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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-stimulated glycogen synthase activity in human muscle is reduced in insulin-resistant subjects. Insulin regulation of human muscle glycogen synthase may require activation of a type-1 protein phosphatase (PP-1). We investigated the change of phosphorylase phosphatase and glycogen synthase activities in muscle biopsies obtained during a 2-h hyperinsulinemic euglycemic clamp in 12 insulin-sensitive (group S) and 8 insulin-resistant (group R) subjects. Fasting phosphorylase phosphatase activity was lower in group R than in group S, and did not increase significantly with insulin infusion in group R until 20 min. In group S, phosphorylase phosphatase was significantly stimulated by 10 min, remaining significantly higher than in group R at all time points. The insulin-mediated changes in phosphatase activities were not decreased by 3 nM okadaic acid but were completely inhibited by 1 microM okadaic acid, thereby verifying that insulin-stimulated phosphorylase phosphatase is accounted for by a PP-1. Subcellular fractionation demonstrated reduced fasting PP-1 activities in both the glycogen and cytosolic fractions of muscle obtained from subjects in group R compared to those in group S. These results suggest that insulin activation of PP-1 could contribute to the stimulation of glycogen synthase by this hormone in human muscle. Lower fasting PP-1 activity in cytosol and glycogen fractions plus lower insulin-stimulated PP-1 activity could explain, in part, reduced insulin-stimulated glycogen synthase in skeletal muscle of insulin-resistant subjects.
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PMID:Defective insulin response of phosphorylase phosphatase in insulin-resistant humans. 173 50

Protein phosphorylation and dephosphorylation are involved in regulation of cell growth. We tested the hypothesis that the growth inhibitory effect of transforming growth factor beta 1 (TGF-beta 1) involves activation of protein phosphatases. Exposure of human keratinocytes in culture to 400 pM TGF-beta 1 for 48 h led to 80% inhibition of DNA synthesis as measured by nuclear labeling. Incubation of cultured keratinocytes with 400 pM TGF-beta 1 rapidly activated (within 30 min) protein serine/threonine phosphatase, measured using phosphorylase as a substrate. Based on several criteria, including neutralization of activity with specific antibodies and inhibitor-2, TGF-beta 1-activated phosphorylase phosphatase was identified as protein phosphatase 1. TGF-beta 1 did not have rapid effects on protein serine/threonine phosphatase activity (type 2A) measured with histone phosphorylated by protein kinase C or on protein tyrosine phosphatase activity. However, protein tyrosine phosphatase was activated at 48 h, coincident with growth arrest. Differentiation, induced by the combination of TGF-beta 1 plus calcium or by serum, was not accompanied by further serine/threonine or tyrosine phosphatase activation. We conclude that induction of growth arrest in keratinocytes by TGF-beta 1 involves acute activation of protein phosphatase 1, while activation of protein tyrosine phosphatase may represent an additional mechanism for maintaining cells in a growth-arrested state.
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PMID:Growth arrest induced by transforming growth factor beta 1 is accompanied by protein phosphatase activation in human keratinocytes. 184 73

Insulin action leads to the rapid stimulation of a cytosolic Kemptide (Leu-Arg-Arg-Ala-Ser-Leu-Gly) kinase (KIK) that has been recently purified to near homogeneity (Klarlund, J. K., Bradford, A. P., Milla, M. G., and Czech, M. P. (1990) J. Biol. Chem. 265, 227-234). To examine its activation mechanism, purified KIK was treated with purified protein phosphatases. The catalytic subunit of phosphatase 2A inhibited the activity of control KIK by about 50% and abolished the 5-fold elevation in KIK activity due to insulin action. The catalytic subunit of phosphatase 1 with equivalent activity based on dephosphorylation of 32P-labeled phosphorylase alpha had no effect on either control or insulin-stimulated KIK activity. The deactivation of insulin-stimulated KIK by phosphatase 2A was time- and concentration-dependent and was blocked by phosphatase inhibitors. The purified native complexes of phosphatase 2A, phosphatase 2A1, and phosphatase 2A2 similarly deactivated KIK. Analyis of control or insulin-stimulated KIK with two antiphosphotyrosine antibodies by immunoblotting and immunoprecipitation failed to detect the presence of phosphotyrosine in the kinase. These results indicate that KIK is activated by phosphorylation as part of a kinase cascade emanating from insulin receptor stimulation.
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PMID:An insulin-stimulated kemptide kinase purified from rat liver is deactivated by phosphatase 2A. 184 13

