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)

Five major polypeptides of 70, 50, 47, 19 and 17 kDa and four minor polypeptides (100, 65, 45 and 39 kDa) become phosphorylated when clathrin-coated vesicles (CCV) from zucchini hypocotyls are incubated in [gamma 32P]Mg-ATP. After dissociation with 0.5 M Tris/HCl the CCV coat polypeptides were subjected to gel filtration in order to separate clathrin triskelions from beta-adaptin-containing fractions. Only the latter bore kinase activities, with phosphorylated polypeptides of 39 kDa in addition to the 50, 19-kDa and 17-kDa polypeptides just mentioned. Heparin, an inhibitor of casein kinase II, permitted the phosphorylation of only the 19-kDa and 17-kDa polypeptides. Staurosporine, an inhibitor of protein kinase c-like activities, prevented the phosporylation of the 70-kDa polypeptide. When recombined with the triskelions the beta-adaptin fractions achieved the phosphorylation of the 45-kDa and 70-kDa polypeptides. Because of its heat stability and calcium-binding properties we interpret the 45-kDa polypeptide as being a clathrin light chain. Antibodies raised against the 70-kDa group of heat-shock proteins (Hsp70) recognize a 70-kDa polypeptide in the beta-adaptin-containing fractions. Because this polypeptide only phosphorylates in the presence of triskelions we consider it to be the uncoating ATPase, which is known to aggregate upon dissociation of the CCV coat. Our results therefore indicate that zucchini CCV contain a number of phosphorylable polypeptides equivalent to the beta, mu and sigma adaptins of bovine brain. Just as in bovine brain CCV a casein-kinase-II-like activity is associated with the zucchini CCV 50/47-kDa polypeptides, further pointing to their identity as plant mu2/mu1 adaptin equivalents.
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PMID:Localization and properties of kinases in clathrin-coated vesicles from zucchini hypocotyls. 885 56

Epidermal growth factor (EGF) is a potent mitogen for many cell types; however, the best known effect of EGF on gastric parietal cell HCl secretion is inhibition of this response. Using rabbit parietal cells in primary culture, we recently showed that the effect of EGF is biphasic with acute inhibition followed by sustained enhancement of acid secretory-related responses. We hypothesized that EGF might activate a mitogen-activated protein (MAP) kinase signaling pathway in parietal cells, and this pathway might play a role in mediating sustained and/or acute effects of EGF on parietal cell acid secretory-related functions [C. S. Chew, K. Nakamura, and A. C. Petropolous. Am. J. Physiol. 267 (Gastrointest. Liver Physiol. 30): G818-G826, 1994]. We used several methodological approaches to demonstrate the presence of MAP kinase (MAPK) isoforms, extracellular signal-regulated kinases (ERKs) 1 and 2, in parietal cells and to begin to characterize their mechanisms of activation in this highly differentiated cell type. In acutely isolated, 90-98% enriched parietal cells, EGF biphasically activated ERK-1 and ERK-2, with peak response occurring at approximately 5 min followed by a sustained lower level of activation for at least 2 h. The EC50 for EGF (1.2 +/- 0.4 nM) was similar to the previously determined EC50 for the stimulatory effect of EGF on acid secretory responses. In contrast to EGF, the phorbol ester protein kinase C activator 12-O-tetradecanoylphorbol 13-acetate (TPA) induced a sustained activation of ERK-1 and ERK-2 for at least 2 h. Carbachol also activated ERK-1 and ERK-2; however, this response was weaker and monophasic. Neither the Ca2+ ionophore ionomycin nor the adenylyl cyclase activator forskolin altered basal or stimulated ERK activity. Carbachol, but not EGF or TPA, also activated an unidentified 70-kDa protein kinase as detected with in-gel myelin basic protein (MBP) kinase renaturation assays. Parietal cell MAPK activation was not correlated to a shift in apparent relative molecular mass on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels, suggesting that basal phosphorylation of ERK isoforms may be higher in parietal cells compared with actively proliferating cell lines. Also, in contrast to observations in neutrophils, the phosphatidylinositol 3-kinase (PtdIns 3-kinase) inhibitor, wortmannin (0.3-3 microM), failed to inhibit ERK activation in response to EGF, carbachol, or TPA. The combined data indicate that 1) EGF, TPA, and carbachol activate overlapping as well as distinct intracellular signaling pathways in gastric parietal cells, 2) EGF activates ERKs and enhances parietal cell acid secretory related functions via receptors with similar affinities, and 3) in contrast to some cell types, the parietal cell ERK-signaling cascade does not appear to be directly modulated by the PtdIns 3-kinase pathway or by elevated intracellular free Ca2+ or adenosine 3',5'-cyclic monophosphate concentrations.
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PMID:Parietal cell MAP kinases: multiple activation pathways. 889 83

