 1,25(OH)2D3 and its analogues, and retinoic acid were tested. As inhibitors of protein kinases, 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7), N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide (H-8) and 1,(5-isoquinolynylsulfonyl)-2,3-dimethylpiperazine (H-5) were used. In addition, a calmodulin inhibitor, N-(4-aminobutyl)-5-chlor-2-naphthalenesulfonamide (W13) and its inactive analogue, N-(4-aminobutyl)-2-naphthalenesulfonamide (W12) were also tested. 1,25(OH)2D3 and its active analogues inhibited both TPA-induced HTLV-I p19 antigen expression and multinucleated cell formation after 4 days of culture with TPA. On the other hand, an inhibitor of ODC, DFMO, the protein kinase inhibitors, the calmodulin inhibitor and retinoic acid suppressed TPA-induced HTLV-I p19 expression but did not suppress multinucleated cell formation.
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PMID:Inhibitors of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced multinucleated cell formation and HTLV-I p19 antigen expression in HTLV-I-infected T-cell line KH-2Lo. 301 86

Naphthalenesulfonamides such as N-(6-amino-hexyl)-5-chloro-1-naphthalenesulfonamide (W-7) are potent calmodulin (CaM) antagonists and act upon several protein kinases at higher concentration. When the naphthalene ring was replaced by isoquinoline, the derivatives were no longer CaM antagonists but retained the ability to inhibit protein kinases, and some of the derivatives exhibited selective inhibition toward a certain protein kinase. cAMP-dependent, cGMP-dependent, and Ca2+-phospholipid-dependent (protein kinase C) protein kinases were inhibited significantly by addition of 10(-6) M N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide (H-8) and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7). H-8 was the most active of the inhibitors in this series and inhibited more markedly cyclic nucleotide dependent protein kinases, than other kinases, while the derivative with the sulfonylpiperazine residue (H-7) was the most potent in inhibiting protein kinase C. Apparent Ki values of H-8 were 0.48 and 1.2 microM for cGMP-dependent and cAMP-dependent protein kinases, respectively, and the Ki value of H-7 for protein kinase C was 6 microM. Both the holoenzyme and the catalytic subunit (or fragment), which is active without an enzyme activator, are susceptible to these compounds with a similar concentration dependency, thereby indicating that the inhibitory effect is attributed to the direct interaction of the compound with the active center of the enzyme but not with the enzyme activator. The inhibitions were freely reversible and of the competitive type with respect to ATP and of the noncompetitive type with respect to the phosphate acceptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. 623 27

The effects of the membrane-permeable cGMP analogue, 8-bromoguanosine 3':5'-cyclic monophosphate on acetylcholine-evoked catecholamine secretion and cytosolic calcium increases were studied in chromaffin cells from the bovine adrenal gland. Preincubation with 100 microM 8-bromoguanosine 3':5'-cyclic monophosphate during 10 and 30 min decreased the acetylcholine-evoked catecholamine release by 16 +/- 3% and 27 /+- 5%, respectively. The cytosolic calcium increases triggered by acetylcholine and 30 mM KCl were also inhibited by 30 min of preincubation with this compound by 27 +/- 4 and 34 /+- 12%, respectively. Changes in membrane potential induced by acetylcholine and KCl were not affected by preincubation with 8-bromoguanosine 3':5'-cyclic monophosphate. The cyclic GMP-dependent protein kinase inhibitor N-[2-(methylamino)ethyl]-5-isoquinoline sulfonamide dihydrochloride-at l micron abolished the inhibitory effect of 8-bromoguanosine 3':5'-cyclic monophosphate on acetylcholine-evoked calcium increase. By contrast, a potent and selective inhibitor against cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide did not block the 8-bromoguanosine 3':5'-cyclic monophosphate effect. Additionally, 8-bromoguanosine 3':5'-cyclic monophosphate stimulated histone F2b phosphorylation by a partial purified cGMP-dependent protein kinase from chromaffin cells. The extent of histone phosphorylation was reduced by N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride and 8-(4-chlorophenylthio)-guanosine 3':5'-cyclic monophosphorothioate, Rp-isomer, a specific inhibitor against cyclic GMP-dependent protein kinase, whereas it was not modified by N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline sulfonamide. The results suggest that the inhibitory effects of 8-bromoguanosine 3':5' cyclic monophosphate on chromaffin cells are mediated through the activation of cGMP-dependent protein kinase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic GMP-dependent protein kinase activation mediates inhibition of catecholamines secretion and Ca2+ influx in bovine chromaffin cells. 747 95

Available data indicate that adipocytes are targets for PTH action, and chronic excess of PTH increases calcium burden of fat tissue, suggesting that PTH increases entry of calcium into adipocytes. The present study examined the effects of PTH-(1-84) and its amino-terminal fragment, PTH-(1-34), on cytosolic calcium ([Ca2+]i) of adipocytes and evaluated the cellular pathways that mediate the potential effect of PTH on [Ca2+]i of these cells. PTH-(1-84) but not PTH-(1-34) produced a dose-dependent rise in [Ca2+]i of adipocytes. This effect occurred in the presence or absence of calcium in the media, but the magnitude of the rise in [Ca2+]i was significantly greater when calcium was present in the media. The PTH antagonist [Nle8,18Tyr34]bPTH(7-34)NH2, verapamil, and nifedipine blocked to variable degrees the PTH-induced rise in [Ca2+]i. The phorbol ester 12-O-tetradecanoyl phorbol-13-acetate, and the GTP-binding protein (G protein) GTP gamma S also produced a dose-dependent rise in [Ca2+]i of adipocytes. These effects were inhibited by staurosporine and the G protein inhibitor guanosine 5'-O-1(2-thiodiphosphate), respectively. Similary, staurosporine, calphostin C, guanosine 5'-O-1(2-thiodiphosphate), and pertussis toxin inhibited the effect of PTH on [Ca2+]i of adipocytes. (Bu)2cAMP also increased [Ca2+]i of adipocytes, but PTH did not stimulate cAMP production by adipocytes, and N-[2(p-bromocin-namylamino)ethyl]5-isoquinoline-sulfonamide, an inhibitor of protein kinase A, did not affect the PTH-induced rise in [Ca2+]i of adipocytes. The data indicate that: 1) PTH-(1-84) increases [Ca2+]i of adipocytes; 2) this action of the hormone is receptor mediated; 3) the hormone uses a G protein activation of calcium channels and the phospholipase C pathway in mediating its action on [Ca2+]i; and 4) the rise in [Ca2+]i is due to both increased calcium influx into the adipocytes and mobilization of calcium from intracellular stores.
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PMID:Effects of parathyroid hormone on cytosolic calcium of rat adipocytes. 752 54


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