Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The roles of protein kinase C, Ca2+/calmodulin-dependent protein kinase and AMP-activated protein kinase in the phosphorylation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase induced by Ca2(+)-mobilizing conditions in isolated hepatocytes were investigated. Only partial evidence for the involvement of AMP-activated kinase was found. Antagonism of calmodulin action prolonged the decrease in expressed/total activity ratio induced by vasopressin plus glucagon. Protease inhibitors active against Ca2(+)-dependent cytosolic proteases or lysosomal proteolysis did not attenuate the loss of total HMG-CoA reductase induced by glucagon plus vasopressin, but calmodulin antagonists largely prevented this effect.
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PMID:The roles of different protein kinases and of calmodulin in the effects of Ca2+ mobilization on 3-hydroxy-3-methylglutaryl-CoA reductase activity in isolated rat hepatocytes. 199 Oct 44

Calmodulin-dependent multiprotein kinase and protein kinase C phosphorylate and inactivate both intact, microsomal HMG-CoA reductase, and the purified 53 kDa catalytic fragment. Isolation of the single phosphopeptide produced by combined cleavage with cyanogen bromide and Lys-C proteinase reveals that this is due to phosphorylation of a single serine residue near the C-terminus, corresponding to serine-872 in the human enzyme. This is identical with the single serine phosphorylated by the AMP-activated protein kinase. The nature of the protein kinase responsible for phosphorylation of this site in vivo is discussed.
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PMID:Calmodulin-dependent multiprotein kinase and protein kinase C phosphorylate the same site on HMG-CoA reductase as the AMP-activated protein kinase. 238 4

Subcellular fractionation of rabbit pancreatic acini was performed to study the distribution of endogenous substrates for protein kinase C. Substrates for protein kinase C were found to be predominantly low molecular mass proteins of cytosolic origin. At least three of these soluble substrates, with molecular masses of 17-19 kDa, were relatively heavily phosphorylated by endogenous as well as purified pancreatic protein kinase C. In the same molecular mass range, 16-18 kDa, soluble proteins were also phosphorylated by protein kinase A. Moreover, addition of cyclic AMP under conditions that activated protein kinase C gave a more than additive labelling of these low molecular mass proteins. The latter observation may be of interest in view of the potentiating effect cyclic-AMP-activated protein kinase A has on amylase secretion stimulated by secretagogues which increase free cytosolic Ca2+ and activate protein kinase C.
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PMID:Phosphorylation of low molecular mass cytosolic proteins by protein kinase C and protein kinase A in the rabbit exocrine pancreas. 255 92

A calcium-activated and phospholipid-dependent protein kinase (protein kinase C) catalyzes the phosphorylation of both insoluble microsomal (Mr approximately 100,000) and purified soluble (Mr = 53,000) 3-hydroxy-3-methylglutaryl coenzyme A reductase. The phosphorylation and concomitant inactivation of enzymic activity of HMG-CoA reductase was absolutely dependent on Ca2+, phosphatidylserine, and diolein. Dephosphorylation of phosphorylated HMG-CoA reductase was associated with the loss of protein bound radioactivity and reactivation of enzymic activity. Maximal phosphorylation of purified HMG-CoA reductase was associated with the incorporation of 1.05 +/- 0.016 mol of phosphate/mol of native form of HMG-CoA reductase (Mr approximately 100,000). The apparent Km for purified HMG-CoA reductase and histone H1 was 0.08 mg/ml, and 0.12 mg/ml, respectively. The tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate stimulated the protein kinase C-catalyzed phosphorylation of HMG-CoA reductase. Increased phosphorylation of HMG-CoA reductase by phorbol 12-myristate 13-acetate suggests a possible in vivo protein kinase C-mediated mechanism for the short-term regulation of HMG-CoA reductase activity. The identification of the protein kinase C system in addition to the reductase kinase-reductase kinase kinase bicyclic cascade systems for the modulation of the enzymic activity of HMG-CoA reductase may provide new insights into the molecular mechanisms involved in the regulation of cholesterol biosynthesis.
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PMID:Phosphorylation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase and modulation of its enzymic activity by calcium-activated and phospholipid-dependent protein kinase. 315 37

