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)

Highly purified insulin receptor was shown to be a substrate for cAMP kinase. Approximately 1 phosphate was incorporated per molecule of receptor, and the cAMP kinase's affinity for the receptor was at least as high as its affinity for histone. The sites phosphorylated by cAMP kinase seemed distinct from those phosphorylated by the protein kinase C. Phosphorylation by cAMP kinase had no effect on the ability of several monoclonal antibodies to recognize the receptor or on the insulin-binding activity of the receptor. However, cAMP phosphorylation partially inhibited the tyrosine kinase activity of the receptor (approximately 25%). These results suggest that catecholamine-induced resistance to insulin may be partly due to a direct phosphorylation of the receptor by cAMP kinase and a subsequent inhibition of the ability of the receptor kinase to be activated by insulin.
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PMID:Phosphorylation of purified insulin receptor by cAMP kinase. 353 74

Insulin stimulation of 2-deoxyglucose transport and lipogenesis from glucose was examined in fat cells in which protein kinase C had been down-modulated by a 3 h pretreatment with 5 X 10(-7) M 4 beta-phorbol 12 beta-myristate, 13 alpha-acetate (PMA). As compared to control fat cells, the down-modulated cells exhibited a 55-65% decrease in insulin responsiveness with no change in either the hormone sensitivity or the insulin receptor affinity. The present study shows that fat cells made protein kinase C-deficient by chronic treatment with PMA exhibit an insulin-resistant state, distal to the initial step of hormone binding.
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PMID:Decreased insulin responsiveness in fat cells rendered protein kinase C-deficient by a treatment with a phorbol ester. 355 33

A method is described for preparing a plasma-membrane fraction from hepatocytes by a rapid, gentle, Percoll fractionation procedure. Cholera toxin elicited the ribosylation of a number of proteins in these membranes, including the components of the stimulatory guanine nucleotide regulatory protein, Ns. Insulin, however, inhibited the ability of cholera toxin to ribosylate a protein of Mr 25 000. The action was decreased in membranes from cells that had been pre-treated with glucagon. Ribosylation of both the components of Ns and the Mr-25 000 species occurred in whole cells treated with cholera toxin, because membranes from such treated cells exhibited decreased labelling when incubated with [32P]NAD+ and activated cholera toxin. The labelling of proteins, including the Mr-25 000 species, with [32P]NAD+ and cholera toxin in the plasma membranes was decreased by an inhibitor of ribosylation. Azido-GTP photoaffinity labelling identified several high-affinity GTP-binding proteins, including one of Mr 25 000. Cholera toxin failed to ribosylate the Mr-25 000 protein in membranes from cells that had been pre-treated with the tumour-promoting agent 12-O-tetradecanoylphorbol 13-acetate (TPA). In membranes from such treated cells, insulin actually allowed cholera toxin to label this species. As TPA activates protein kinase C, it is possible that the Mr-25 000 protein, or a species that interacts with it, is a substrate for phosphorylation. These observations may offer an explanation for some of the perturbing effects that TPA exerts on insulin's action. It is suggested that the insulin receptor interacts with the guanine nucleotide regulatory protein system in the liver, and that the Mr-25 000 species may be a component of Nin, a specific guanine nucleotide regulatory protein that has been proposed to mediate certain of the actions of insulin on target cells [Houslay & Heyworth (1983) Trends Biochem. Sci. 8, 449-452].
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PMID:Insulin inhibits the cholera-toxin-catalysed ribosylation of a Mr-25000 protein in rat liver plasma membranes. 389 32

The effect of phorbol esters on the extent of phosphorylation of receptors for insulin and somatomedin C (insulin-like growth factor I) was studied in intact IM-9 cells that were labeled by incubation with H332PO4. The tumor-promoting phorbol esters phorbol tetradecanoate acetate (TPA) and phorbol dibutyrate, but not the inactive 4 alpha-phorbol, enhanced phosphorylation of the beta subunit of both receptors approximately 4-fold; 70 nM TPA maximally stimulated phosphorylation of both receptors, whereas concentrations less than or equal to 0.7 nM had no observable effect. Insulin also enhanced the phosphorylation of the beta subunit of the insulin receptor, and its effects appeared to be additive to those of TPA. Peptide maps indicated that at least some of the residues phosphorylated by these two agents are distinct. These results suggest a possible role of protein kinase C in regulating insulin and somatomedin C receptors.
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PMID:Phorbol esters stimulate the phosphorylation of receptors for insulin and somatomedin C. 631 47

