Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase activity in high-speed supernatant fractions prepared from rat epididymal adipose tissue previously incubated in the absence or presence of insulin was investigated by following the incorporation of 32P from [gamma-32P]ATP into phosphoproteins separated by sodium dodecyl sulphate/polyacrylamide-gel electro-phoresis. Incorporation of 32P into several endogenous proteins in the supernatant fractions from insulin-treated tissue was significantly increased. These included acetyl-CoA carboxylase and ATP citrate lyase (which exhibit increased phosphorylation within fat-cells exposed to insulin), together with two unknown proteins of subunit Mr 78000 and 43000. The protein kinase activity increased by insulin was distinct from cyclic AMP-dependent protein kinase, was not dependent on Ca2+ and was not appreciably affected by dialysis or gel filtration. The rate of phosphorylation of added purified fat-cell acetyl-CoA carboxylase and ATP citrate lyase was also increased by 60-90% in high-speed-supernatant fractions prepared from insulin-treated tissue. No evidence for any persistent changes in phosphoprotein phosphatase activity was found. It is concluded that insulin action on acetyl-CoA carboxylase, ATP citrate lyase and other intracellular proteins exhibiting increased phosphorylation involves an increase in cyclic AMP-independent protein kinase activity in the cytoplasm. The possibility that the increase reflects translocation from the plasma membrane, perhaps after phosphorylation by the protein tyrosine kinase associated with insulin receptors, is discussed.
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PMID:Studies on insulin-stimulated phosphorylation of acetyl-CoA carboxylase, ATP citrate lyase and other proteins in rat epididymal adipose tissue. Evidence for activation of a cyclic AMP-independent protein kinase. 614 4

In polymorphonuclear leukocytes from severely diabetic patients the rate of glycolysis is decreased due to decreased activity of phosphofructokinase, and the glycogen content and rate of glycogen synthesis are decreased due to a decreased total activity of glycogen synthase and an impaired activation of this enzyme. Covalent modification of glycogen synthase by phosphorylation creates a continuum of phosphorylated enzyme forms of decreasing activity. Phosphorylation of a single peptide, whether by the synthase kinase or the cyclic AMP dependent protein kinase, is critical for the associated kinetic changes during the initial phosphorylation. Conversely, dephosphorylation of this particular peptide is associated with complete activation. The protein phosphatase activity of the microsomal fraction may be separated into functionally and possibly also structurally different phosphorylase- and synthase-phosphatase activities, where the latter appears to be dependent on free cytoplasmic Ca2+. It is hypothesized that it is synthase-phosphatase activity that is absent in leukocytes from diabetic patients and is restored upon insulin treatment.
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PMID:The polymorphonuclear leukocyte in diabetes mellitus. 622 61

An increase in glycogen synthase phosphatase (phosphoprotein phosphatase) activity was observed in the rat skeletal muscle extract following insulin administration. The phosphoprotein phosphatase activity present in the muscle extract from insulin treated rats was observed to remain elevated after the extract had been subjected to a molecular sieve chromatography. These results indicate that the stimulatory effects of insulin is due to modification of phosphatase itself or some macromolecular weight modifiers. The heat-stable protein inhibitors of the phosphoprotein phosphatase were isolated from skeletal muscle of insulin treated and control rats and their inhibitory potencies were compared over a wide range of protein concentrations. The inhibitory potency in the insulin treated rat skeletal muscle was found to be significantly less than that in the control muscle. Since type-1 inhibitor is well-known to be active only after being phosphorylated by cyclic AMP-dependent protein kinase, we suggest that the observed change in phosphoprotein phosphatase inhibitor potency is most likely mediated by an alteration in the phosphorylation state of type-1 inhibitor.
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PMID:Effects of insulin treatment on the activities of phosphoprotein phosphatase and its inhibitors. 625 14

Insulin treatment significantly altered the elution profile of deproteinized muscle extracts chromatographed on Sephadex G-25 columns, particularly in fraction II, which contains the insulin mediator. Further purification of fraction II by high-voltage paper electrophoresis at pH 1.9 and 3.5 resulted in two active fractions. Fraction 1 leads to 4 stimulated the cyclic AMP-dependent protein kinase and inhibited glycogen synthase phosphoprotein phosphatase, and may be a novel substance. Fractions 1 leads to 6 and 3 leads to 6 inhibited the cyclic AMP-dependent protein kinase and stimulated glycogen synthase phosphatase. It is proposed that the insulin mediator is present in fractions 1 leads to 6 and 3 leads to 6.
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PMID:Studies on the insulin mediator. II. Separation of two antagonistic biologically active materials from fraction II. 625 25

