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)

The role of protein kinases in renal noradrenergic stimulation was examined using sphingosine, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperizine (H7), using sphingosine, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperizine (H7), or staurosporine to inhibit the responses to norepinephrine (NE, 60 nM) in isolated perfused rat kidneys. Sphingosine (20 mumol/L) increased the noradrenergic vasoconstrictor response. H7 (10 mumol/L) partially blocked the immediate vasoconstrictor response and completely inhibited it after 2 min without altering the antinatriuretic and antilithuretic responses. H7 also blocked the increase in free water produced by NE, which is consistent with the inhibition of protein kinase A linked to beta-adrenergic stimulation. Staurosporine (10 nmol/L) partially inhibited noradrenergic vasoconstriction and antinatriuresis, and it completely blocked the depression of gluconeogenic responses to NE in pyruvate-perfused kidneys. To examine the role of diacylglycerol and protein kinase C in the renal responses to NE, we used oleoyl-acetyl-glycerol (OAG, 50-100 microM) or phorbol-12-myristyl-13-acetate (TPA, 5-50 nM). TPA slowly vasoconstricted the kidney and reduced GFR and fractional Na+, Li+, and free water excretion. Amiloride (1 mM) prevented the TPA responses. OAG mimicked the effects of TPA except that vasoconstriction occurred more rapidly and was brief. Both TPA and OAG acted like alpha 1-adrenergic agonists. These results indicate that diaclyglycerol and protein kinase are involved in the prolonged effects of NE on vasoconstriction. GFR, and proximal tubular reabsorption.
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PMID:Diacylglycerol and protein kinase mediated noradrenergic responses in perfused rat kidneys. 239 Jul 42

A calcium-unresponsive, phorbol ester/phospholipid-activated protein kinase was purified to apparent homogeneity from a Triton X-100 extract of an EGTA/EDTA-preextracted particulate fraction of porcine spleen by chromatography on S-Sepharose Fast Flow, phenyl-Sepharose Fast Flow, protamine-agarose, and Superdex 200. The enzyme had a Mr of 76,000, as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (p76-kinase). A similar value (78,000) was obtained by gel filtration. The purified p76-kinase proved to be much more stable than the enzyme in crude preparations. Storage in a buffer containing 50 mM mercaptoethanol and 20% glycerol at -20 degrees C for at least 4 months caused less than 20% loss in enzyme activity. The enzyme exhibited a pH optimum of 8.3. The affinity of the novel enzyme for substrates and cofactors differed to some extent from that of conventional alpha, beta, gamma protein kinase C (PKC). p76-kinase did not respond to calcium, had a lower requirement for magnesium, and a higher affinity for histone III-S than PKC. Both the p76-kinase-catalyzed phosphorylation of histone III-S and the autophosphorylation of the enzyme could be activated by the phorbol ester TPA (or diacylglycerol) plus phosphatidyl serine, but not by calcium plus phosphatidyl serine. The stoichiometry of autophosphorylation suggested that fully phosphorylated p76-kinase contained two phosphoserine residues and one phosphothreonine residue. Like PKC, p76-kinase bound TPA with high affinity (KD = 9.6 nM). In the absence of TPA, various unsaturated fatty acids, particularly arachidonic acid, were more potent as activators of the enzyme than phosphatidyl serine. The p76-kinase was recognized by an antiserum raised against a delta PKC-specific peptide, but not by an alpha, beta, gamma PKC-specific antiserum. The previously described p82-kinase of mouse epidermis and spleen exhibiting the same properties as the p76-kinase did also react with the p76-kinase-specific antiserum.
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PMID:Purification and characterization of a calcium-unresponsive, phorbol ester/phospholipid-activated protein kinase from porcine spleen. 239 47