The effect of the tumor-promoting agent phorbol 12-myristate 13-acetate (PMA) on insulin receptors and insulin action was studied in rat hepatoma cells in culture. PMA (0.1-1.0 micrograms/ml) did not affect insulin binding either acutely or chronically but inhibited insulin stimulation of glycogen synthase and tyrosine aminotransferase. PMA (1 microgram/ml) stimulated the phosphorylation of the beta subunit of insulin receptor purified from [32P]phosphate-labeled Fao cells by 1.3-fold in the absence of insulin. In contrast, insulin-stimulated phosphorylation in the presence of PMA was reduced. Phosphoamino acid analysis of the beta subunit after PMA stimulation revealed an increase of both phosphoserine and phosphothreonine residues, whereas insulin stimulated primarily phosphorylation of tyrosine and serine residues. Insulin stimulation of cells after PMA treatment revealed a decrease in phosphotyrosine when compared to cells stimulated by insulin alone. Tryptic peptide mapping of the beta subunit by a two-dimensional chromatographic/electrophoretic separation revealed nine phosphopeptides from the cells treated with PMA. Insulin stimulated phosphorylation at six new sites in the receptor, three of which appeared to be similar to those in PMA-treated cells. This report shows that phorbol esters stimulate insulin receptor phosphorylation, inhibit insulin-induced receptor phosphorylation and insulin action, and suggest a physiologic relation between insulin action and the calcium-activated and phospholipid-dependent protein kinase C.
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PMID:Phorbol esters modulate insulin receptor phosphorylation and insulin action in cultured hepatoma cells. 639 28

Brazilin (7,11b-dihydrobenz[b]indeno-[1,2-d]pyran-3,6a,9,10(6H)- tetrol) was found to have hypoglycemic action and increase glucose metabolism in experimental diabetic animals. In order to investigate the mechanism of hypoglycemic action of brazilin, the effects of brazilin on glucose transport, insulin receptor autophosphorylation, and protein kinase C(PKC) activity in 3T3-L1 cells were studied. Brazilin increased basal glucose transport in 3T3-L1 fibroblasts and adipocytes. However, insulin-stimulated glucose transport was not influenced. Autophosphorylation of the partially purified insulin receptor was not affected by brazilin treatment in 3T3-L1 fibroblasts. However, brazilin decreased the PKC activity in 3T3-L1 fibroblasts and adipocytes.
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PMID:Brazilin stimulates the glucose transport in 3T3-L1 cells. 748 Jan 73

Troglitazone (CS045), a compound belonging to the thiazolidine diones, is being tested as a new oral antidiabetic agent. Evidence exists from animal studies and clinical trials with non-insulin-dependent diabetes mellitus patients that Troglitazone might reduce insulin resistance. The molecular mechanism of this effect is not understood. In this study, we investigated whether Troglitazone might interfere with the mechanism of glucose-induced insulin resistance. Several studies indicate that hyperglycemia reduces the kinase activity of the insulin receptor in different cell types. This effect is paralleled by translocation of several protein kinase C (PKC) isoforms, and it can be prevented by PKC inhibitors, which suggests that glucose-induced receptor desensitization is mediated by activation of PKC. We studied the effect of hyperglycemia on the insulin receptor kinase activity and its modulation by Troglitazone in rat-1 fibroblasts that stably overexpress the human insulin receptor. Before stimulation with insulin (10(-7) M), cells were acutely exposed to hyperglycemic conditions in the absence or presence of Troglitazone (0.01-2 micrograms/ml). The insulin receptor was solubilized from a plasma membrane fraction or whole cell lysates, and proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotted against antiphosphotyrosine and anti-insulin receptor beta-subunit (CT 104) antibodies. Acute hyperglycemia (25 mM glucose) induced a significant inhibition of the insulin receptor kinase (IRK) activity within 30 min (inhibition to 30 +/- 12.5% of maximal insulin-stimulated beta-subunit phosphorylation, n = 9, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Troglitazone prevents glucose-induced insulin resistance of insulin receptor in rat-1 fibroblasts. 750 75