Possible inhibitory effects of insulin on epinephrine-induced changes in the enzymes of glycogen metabolism in skeletal muscle were tested using a perfused rat hindlimb preparation. Epinephrine and/or insulin were infused over a wide range of concentrations. Insulin at 6 X 10(-9) M increased the activity ratio (--Glc-6-P/+Glc-6-P) of glycogen synthase from a basal value of 0.09 +/- 0.01 to 0.13 +/- 0.01 and caused a 23% decrease in the Ka for Glc-6-P. In contrast, epinephrine at 10(-7) M decreased the activity ratio to 0.05 +/- 0.01 and increased the Ka for Glc-6-P 6.3-fold. Insulin was without effect on the concentration of cAMP or the activity ratio (-cAMP/+cAMP) of cAMP-dependent protein kinase and caused a small decrease in the activity ratio (-AMP/+AMP) of phosphorylase, whereas epinephrine caused large increases in all these parameters. Insulin at 6 X 10(-11) to 6 X 10(-8) M had no inhibitory effect on the actions of 10(-8) or 10(-7) M epinephrine on glycogen synthase, phosphorylase or cAMP-dependent protein kinase at 30 min or at earlier times. Insulin (6 X 10(-9) M) also did not alter th concentration of cAMP in the presence of 10(-8) or 10(-7) M epinephrine. These data are not consistent with the view that insulin activates glycogen synthase by producing an inhibitor of cAMP-dependent protein kinase. Nor do they support the hypothesis that insulin acts by decreasing the activity of an inhibitor of a multisubstrate phosphoprotein phosphatase.
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PMID:Studies on the interactions between insulin and epinephrine in the control of skeletal muscle glycogen metabolism. 626 Jul 99

The recent literature regarding the mechanisms of regulation of lipolysis with emphasis on the role of cyclic nucleotides is reviewed. The following conclusions appear warranted at present. (1) Cyclic AMP (cAMP) is a major regulator of lipolysis. However, mechanisms other than the production and catabolism of cAMP also exist. (2) Insulin can lower adipocyte cyclic AMP levels, but this effect cannot explain all aspects of the antilipolytic effect of insulin. (3) Insulin stimulates cyclic AMP phosphodiesterase and inhibits adenylate cyclase in adipocytes. In addition, there are probably other targets of insulin action. The possibilities include cAMP dependent protein kinase, phosphoprotein phosphatase, and triacylglycerol lipase. (4) Cyclic GMP is probably not directly involved in the regulation of lipolysis. (5) Cytosolic Ca2+ probably plays an important role in the regulation of lipolysis. The nature of such a role for Ca2+ and the potential role of calmodulin in the regulation of lipolysis remain to be explored.
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PMID:Cyclic nucleotides and lipolysis. 627 17

Intracellular insulin action has been investigated in terms of the control of glycogen synthesis. The action was systematically traced back to the initial action of insulin at the cell membrane. Insulin activates the rate-controlling enzyme, glycogen synthase. The mechanism of this activation was found to be the control of glycogen synthase by covalent phosphorylation and dephosphorylation. Insulin brought about dephosphorylation and enzyme activation, which led to increased glycogen synthesis. A study of the interconversion reactions led to the discovery of the cyclic adenosine monophosphate dependent (cAMP-dependent) protein kinase which phosphorylates glycogen synthase and inactivates the enzyme, and a phosphoprotein phosphatase which dephosphorylates glycogen synthase and activates it. Studies revealed that insulin does not act on glycogen synthase by decreasing basal tissue concentrations of cAMP (or by altering cyclic guanosine monophosphate (cGMP) tissue concentrations); rather, insulin acts more directly on the cAMP-dependent protein kinase to inactivate the kinase and to desensitize it to the activating action of cAMP. An intracellular mediator of insulin action was hypothesized to carry out this effect on the kinase; therefore, the kinase was used as an assay to search for the putative mediator. Such an insulin-generated mediator was found to be present initially in skeletal muscle and more recently in several insulin-sensitive tissues. Present evidence, although indirect, strongly suggests (1) that the mediator is a small peptide or peptide-like molecule, (2) that probably several mediators (or a family of mediators) are formed rapidly with insulin action; and (3) that they are formed from cell-membrane proteins by a process of limited proteolysis, which is initiated by the binding of insulin to its receptor. The present status of the rapidly developing area of hormone-induced transmembrane signaling via mediators is reviewed.
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PMID:Mediators of postreceptor action of insulin. 629