The effect of cholecystokinin (CCK)-gastrin family peptides (caerulein, unsulfated gastrin-17, and pentagastrin) and secretin in activating amiloride-sensitive 22Na uptake were investigated in guinea pig pancreatic acini. Secretin had no effect, but CCK-gastrin peptides stimulated the amiloride-sensitive 22Na uptake. The effect of caerulein was inhibited by dibutyryl guanosine 3',5'-cyclic monophosphate (cGMP) and asperlicin, indicating that activation of the Na+-H+ antiport caused by caerulein is mediated by CCK receptors. The effect of gastrin was dibutyryl cGMP and asperlicin insensitive, whereas the effect of pentagastrin was inhibited by the CCK antagonists but with a low affinity, indicating that the effect of gastrin and that of pentagastrin was CCK receptor independent. The calcium ionophore A23187 caused an increase in amiloride-sensitive 22Na uptake. However, the effect of caerulein, which increased internal calcium concentration, was not modified after depletion of intracellular calcium, and that of CCK-gastrin family peptides was not dependent on external calcium concentration. Activation of amiloride-sensitive 22Na uptake was also induced by 12-O-tetradecanoylphorbol 13-acetate and 1-oleoyl-2-acetyl-glycerol. Activation of protein kinase c may be involved in the mechanism of caerulein or gastrin in activating the Na+-H+ exchange.
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PMID:Distinct activation of Na+-H+ exchange by gastrin and CCK peptide in acini from guinea pig. 244 99

We tested the possibility that the activation of protein kinase-C by the tumor-promoter phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) or diacylglycerol stimulates the production of prostaglandin E2 (PGE2) by the amnion. Confluent primary cultures of human amnion epithelial cells were adapted to serum-free medium and treated with the agonists for up to 8 h. Cumulative PGE2 output in the medium was measured by RIA. TPA, a potent activator of protein kinase-C, stimulated basal PGE2 output from less than 50 pg/well.5 h to 3 ng/well.5 h (P less than 0.01) in a time- and dose-dependent manner. 4-Methoxy-TPA, a weak tumor promoter derivative of TPA, was ineffective when tested in the same concentration range as TPA (1 nmol/L to 1 mumol/L). Neither calcium ionophore A23187 (20 nmol/L) nor arachidonate (1 mumol/L) stimulated PGE2 output alone, but each agonist potentiated the effect of TPA as much as 5-fold (P less than 0.01). 1,2-Dioctanoyl-sn-glycerol stimulated PGE2 output 4- to 7-fold (P less than 0.05), and this effect was potentiated by Ca ionophore and arachidonate. Studies involving actinomycin-D and cycloheximide indicated that the stimulatory effect of TPA was dependent on RNA synthesis during the first 60 min and on protein synthesis during the entire length of the phorbol ester treatment period (300 min). TPA was also able to stimulate PGE2 production after irreversible inactivation of PG endoperoxide synthase activity with acetylsalicylic acid. These results suggest that activation of protein kinase-C in amnion cells increases the de novo synthesis of the PG endoperoxide synthase enzyme in a RNA synthesis-dependent manner. Elevated intracellular calcium levels contribute to the stimulation apparently by increasing the availability of endogenous arachidonate for subsequent conversion to PGE2.
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PMID:Stimulation of human amnion prostaglandin E2 production by activators of protein kinase-C. 246 Apr 86

Sites at which the calcium-sensitive phospholipid-dependent protein kinase, protein kinase C, may influence acid secretion have been investigated in rat isolated parietal cells. In both crude and enriched preparations of parietal cells incubated in a medium containing 100 mM K+, the activators of protein kinase C, 12-O-tetradecanoylphorbol 13-acetate (TPA) and 1-oleoyl-2-acetyl-glycerol (OAG), produced a dose-dependent stimulation [half-maximally effective concentration (EC50) values of 1 nM and 70 microM, respectively] of aminopyrine accumulation, an index of the sequestration of acid in the cell. In a medium containing 4.5 mM K+, and with no added secretagogues, TPA and OAG did not affect aminopyrine accumulation. Histamine-stimulated aminopyrine accumulation was inhibited by TPA [half-maximally effective inhibitory concentration (IC50) of 2.9 nM]. TPA reduced the histamine-stimulation of the adenosine 3',5'-cyclic monophosphate (cAMP) content of parietal cells (47% inhibition at 100 nM TPA) but also inhibited aminopyrine accumulation at or distal to cAMP-dependent protein kinase. Activators of protein kinase C can produce multiple effects on secretory activity in the rat parietal cell.
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PMID:Sites of action of protein kinase C on secretory activity in rat parietal cells. 246 66