The gene SIT4 of S. cerevisiae, which codes for a protein structurally related to the catalytic subunit of mammalian protein phosphatase 2A, was disrupted in vitro. Analysis of glycogen synthase activity ratio in mutant haploid cells indicated that the enzyme was less active than in wild-type cells. On the contrary, glycogen phosphorylase alpha activity was much higher. The activation of glycogen synthase observed in wild-type cells after incubation with lithium ions was not detected in mutant cells. These results suggest that the product of gene SIT4, a putative protein phosphatase, could be involved in the control of glycogen metabolism in yeast cells.
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PMID:Saccharomyces cerevisiae gene SIT4 is involved in the control of glycogen metabolism. 184 94

Glycogen-bound protein phosphatase G from rat liver was transferred from glycogen to beta-cyclodextrin (cycloheptaamylose) linked to Sepharose 6B. After removal of the catalytic subunit and of contaminating proteins with 2 M NaCl, elution with beta-cyclodextrin yielded a single protein on native polyacrylamide gel electrophoresis and two polypeptides (161 and 54 kDa) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Several lines of evidence indicate that the latter polypeptides are subunits of the protein phosphatase G holoenzyme. First, these polypeptides were also present, together with the catalytic subunit, in the extensively purified holoenzyme. Also, polyclonal antibodies against these polypeptides were able to bind the holoenzyme. Further, while bound to cyclodextrin-Sepharose, the polypeptides were able to recombine with separately purified type-1 (AMD) catalytic subunit, but not with type-2A (PCS) catalytic subunit. The characteristics of the reconstituted enzyme resembled those of the nonpurified protein phosphatase G. At low dilutions, the spontaneous phosphorylase phosphatase activity of the reconstituted enzyme was about 10 times lower than that of the catalytic subunit, but it was about 1000-fold more resistant to inhibition by the modulator protein (inhibitor-2). In contrast with the free catalytic subunit, the reconstituted enzyme co-sedimented with glycogen, and it was able to activate purified liver glycogen synthase b. Also, the synthase phosphatase activity was synergistically increased by a cytosolic phosphatase and inhibited by physiological concentrations of phosphorylase alpha and of Ca2+.
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PMID:Purification and characterization of the glycogen-bound protein phosphatase from rat liver. 189 24

Regulation of glycogenolysis in skeletal muscle is dependent on a network of interacting enzymes and effectors that determine the relative activity of the enzyme phosphorylase. That enzyme is activated by phosphorylase kinase and inactivated by protein phosphatase-1 in a cyclic process of covalent modification. We present evidence that the cyclic interconversion is subject to zero-order ultrasensitivity, and the effect is responsible for the "flash" activation of phosphorylase by Ca2+ in the presence of glycogen. The zero-order effect is observable either by varying the amounts of kinase and phosphatase or by modifying the ratio of their activities by a physiological effector, protein phosphatase inhibitor-2. The sensitivity of the system is enhanced in the presence of the phosphorylase limit dextrin of glycogen which lowers the Km of phosphorylase kinase for phosphorylase. The in vitro experimental results are examined in terms of physiological conditions in muscle, and it is shown that zero-order ultrasensitivity would be more pronounced under the highly compartmentalized conditions found in that tissue. The sensitivity of this system to effector changes is much greater than that found for allosteric enzymes. Furthermore, the sensitivity enhancement increases more rapidly than energy consumption (ATP) as the phosphorylase concentration increases. Energy effectiveness is shown to be a possible evolutionary factor in favor of the development of zero-order ultrasensitivity in compartmentalized systems.
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PMID:Muscle glycogenolysis. Regulation of the cyclic interconversion of phosphorylase a and phosphorylase b. 189 38

S. cerevisiae gene DIS2S1, which codes for a protein very similar to the catalytic subunit of mammalian protein phosphatase 1, was disrupted "in vitro". Diploid yeast cells were transformed and sporulated. Tetrad analysis demonstrated that disruption of DIS2S1 is lethal for the cell. Glycogen phosphorylase alpha and glycogen synthase activity ratio were measured in diploids carrying a disrupted allele of the gene. Phosphorylase was dramatically activated in mutant cells but, under the same conditions, glycogen synthase activity was essentially identical in both mutant and wild-type cells.
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PMID:The gene DIS2S1 is essential in Saccharomyces cerevisiae and is involved in glycogen phosphorylase activation. 191 73