The intracellular signaling pathways responsible for tumor necrosis factor (TNF)-alpha stimulation of lymphocyte adhesion to brain microvascular endothelial cells (BMEC) were studied using inhibitors of protein kinase C (bisindolylmaleimide HCl, H-7, or staurosporine), or protein tyrosine kinase (genistein). Each of these blocked the ability of BMEC to respond to TNF-alpha. In contrast, BMEC treated with H-89, an inhibitor of protein kinase A, or the adenylate cyclase inhibitor, dideoxyadenosine, responded normally to TNF-alpha. Forskolin, an adenylate cyclase agonist, significantly increased lymphocyte adhesion to BMEC. These data indicate that intracellular signaling by TNF-alpha in BMEC is mediated through a protein kinase C and tyrosine kinase dependent pathway.
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PMID:Intracellular signaling of tumor necrosis factor-alpha in brain microvascular endothelial cells is mediated by a protein tyrosine kinase and protein kinase C-dependent pathway. 889 28

We investigated the inhibitory effects of intracellular cyclic adenosine monophosphate (cAMP) levels in regulating class 3 aldehyde dehydrogenase (aldh3) gene expression using cultures of primary rat hepatocytes and transient transfection experiments with HepG2 cells. In addition to regulation by an Ah receptor-dependent mechanism, expression of many members of the Ah gene battery have been shown to be negatively regulated. As was seen for the cytochrome P450 (cyp1A1) gene, aldh3 is transcriptionally inducible by polycyclic aromatic hydrocarbons (PAH), and this induction involving function of the arylhydrocarbon (Ah) receptor is inhibited by the protein kinase C (PKC) inhibitors, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine di-HCl (H7) and staurosporine. However, PAH induction of ALDH-3 activity, protein, and mRNA was potentiated 2-4-fold by addition of the protein kinase A (PKA) inhibitors, N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide di-HCl (H8) and N-(2-guanidinoethyl)-5-isoquinolinesulfonamide HCl (HA1004). These PKA inhibitors had no effect on the PAH induction of the cyp1A1. Protein kinase A activity of cultured hepatocytes was specifically inhibited by H8 and HA1004 in a concentration-dependent manner, but not by H7, and there was an inverse correlation observed between potentiation of PAH-induced aldh3 gene expression and inhibition of specific PKA activity by the PKA inhibitors. The cAMP analog dibutyryl cAMP, the adenylate cyclase activator forskolin, and the protein phosphatase 1 and 2A inhibitor okadaic acid all dramatically inhibited both PAH induction and H8 potentiation of PAH induction of aldh3 expression but had no effect on induction of cyp1A1 expression in cultured hepatocytes. Both basal and PAH-dependent expression of a chloramphenicol acetyltransferase expression plasmid containing approximately 3.5 kilobase pairs of the 5'-flanking region of aldh3 (pALDH3.5CAT) were enhanced 3-4-fold by the PKA inhibitor H8 but not by the PKC inhibitor H7 (>20 microM). cAMP analogs, activators of PKA activity, or protein phosphatase inhibitors diminished expression of the reporter gene in a manner identical to the native gene in cultured rat hepatocytes. Using deletion analysis of the pALDH3.5CAT construct, we demonstrated the existence of a negative regulatory region in the 5'-flanking region between -1057 and -991 base pairs which appears to be responsible for the cAMP-dependent regulation of this gene under both basal and PAH-induced conditions. At least two apparently independent mechanisms which involve protein phosphorylation regulate aldh3 expression. One involves function of the Ah receptor which requires PKC protein phosphorylation to positively regulate both aldh3 and cyp1A1 gene expression and the other a cAMP-responsive process which allows PKA activity to negatively regulate expression of aldh3 under either basal or inducible conditions.
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PMID:cAMP-dependent negative regulation of rat aldehyde dehydrogenase class 3 gene expression. 901 60

Insulin mediators (inositol phosphoglycans) have been shown to mimic insulin action in vitro and in intact mammals, but it is not known which mediator is involved in insulin action under physiological conditions, nor is it known whether insulin resistance alters the mediator profile under such conditions. We therefore investigated the effects of glucose ingestion on changes in the bioactivity of serum inositol phosphoglycan-like substances (IPG) in healthy men and insulin resistant (obese, non-insulin-dependent diabetic) men. Two classes of mediators were partially purified from serum before and after glucose ingestion. The first was eluted from an anion exchange resin with HCl pH 2.0, and bioactivity was determined by activation of pyruvate dehydrogenase in vitro. The second was eluted with HCl pH 1.3, and bioactivity was determined by inhibition of cyclic AMP-dependent protein kinase. In healthy men, the bioactivity of the pH 1.3 IPG was not altered by glucose ingestion, whereas bioactivity of the pH 2.0 IPG increased to approximately 120% of the pre-glucose ingestion value at 60-240 min post-glucose ingestion (p < 0.05 vs pre-glucose). There was no change in either IPG after glucose ingestion in the insulin-resistant group. These data suggest that the pH 2.0 IPG plays an important role in mediating insulin's effect on peripheral glucose utilization in man under physiological conditions. The data further show, for the first time, a defective change in the bioactivity of an insulin mediator isolated from insulin-resistant humans after hyperinsulinaemia, suggesting that inadequate generation/release of IPGs is associated with insulin resistance.
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PMID:Insulin mediators in man: effects of glucose ingestion and insulin resistance. 916 24