The diuretic drug amiloride antagonises the insulin-dependent increase in phosphorylation of ATP-citrate lyase in hepatocytes isolated from rats that had been starved and refed a fat-free diet. Studies with a range of protein kinases and protein phosphatases that have been shown to phosphorylate or dephosphorylate purified ATP-citrate lyase in vitro revealed that amiloride was a non-specific inhibitor of all protein kinases tested, but did not significantly affect any of the protein phosphatases. These results cast doubt on previous claims that growth factors stimulate phosphorylation of ribosomal protein S6 by activating an amiloride-sensitive Na+/H+ exchange system, and that insulin inhibits a protein phosphatase that is activated by amiloride.
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PMID:Evidence that amiloride antagonises insulin-stimulated protein phosphorylation by inhibiting protein kinase activity. 629 2

Insulin, epidermal growth factor (EGF), platelet-derived growth factor, multiplication-stimulating activity and 10% foetal-calf serum each stimulated the phosphorylation of a cytosolic Mr-22000 acidic heat-stable protein in Swiss mouse 3T3-L1 adipocytes. Phosphorylation of this protein was not stimulated by isoprenaline or dibutyryl cyclic AMP. The effect of insulin was maximal (3-fold increase) by 10 min; half-maximal stimulation was observed at 70 pM-insulin. Both [32P]phosphoserine and [32P]phosphothreonine residues were present in the Mr-22000 protein after insulin- and growth-factor-stimulated phosphorylation, but no [32P]phosphotyrosine. The major site of insulin- and EGF-stimulated phosphorylation appeared to be a threonine residue, in contrast with previously studied insulin-stimulated phosphorylation of serine residues. Insulin treatment appeared to result in a shift of the protein toward the anode on isoelectric focusing. Insulin and EGF present simultaneously did not lead to phosphorylation beyond that seen with each hormone singly. We surmise that insulin, EGF and perhaps other growth factors may activate a common protein kinase or inhibit a common protein phosphatase in 3T3-L1 adipocytes which acts on the Mr-22000 protein.
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PMID:Insulin and growth factors stimulate the phosphorylation of a Mr-22000 protein in 3T3-L1 adipocytes. 631 Nov 74

In this report we describe a novel in vitro phenomenon involving the interaction of insulin with purified protein phosphatases. Evidence is presented that porcine insulin is capable of activating and binding to rabbit skeletal muscle protein phosphatases in vitro. Its effects were examined on four rabbit skeletal muscle protein phosphatases. Two of these, phosphatases C-I and C-II, are of Mr approximately 35,000 and are the dissociated forms of protein phosphatase. The two other phosphatases, H-I and H-II, have Mr approximately 250,000 by gel filtration and represent nondissociated forms of phosphatase. Insulin reproducibly activated homogeneous preparations of protein phosphatase C-II and H-II approximately 3-5-fold in vitro. The activation was dependent on temperature, time, and insulin concentration. The activities of the phosphatases toward both phosphorylase alpha and histone were affected, indicating that this was not a substrate-directed effect. The activation phenomenon was not mimicked by insulin A or B chains, somatostatin, glucagon, or bovine serum albumin, and could be prevented by insulin antiserum. 125I-Insulin was shown to bind to the protein phosphatases by solid phase binding assays. Phosphatases C-I, C-II, and H-II, but not phosphatase H-I, were found to bind insulin reversibly. Half-maximal binding to the protein phosphatases was observed at approximately 5 X 10(-10) M insulin. Labeled insulin was found to coelute with protein phosphatase H-II on gel filtration when a mixture of the two was chromatographed, providing evidence for the formation of an enzyme-insulin complex. These findings suggest that certain protein phosphatases may have a specific binding site(s) for insulin and that these insulin-phosphatase complexes may also exhibit enhanced catalytic activity.
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PMID:A novel in vitro interaction of insulin with rabbit skeletal muscle protein phosphatases. 632 53


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