Compound 1,2-isopropylidene-3-decanoyl-sn-glycerol (IpOCOC9) augments the phosphorylation in vitro of histone III-S and myelin basic protein (MBP) by a partially purified Ca2(+)- and phospholipid-dependent protein kinase activity (protein kinase C) from human polymorphonuclear leukocytes. IpOCOC9 can substitute for either Ca2+ and phosphatidylserine or for phorbol ester. The related compound decanoid acid cyclopentyl methylester (DACPME) is less effective than IpOCOC9 in this respect. These data lend support to the notion that the secretagogue activity of IpOCOC9 with respect to human basophil histamine release and neutrophil superoxide radical generation is due to protein kinase C activation.
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PMID:Activation of human neutrophil protein kinase C in vitro by 1,2-isopropylidene-3-decanoyl-sn-glycerol (IpOCOC9). 248 37

Activation of glycolysis by insulin in cultured rat hepatocytes is preceded by an activation of phosphofructokinase 2 (PFK 2) and subsequent rise of the fructose 2,6-bisphosphate [Fru(2,6)P2] level. Extracellular addition of ATP or puromycin prevented the hormonal effect on glycolysis. The mechanism through which the purines abolished glycolytic stimulation was investigated. 1. 50 microM ATP completely prevented the 3-5-fold insulin-dependent increase of glycolysis, irrespective of whether the cells initially possessed a low or a high Fru(2,6)P2 content. 50 microM puromycin prevented the stimulation of glycolysis by insulin only in cells whose initial Fru(2,6)P2 levels were low and had to be increased by insulin prior to the increase in glycolysis. It did not antagonize the action of insulin cells with initial high Fru(2,6)P2 content. 2. ATP exerted effects on its own; it decreased initially high Fru(2,6)P2 levels by 95% within 10 min and decreased the basal glycolytic rate by 60%. Half-maximal effects on the Fru(2,6)P2 level were obtained with about 25 microM ATP or 15 microM adenosine 5'[beta, gamma-methylene]triphosphate. ADP and adenosine-5-[gamma-thio]triphosphate were as effective as ATP, whereas 100 microM adenosine 5'[alpha, beta-methylene]triphosphate elicited no effect. Puromycin neither decreased high Fru(2,6)P2 levels nor inhibited basal glycolysis. 3. Extracellular ATP (100 microM) led to inhibition of the active form of PFK 2. Intracellular levels of Glc6P, citrate, ATP, ADP and AMP were increased by extracellular ATP, the phosphoenolpyruvate content was decreased, Fru6P and glycerol 3-phosphate levels stayed constant. Puromycin did not inhibit PFK 2. 4. Both puromycin and ATP prevented the insulin-dependent rise of the Fru(2,6)P2 level, they abolished the activation of PFK 2 by the hormone. Puromycin did not block the accumulation of Fru(2,6)P2 provoked by glucose addition; ATP also antagonized the glucose-dependent increase. 5. 100 microM ATP elevated the cAMP-dependent protein kinase activity ratio from 0.1 to 0.38 and increased the level of inositol trisphosphate by 16-fold within 5 min, whereas puromycin was without effect on either level. It is concluded that the two purines block the insulin effect on glycolysis by preventing the hormone increasing the Fru(2,6)P2 level. The mode of action, however, seems to be different: ATP antagonizes insulin action in that it leads to increased inhibition of PFK 2 whereas puromycin prevents the activation of PFK 2 by insulin.
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PMID:Stimulation by insulin of glycolysis in cultured hepatocytes is attenuated by extracellular ATP and puromycin through purine-dependent inhibition of phosphofructokinase 2 activation. 252 68