Rat-1 fibroblasts stably overexpressing high levels of human insulin receptor were used as a model system to study the effects of hyperglycemia on insulin receptor tyrosine kinase (IRK) activity and protein kinase C (PKC) translocation in parallel in the intact cell. Glucose (10-25 mM) induced a significant reduction of IRK activity (tyrosine phosphorylation of IR-beta-subunit and IR-substrate-1) within 10 min. This effect was paralleled by a rapid translocation of several PKC isoforms (cPKC alpha, nPKC delta, nPKC epsilon, nPKC zeta) to the plasma membrane within 1 min. Kinetics of IRK inhibition and PKC translocation are consistent with the idea that the glucose effect on IRK is mediated by PKC activation. This hypothesis is supported by further observations. Addition of the protein kinase C inhibitor H-7 can prevent the effect of glucose on IRK. Inhibition of IRK is also observed after stimulation of the cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, which can substitute for a physiological activator of PKC. Glucose (25 mM) increases the 32P incorporation in serine residues of the beta-subunit of IRK. We conclude that high levels of glucose induce inhibition of IRK in vivo. There is indirect evidence that this effect is mediated by a glucose-induced PKC translocation/activation and serine phosphorylation of the insulin receptor.
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PMID:Glucose-induced translocation of protein kinase C isoforms in rat-1 fibroblasts is paralleled by inhibition of the insulin receptor tyrosine kinase. 750 12

Insulin, in the presence of phorbol esters, was observed to stimulate the tyrosine phosphorylation of a major 80 kDa protein by immunoblotting with anti-phosphotyrosine antibodies in Chinese hamster ovary cells overexpressing the insulin receptor and protein kinase C alpha. The protein was specifically immunoprecipitated by antibodies to protein kinase C and anti-phosphotyrosine antibodies were capable of immunoprecipitating protein kinase C enzymatic activity from these cells. When this tyrosine phosphorylated protein kinase C was treated with a tyrosine-specific phosphatase, a 35% decrease in its enzymatic activity was observed and this inhibition was blocked by inclusion of a tyrosine phosphatase inhibitor, vanadate, in the reaction mixture. These results indicate that under certain conditions insulin can stimulate the tyrosine phosphorylation of protein kinase C and this phosphorylation can affect its enzymatic activity.
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PMID:Insulin-stimulated tyrosine phosphorylation of protein kinase C alpha: evidence for direct interaction of the insulin receptor and protein kinase C in cells. 751 4

In digitonin-permeabilized cultured foetal hepatocytes, insulin receptor beta-subunit was highly phosphorylated on serine residues in the presence of [gamma-32P]ATP and Ca2+, a process enhanced after short exposure to insulin with no detectable insulin receptor autophosphorylation. By contrast with this situation, experiments performed with isolated foetal insulin receptors revealed an insulin stimulation of both serine phosphorylation and tyrosine autophosphorylation. In permeabilized cells, insulin receptor beta-subunit phosphorylation was increased after a 2-min exposure to phorbol 12-myristate 13-acetate (PMA) prior to applying the permeabilization/phosphorylation step, while it was inhibited by chronic treatment with PMA leading to protein kinase C (PKC) down modulation. The PKC specific inhibitor, GF109203X, strikingly reduced basal and insulin-enhanced phosphorylation of insulin receptor beta-subunit in permeabilized cells, but failed to exert any effect with isolated receptors. Labelling of glycogen from [U-14C]glucose determined 1 h after a 10-min transitory exposure to insulin and/or modulators of PKC activity showed that PMA prevented insulin glycogenic response, whereas GF109203X was ineffective. Thus, although not directly responsible for insulin receptor serine phosphorylation in cultured foetal hepatocytes, PKC physiologically regulates this process which may inhibit insulin receptor tyrosine kinase activity. This regulation is independent of the antagonistic effect of PMA-activated PKC on insulin glycogenic response.
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PMID:Protein kinase C and insulin receptor beta-subunit serine phosphorylation in cultured foetal rat hepatocytes. 752 33


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