This report summarizes the current concepts regarding the in vitro and in vivo modulation of the enzymic activity of HMG-CoA reductase and mevalonate formation in rat and human liver, as well as in cultured fibroblasts from normal and familial hypercholesterolemic subjects. Three separate mechanisms for the short-term modulation of hepatic HMG-CoA reductase activity by covalent phosphorylation have been described. These mechanisms involved three separate specific kinase systems including reductase kinase, protein kinase C, and a Ca+2, calmodulin-dependent kinase. The conceptual schemes presented in this report will provide a basis for future research as well as an overview for improved understanding of the complex and multifaceted short-term regulation of this key enzyme in the biosynthetic pathways of mevalonate, ubiquinones, dolichols, isopentenyl-tRNAs, and cholesterol.
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PMID:Modulation of the enzymic activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase by multiple kinase systems involving reversible phosphorylation: a review. 330 82

A rice (Oryza sativa L.) gene for alpha-amylase, alpha Amy3, was strongly and rapidly induced by treatment of suspension-cultured cells with okadaic acid (OA), a potent and specific inhibitor of protein serine/threonine phosphatases 1 and 2A. The massive accumulation of alpha Amy3 mRNA in response to OA treatment was due to the stimulation of gene transcription and a partial stabilization of this mRNA. This induction of alpha Amy3 message by OA occurred even though cellular protein synthesis was inhibited. Simultaneous treatment of cultured cells with OA and anisomycin synergistically induced alpha Amy3 expression. In addition, the inhibition of protein synthesis stabilized OA-induced alpha Amy3 mRNA. In the presence of protein kinase inhibitors H7, W7, and H8, alpha Amy3 mRNA accumulation induced by OA was unaffected. These results indicate that OA-dependent alpha Amy3 induction is regulated transcriptionally by a signal transduction pathway involving protein phosphorylation, but independent of both protein kinase C and Ca2+/calmodulin- or Ca(2+)-dependent protein kinases. Furthermore, an AMP-activated protein kinase may be required for this induction of alpha Amy3 expression.
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PMID:Protein phosphatase inhibitors enhance the expression of an alpha-amylase gene, alpha Amy3, in cultured rice cells. 799 17

Malonyl-CoA is an allosteric inhibitor of carnitine palmitoyltransferase (CPT) I, the enzyme that controls the transfer of long-chain fatty acyl (LCFA)-CoAs into the mitochondria where they are oxidized. In rat skeletal muscle, the formation of malonyl-CoA is regulated acutely (in minutes) by changes in the activity of the beta-isoform of acetyl-CoA carboxylase (ACCbeta). This can occur by at least two mechanisms: one involving cytosolic citrate, an allosteric activator of ACCbeta and a precursor of its substrate cytosolic acetyl-CoA, and the other involving changes in ACCbeta phosphorylation. Increases in cytosolic citrate leading to an increase in the concentration of malonyl-CoA occur when muscle is presented with insulin and glucose, or when it is made inactive by denervation, in keeping with a diminished need for fatty acid oxidation in these situations. Conversely, during exercise, when the need of the muscle cell for fatty acid oxidation is increased, decreases in the ATP/AMP and/or creatine phosphate-to-creatine ratios activate an isoform of an AMP-activated protein kinase (AMPK), which phosphorylates ACCbeta and inhibits both its basal activity and activation by citrate. The central role of cytosolic citrate links this malonyl-CoA regulatory mechanism to the glucose-fatty acid cycle concept of Randle et al. (P. J. Randle, P. B. Garland. C. N. Hales, and E. A. Newsholme. Lancet 1: 785-789, 1963) and to a mechanism by which glucose might autoregulate its own use. A similar citrate-mediated malonyl-CoA regulatory mechanism appears to exist in other tissues, including the pancreatic beta-cell, the heart, and probably the central nervous system. It is our hypothesis that by altering the cytosolic concentrations of LCFA-CoA and diacylglycerol, and secondarily the activity of one or more protein kinase C isoforms, changes in malonyl-CoA provide a link between fuel metabolism and signal transduction in these cells. It is also our hypothesis that dysregulation of the malonyl-CoA regulatory mechanism, if it leads to sustained increases in the concentrations of malonyl-CoA and cytosolic LCFA-CoA, could play a key role in the pathogenesis of insulin resistance in muscle. That it may contribute to abnormalities associated with the insulin resistance syndrome in other tissues and the development of obesity has also been suggested. Studies are clearly needed to test these hypotheses and to explore the notion that exercise and some pharmacological agents that increase insulin sensitivity act via effects on malonyl-CoA and/or cytosolic LCFA-CoA.
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PMID:Malonyl-CoA, fuel sensing, and insulin resistance. 988 45