The time-courses of isoproterenol activation of rat adipocyte particulate low Km cAMP phosphodiesterase (PDE) activity, cAMP-dependent protein kinase (A-kinase), and glycerol production were measured in the presence and absence of insulin. Isoproterenol (100 nM) alone rapidly activated A-kinase 8- to 10-fold and increased particulate cAMP PDE by approximately 100%. A-kinase and PDE activity remained relatively constant for at least 25 to 30 min. Kact values for isoproterenol activation of PDE and lipolysis were similar. In comparison with isoproterenol, insulin (0.1-0.3 nM) alone increased particulate cAMP PDE at a slower rate and to a lesser extent (by approximately 50% within 12 to 16 min) and without any change in A-kinase. With insulin plus isoproterenol there was a rapid, transient, and synergistic activation of particulate cAMP PDE, which temporally correlated with a decrease in A-kinase and reduction in lipolysis. These and other data suggest the following: 1) there is a close concentration-dependent and temporal relationship in isoproterenol activation of adenylate cyclase, of A-kinase, and of particulate cAMP PDE; 2) isoproterenol and insulin activate particulate cAMP PDE by two distinct mechanisms; 3) the temporal changes in PDE and A-kinase in the presence of insulin and isoproterenol suggest that insulin activation of the PDE does not require, but may be enhanced by, elevated cAMP and is important in the antilipolytic action of insulin.
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PMID:Role of hormone-sensitive low Km cAMP phosphodiesterase in regulation of cAMP-dependent protein kinase and lipolysis in rat adipocytes. 253 13

Several biochemical properties of a 43 kDa v-abl-encoded tyrosine-specific protein kinase (p43v-abl) expressed in Escherichia coli were examined. p43v-abl is a fragment of a 60 kDa v-abl-encoded precursor, p60v-abl, and could be generated by limited proteolysis of a purified p60v-abl with trypsin. Tryptic cleavage of p60v-abl was prevented in the presence of ATP. These results suggest that the catalytic kinase domain of v-abl-derived protein can be separated from other (regulatory) domains by limited proteolysis. p43v-abl readily phosphorylated tyrosine residues on several different protein and peptide substrates, including peptides containing only two amino acid residues. However, the local sequence of the tyrosine-containing peptide substrate significantly affected its rate of phosphorylation. Thus the primary structure and local conformation at the tyrosine acceptor site can play an important role in determining the substrate specificity of v-abl-derived kinase. Phosphorylation by p43v-abl requires Mn2+, Co2+ or Mg2+ and exhibits a strong preference for ATP as phosphate donor. Analogues of ATP and the thiol-reactive reagent N-ethylmaleimide inhibited p43v-abl kinase activity. Purified p43v-abl is intrinsically thermolabile (t1/2 = 5 min at 40 degrees C) and phosphorylates glycerol inefficiently (Km = 1.4 M).
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PMID:A truncated v-abl-derived tyrosine-specific tyrosine kinase expressed in Escherichia coli. 253 83

The tumor-promoting phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) increases 25-hydroxyvitamin D3 (25OHD3)-24-hydroxylase and decreases 25OHD3-1-hydroxylase activity in cultured kidney cells, effects similar to those exerted by 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and opposite those of PTH, forskolin, and cAMP. In this paper it is shown that the effects of TPA and 1,25-(OH)2D3 are additive, suggesting that they operate through distinct mechanisms. TPA did not alter cAMP metabolism by cultured chick kidney cells, not did it alter their response, in terms of 25OHD3 metabolism, to cAMP, suggesting that these two regulators of 25OHD3 metabolism also operate through distinct pathways. Another presumed activator of protein kinase-C 1,oleoyl-2-acetyl-glycerol, was tested and found to have the same effect as TPA in decreasing 1-hydroxylase activity, but it does not increase 24-hydroxylase activity. In addition, 1-oleoyl-2-acetyl-glycerol increases intracellular cAMP levels to approximately 25% of those attained by stimulation with PTH. None of the treatments resulted in altered [3H]PDBu binding by the cells. The results, taken together, suggest that 25OHD3-1-hydroxylase and the 25OHD3-24-hydroxylase are subject to multifactorial regulation and can be regulated independently of one another.
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PMID:Interactions between intracellular signals involved in the regulation of 25-hydroxyvitamin D3 metabolism. 253 73


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