The mechanisms by which glycogen metabolism, glycolysis and gluconeogenesis are controlled in the liver both by hormones and by the concentration of glucose are reviewed. The control of glycogen metabolism occurs by phosphorylation and dephosphorylation of both glycogen phosphorylase and glycogen synthase catalysed by various protein kinases and protein phosphatases. The hormonal effect is to stimulate glycogenolysis by the intermediary of cyclic AMP, which activates directly or indirectly the protein kinases. The glucose effect is to activate the protein phosphatase system; this occurs by the direct binding of glucose to glycogen phosphorylase which is then a better substrate for phosphorylase phosphatase and is inactivated. Since phosphorylase a is a strong inhibitor of synthase phosphatase, its disappearance allows the activation of glycogen synthase and the initiation of glycogen synthesis. When glycogen synthesis is intense, the concentrations of UDPG and of glucose 6-phosphate in the liver decrease, allowing a net glucose uptake by the liver. Glucose uptake is indeed the difference between the activities of glucokinase and glucose 6-phosphatase. Since the Km of the latter enzyme is far above the physiological concentration of its substrate, the decrease in glucose 6-phosphate concentration proportionally reduces its activity. The control of glycolysis and of gluconeogenesis occurs mostly at the level of the interconversion of fructose 6-phosphate and fructose 1,6-bisphosphate under the action of phosphofructokinase 1 and fructose 1,6-bisphosphatase. Fructose 2,6-bisphosphate is a potent stimulator of the first of these two enzymes and an inhibitor of the second. It is formed from fructose 6-phosphate and ATP by phosphofructokinase 2 and hydrolysed by a fructose 2,6-bisphosphatase. These two enzymes are part of a single bifunctional protein which is a substrate for cyclic AMP-dependent protein kinase. Its phosphorylation causes the inactivation of phosphofructokinase 2 and the activation of fructose 2,6-bisphosphatase, resulting in the disappearance of fructose 2,6-bisphosphate. The other major effector of these two enzymes is fructose 6-phosphate, which is the substrate of phosphofructokinase 2 and a potent inhibitor of fructose 2,6-bisphosphatase; these properties allow the formation of fructose 2,6-bisphosphate when the level of glycaemia and secondarily that of fructose 6-phosphate is high.
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PMID:Mechanisms of blood glucose homeostasis. 212 8

Protein phosphatase-1 and 2A, accounting for all the hepatic activity regulating phosphorylase, were assayed in streptozotocin-induced (8 weeks) diabetic Wistar rats. Cytosolic protein phosphatase-1 and 2A were distinguished by chromatography on heparin-Sepharose and by inhibition with inhibitor-2. Approx. 25-35% increases in type-1 phosphorylase phosphatase activity measured in cytosols were registered in diabetic rats when compared with control and 24 h fasting animals. The enrichment of protein phosphatase-1 in the cytosol of streptozotocin-treated rat livers could not be attributed to the reduced glycogen content with the onset of diabetes, since this elevated level of type-1 phosphatase was not observed in fasting rats with low glycogen content. The translocation of type-1 phosphatase from the particulate fraction into the cytosol was also recorded in trypsin-treated samples of diabetic rat livers. The apparent molecular weight of type-1 phosphatase in the cytosol of control and fasted rats was 160,000 as judged by gel filtration. The type-1 phosphatase activity that was released from the particulate fraction by streptozotocin-induced diabetes identified a further enzyme species (Mr 110,000) in the cytosol. Our data imply that the higher levels of cytosolic protein phosphatase-1 in diabetic rat liver could be a consequence of the dissociation of the catalytic subunit of protein phosphatase-1 and the glycogen-binding subunit in rat livers.
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PMID:Phosphorylase phosphatase activities of rat liver in streptozotocin-diabetes. 215

In the course of investigating the neoplastic alterations of protein phosphatases, the particulate fractions of rat liver and AH-13, a strain of rat ascites hepatoma, were chromatographed on DEAE-cellulose and assayed for protein phosphatase using glycogen synthase D and phosphorylase a as substrates. The synthase phosphatase activity of rapidly growing AH-13 was due almost entirely to a divalent cation-inhibited protein phosphatase, tentatively designated phosphatase N, the level of which was elevated remarkably in the hepatoma as compared with liver. Other hepatomas including primary hepatoma induced with 3'-methyl-4-dimethylaminoazobenzene also exhibited high levels of this phosphatase. Phosphatase N exhibited Mr = 49,000 (gel filtration) and has been partially purified with little alteration in properties. Partially purified phosphatase N was inhibited by divalent cations, rabbit skeletal muscle polypeptide inhibitor-2 and heparin, and released the catalytic subunit of type-1 protein phosphatase upon tryptic digestion. It is therefore apparent that phosphatase N is a type-1 protein phosphatase. There is some evidence to suggest that the high levels of phosphatase N in neoplastic cells are due primarily to enhanced synthesis of its non-catalytic (regulatory) subunit.
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PMID:Particulate-associated protein phosphatases of rat hepatomas as compared with the enzymes of rat liver. 215 61


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