Malonyl CoA is an inhibitor of carnitine palmitoyl transferase 1 (CPT1), the enzyme that regulates the transfer of long chain fatty acyl CoA into mitochondria. By virtue of this effect, it is thought to play a key role in regulating fatty acid oxidation. Thus, when the supply of glucose to muscle is increased, malonyl CoA levels increase in keeping with a decreased need for fatty acid oxidation, and fatty acids are preferentially esterified to form diaglycerol and triglycerides. In contrast, during exercise, when the need for fatty acid oxidation is increased, malonyl CoA levels fall. Changes in glucose supply regulate malonyl CoA by modulating the concentration of cytosolic citrate, an allosteric activator of acetyl CoA carboxylase (ACC), the rate-limiting enzyme for malonyl CoA formation and a precursor of its substrate cytosolic acetyl CoA. Conversely, exercise lowers the concentration of malonyl CoA, by activating an AMP-activated protein kinase, which phosphorylates and inhibits ACC. A number of reports have linked sustained increases in the concentration of malonyl CoA in muscle to insulin resistance. In this paper, we review these reports, as well as the notion that changes in malonyl CoA contribute to the increases in long chain fatty acyl CoA, (LCFA CoA), diacylglycerol and triglyceride content and changes in protein kinase C activity and distribution observed in insulin-resistant muscle. We also review the implications of the malonyl CoA/LCFA CoA hypothesis to two other proposed mechanisms for insulin resistance, the glucose-fatty acid cycle and the hexosamine theory.
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PMID:Malonyl CoA, long chain fatty acyl CoA and insulin resistance in skeletal muscle. 1021 40

Wortmannin selectively impairs insulin-stimulated glucose transport in skeletal muscle. To search for an inhibitor specific for contraction-stimulated glucose transport, we screened a number of calmodulin and PKC inhibitors for their ability to impair contraction- and insulin-stimulated 2-deoxyglucose uptake in incubated rat soleus muscles. In concentrations that did not reduce contraction-induced force output, among calmodulin inhibitors W-7 inhibited both contraction- and insulin-stimulated glucose transport by up to 50% (P < 0.05), while Calmidazolium impaired only insulin-stimulated glucose transport (P < 0.05), and Trifluoperazine and Phenoxybenzamine did not influence glucose transport. In concentrations that did not reduce force generation, among PKC inhibitors Calphostin C specifically inhibited contraction-stimulated glucose transport (P < 0.05), whereas insulin-stimulated transport was impaired by Rottlerin and Bisindolylmaleimide I (P < 0.05), and both contraction- and insulin-stimulated glucose transport were inhibited by RO-31-8220 (P < 0.05). Calphostin C did not reduce contraction-induced increase in AMP-activated protein kinase (AMPK) activity. In conclusion, we have identified specific inhibitors of both contraction- and insulin-stimulated glucose transport. Both calmodulin and different isoenzymes of the PKC family may be involved in contraction- and insulin-stimulated glucose transport. Calphostin C does not influence glucose transport during contractions via stimulation of AMPK. Calphostin C may be used to unravel signal transduction in contraction-stimulated glucose transport.
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PMID:Calphostin C is an inhibitor of contraction, but not insulin-stimulated glucose transport, in skeletal muscle. 1051 79

Endothelial nitric-oxide synthase (eNOS) is an important regulatory enzyme in the cardiovascular system catalyzing the production of NO from arginine. Multiple protein kinases including Akt/PKB, cAMP-dependent protein kinase (PKA), and the AMP-activated protein kinase (AMPK) activate eNOS by phosphorylating Ser-1177 in response to various stimuli. During VEGF signaling in endothelial cells, there is a transient increase in Ser-1177 phosphorylation coupled with a decrease in Thr-495 phosphorylation that reverses over 10 min. PKC signaling in endothelial cells inhibits eNOS activity by phosphorylating Thr-495 and dephosphorylating Ser-1177 whereas PKA signaling acts in reverse by increasing phosphorylation of Ser-1177 and dephosphorylation of Thr-495 to activate eNOS. Both phosphatases PP1 and PP2A are associated with eNOS. PP1 is responsible for dephosphorylation of Thr-495 based on its specificity for this site in both eNOS and the corresponding synthetic phosphopeptide whereas PP2A is responsible for dephosphorylation of Ser-1177. Treatment of endothelial cells with calyculin selectively blocks PKA-mediated dephosphorylation of Thr-495 whereas okadaic acid selectively blocks PKC-mediated dephosphorylation of Ser-1177. These results show that regulation of eNOS activity involves coordinated signaling through Ser-1177 and Thr-495 by multiple protein kinases and phosphatases.
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PMID:Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase. 1129 21


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