The objective of the present study was to assess the effect of low concentrations of protein kinase inhibitors on activation. Pig eggs were electrostimulated or cultured with the following: 10 microM 1-[5-isoquinolinylsulfonyl]-2-methylpiperazine, HCl H7 for 24 h; 100 microM H7 for 24 h; 10 nM staurosporine for 24 h; or with 20 microM staurosporine for 20 min followed by Whitten's medium for 24 h. Rates of pronuclear formation in eggs (n = 1240) subjected to these treatments were: untreated, 6.2%; electrostimulated, 77.1%; 10 microM H7, 10.0%; 100 microM H7, 65%; 10 nM staurosporine, 24.2%; and 20 microM staurosporine, 67.3% (significance at P < or = 0.05: 10 microM H7 vs untreated, not significant; 20 microM staurosporine vs 100 microM H7, not significant). Percentages of eggs (n = 125) expressing a 22-kDa band after treatment were: untreated, 37.5%; electrostimulated, 100%; 10 microM H7, 72%; 100 microM H7, 66.7%; 10 nM staurosporine, 40.0%; and 20 microM staurosporine, 77.3% (significance at P < or = 0.10: 100 microM H7, 10 nM staurosporine and 20 microM staurosporine vs 10 microM H7, not significant; 100 microM H7 and 10 nM staurosporine vs untreated, not significant). Transmission electron microscopy of ultrathin sections of treated eggs revealed that cortical granules were present in over half the untreated eggs, as well as over half of the eggs treated with 100 microM H7 or 10 nM staurosporine; in contrast, all cortical granules were absent from electrically-activated eggs. The results indicate that long-term exposure of eggs to low concentrations of broad-spectrum protein kinase inhibitors induces some of the events commonly associated with fertilization.
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PMID:Parthenogenetic activation of pig eggs by exposure to protein kinase inhibitors. 941 84

Mastoparan induced a transient elevation of cytosolic free Ca2+ concentration ([Ca2+]cyt) in tobacco suspension culture cells. The mastoparan-induced [Ca2+]cyt elevation was inhibited by 8-(N,N-diethylamino)-octyl 3,4,5-trimethoxybenzoate-HCl and neomycin but not by depletion of extracellular Ca2+, suggesting that the elevation was the result of Ca2+ release from the intracellular stores caused by stimulation of phosphoinositide turnover. Hydrogen peroxide which has been shown to induce an oxidative burst in soybean cells by mastoparan treatment [L. Legendre, P.F. Heinstein, P.S. Low, Evidence for participation of GTP-binding proteins in elicitation of the rapid oxidative burst in cultured soybean cells, J. Biol. Chem., 267 (1992) 20140-20147], also induced a transient [Ca2+]cyt elevation in the tobacco cells. However, mastoparan did not induce an oxidative burst in the tobacco cells. Activation of a 50, a 75 and a 80 kDa protein kinases after the mastoparan-induced [Ca2+]cyt elevation was shown by an in-gel protein kinase assay. This activation was inhibited by neomycin, suggesting that the [Ca2+]cyt elevation is necessary for the mastoparan-induced activation of the protein kinases. The activation was inhibited also by pretreatment with staurosporine and was sustained by pretreatment with calyculin A, suggesting that the protein kinase activity is regulated by protein phosphorylation/dephosphorylation. The present report shows that mastoparan induces an increase in [Ca2+]cyt without oxidative burst and subsequent activation of protein kinases in tobacco cells.
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PMID:Mastoparan induces an increase in cytosolic calcium ion concentration and subsequent activation of protein kinases in tobacco suspension culture cells. 954 Aug 24

We have evaluated the role of various protein kinases on the induction of the gadd (growth arrest and DNA damage inducible) genes, using a panel of protein kinase inhibitors. Our data indicate that three different stress response pathways mediating gadd gene induction are most likely regulated by different protein kinases or combinations of protein kinases. The protein kinase inhibitor staurosporine and the temperature sensitive (ts) p34cdc2 mutant reduced induction by the alkylating agent methylmethane sulfonate (MMS) of the rodent gadd45 and gadd153 genes. However, staurosporine had no effect of the ionizing radiation (IR) induction of the human GADD45. Caffeine and 2-aminopurine, on the other hand, completely blocked this IR induction. Suramin, an antitumor drug that interferes with the interaction of growth factors with their receptors, inhibited the UV radiation induction of GADD45 and GADD153 but had no effect on the MMS and IR pathways. Elevated expression of gadd45 by medium depletion (starvation) was partially reduced by the addition of either genistein or tyrphostin, two protein tyrosine kinase inhibitors, while gadd153 was affected by tyrphostin only. Two inhibitors acting preferentially on cAMP-dependent protein kinase (PKA), N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide, HCl (H8) and protein kinase inhibitor (PKI), also had a moderate effect on the medium depletion-induced levels of both gadd genes. Thus, these varied effects of inhibitors on gadd gene responses point to important differences in the pathways controlling these responses.
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PMID:Evidence for distinct kinase-mediated pathways in gadd gene responses. 958 58

The regulatory effects of cyclic GMP on purinoceptor-operated cytoplasmic Ca2+ oscillation of rat megakaryocytes were investigated by using whole-cell patch-clamp technique. ATP-induced oscillatory K+ currents though Ca2+-activated K+ channels (I(KCa)S) were depressed by pretreatment with the guanylate cyclase activator, sodium nitroprusside, and a stable membrane-permeable cGMP analogue, 8-bromo-cGMP. The inhibition by sodium nitroprusside was blocked by treatment with a cyclic nucleotide-dependent protein kinase inhibitor, N-[2-(methylamino)]-5-isoquinolinesulfonamide x HCl (H-8) (10 microM), but not by a selective cAMP-dependent-protein kinase inhibitor, Rp-cAMPS (100 microM). The oscillatory I(KCa) directly evoked by intracellular D-myo-inositol-trisphosphate (IP3) perfusion was also inhibited by the application of sodium nitroprusside. The inhibitory effect of sodium nitroprusside disappeared when the ATP-induced oscillatory I(KCa) was changed to a monophasic sustained I(KCa) current by inhibition of Ca2+-ATPase. These results suggested that cGMP depressed Ca2+ mobilization by improving Ca2+-ATPase activity by phosphorylation.
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PMID:Cyclic GMP inhibits cytoplasmic Ca2+ oscillation by increasing Ca2+-ATPase activity in rat megakaryocytes. 965 3

Rats implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus or in the amygdala were trained in one-trial step-down inhibitory (passive) avoidance using a 0.4 mA footshock. At various times after training (0, 1.5, 3, 6 or 9 h for animals implanted in the hippocampus; 0 or 3 h for those implanted in the amygdala), they received infusions of 8-Br-cAMP (cyclic adenosine monophosphate) (1.25 micrograms/side), SKF38393 (7.5 micrograms/side), SCH23390 (0.5 microgram/side), norepinephrine ClH (0.3 microgram/side), timolol ClH (0.3 microgram/side), 8-HO-DPAT (2.5 micrograms/side), NAN-190 (2.5 micrograms/side), forskolin (0.5 microgram/side) or KT5720 (0.5 microgram/side). Rats were tested for retention 24 h after training. SKF38393 is an agonist and SCH23390 an antagonist at dopamine D1 receptors, timolol is a beta-adrenoceptor antagonist, 8-HO-DPAT is an agonist and NAN-190 an antagonist at 5HT1A receptors, forskolin enhances adenylyl cyclase, and KT5720 inhibits protein kinase A. When given into the hippocampus 0 h post-training, norepinephrine enhanced memory and KT5720 was amnestic. When given 1.5 h after training, all treatments were ineffective. When given 3 or 6 h post-training, 8-Br-cAMP, forskolin, SKF 38393, noradrenaline and NAN-190 caused memory facilitation, and KT5720, SCH23390, timolol and 8-HO-DPAT caused retrograde amnesia. At 9 h from training, all treatments were again ineffective. When given into the amygdala 0 or 3 h post-training all treatments were ineffective, except for noradrenaline at 0 h, which caused retrograde facilitation. The data agree with the suggestion that in the hippocampus, but not the amygdala, a cAMP/protein kinase A pathway is involved in memory consolidation at 3 and 6 h from training, and that this is regulated by D1, beta, and 5HT1A receptors. This correlates with a previous report of increased cAMP levels, protein kinase A activity and P-CREB levels at 3-6 h from training in rat hippocampus in this task. This may be taken to suggest that the hippocampus, but not the amygdala, is involved in the long-term storage of step-down inhibitory avoidance in the rat.
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PMID:Drugs acting upon the cyclic adenosine monophosphate/protein kinase A signalling pathway modulate memory consolidation when given late after training into rat hippocampus but not amygdala. 983 92


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