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

sds22 is a regulatory polypeptide of protein phosphatase-1 that is required for the completion of mitosis in both fission and budding yeast. We report here the cDNA cloning of a human polypeptide that is 46% identical to yeast sds22. The human homolog of sds22 consists of 360 residues, has a calculated molecular mass of 41.6 kDa and shows a tandem array of 11 leucine-rich repeat structures of 22 residues. Northern analysis revealed a major transcript of 1.39 kb in all 8 investigated human tissues. sds22 was detected by western analysis in both the cytoplasm and the nucleus of rat liver cells as a polypeptide of 44 kDa.
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PMID:Molecular cloning of a human polypeptide related to yeast sds22, a regulator of protein phosphatase-1. 749 85

A full-length cDNA encoding the putative hepatic glycogen-binding (GL) subunit of protein phosphatase-1 (PP1) was isolated from a rat liver library. The deduced amino acid sequence (284 residues, 32.6 kDa) was 23% identical (39% similar) to the N-terminal region of the glycogen-binding (GM) subunit of PP1 from striated muscle. The similarities between GM and GL were most striking between residues 63-86, 144-166 and 186-227 of human GM (approximately 40% identity), nearly all the identities with the putative yeast homologue GAC1 being located between 144-166 and 186-227. The cDNA was expressed in E. coli, and the expressed protein transformed the properties of PP1 to those characteristic of the hepatic glycogen-associated enzyme. These experiments establish that the cloned protein is GL.
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PMID:Amino acid sequence and expression of the hepatic glycogen-binding (GL)-subunit of protein phosphatase-1. 749 21

NIPP-1 was originally isolated as a potent and specific nuclear inhibitory polypeptide (16-18 kDa) of protein phosphatase-1. We report here the cDNA cloning of NIPP-1 from bovine thymus and show that the native polypeptide consists of 351 residues and has a calculated mass of 38.5 kDa. The bacterially expressed central third of NIPP-1 completely inhibited the type-1 catalytic subunit, but displayed a reduced inhibitory potency after phosphorylation by protein kinase A and casein kinase 2. Translation of NIPP-1 mRNA in reticulocyte lysates resulted in the accumulation of both intact NIPP-1 and a smaller polypeptide generated by alternative initiation at the codon corresponding to Met143. A data base search showed that the COOH terminus of NIPP-1 is nearly identical to the human ard-1 protein (13 kDa), which has been implicated in RNA processing (Wang, M., and Cohen, S. N. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 10591-10595). Comparison of the cDNAs encoding ard-1 and NIPP-1 suggests that their mRNAs are generated by alternative splicing of the same pre-mRNA. Western blotting with antibodies against the COOH terminus of NIPP-1, however, showed a single polypeptide of 47 kDa, which was enriched in the nucleus. Northern analysis revealed a single transcript of 2.2 kilobases in bovine thymus and of 2.4 kilobases in various human tissues.
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PMID:Molecular cloning of NIPP-1, a nuclear inhibitor of protein phosphatase-1, reveals homology with polypeptides involved in RNA processing. 749 93

In this study, we examined the role of insulin, protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) cascade in activation of protein phosphatase-1 (PP-1) by using three complementary approaches. First, differentiated L6 cells were acutely exposed to 12-O-tetradecanoylphorbol-13-acetate (TPA, 400 nM) to activate PKC. In these cells, TPA caused 32% stimulation of PP-1 activity. The PP-1 stimulation by TPA was comparable to stimulation by insulin (t1/2 = 1 min and EC50 = 5 nM) with a maximum effect in 5 min. The effects of insulin and TPA were not additive. Insulin and TPA also stimulated MAPK (> 2-fold increase over basal, with myelin basic protein as a substrate). ML-9, a myosin light chain kinase inhibitor, blocked the effects of insulin and TPA on both MAPK and PP-1 activation. In the second approach, PKC was down-regulated by chronic treatment with TPA. In these cells subsequent effects of insulin on MAPK and PP-1 activation were blocked, without an effect on basal enzyme levels. In the third approach, two selective inhibitors of PKC, calphostin and chelerythrine chloride, were used to inhibit PKC. These inhibitors completely prevented insulin and TPA stimulation of MAPK and PP-1 and blocked insulin-induced translocation of PKC to the plasma membranes. We conclude that PKC plays an important role in insulin stimulation of PP-1 via the activation of MAPK cascade.
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PMID:Stimulation of protein phosphatase-1 activity by phorbol esters. Evaluation of the regulatory role of protein kinase C in insulin action. 751 82

Levels of the mRNA encoding the catalytic subunit of protein phosphatase type-1 (PP-1cat) were reduced in skeletal muscle but not liver in response to short-term (2h) chow refeeding after prolonged (40h) starvation in the rat. This reduction did not appear to be mediated by insulin per se since streptozotocin-induced diabetes was associated with a reduction in PP-1cat levels in skeletal muscle. It is suggested that glucose levels may be one factor that modulates skeletal muscle PP-1cat mRNA levels. Despite the changes in PP-1cat mRNA levels in skeletal muscle, total protein phosphatase-1 catalytic activity was not altered by either chow refeeding or streptozotocin-diabetes. By contrast, although total hepatic PP-1cat mRNA levels were not altered in response to chow refeeding, there was a marked reduction in glycogen phosphorylase phosphatase activity in the cytosol but not in the glycogen/microsomal fraction.
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PMID:Protein phosphatase type-1 mRNA levels in response to starvation-refeeding and streptozotocin-diabetes. 754 40

The Saccharomyces cerevisiae gene PPZ1 codes for a 692-residues protein that shows in its carboxyl-terminal half about 60% identity with the catalytic subunit of mammalian and yeast protein phosphatase-1 and that is involved in salt homeostasis. The complete PPZ1 protein has been successfully expressed as a soluble glutathione-S-transferase fusion protein. The recombinant protein, after purification by a single affinity chromatography step, displayed phosphatase activity towards a number of substrates, including myelin basic protein, histone 2A and casein, but was ineffective in dephosphorylating glycogen phosphorylase. It was also active towards p-nitrophenylphosphate. The activity was severalfold increased by the presence of Mn2+ ions and by limited trypsinolysis. The enzyme was inhibited by okadaic acid and microcystin-LR at concentrations comparable to what is found for type 1 protein phosphatase although it was much less sensitive to inhibitor-2. The recombinant protein was phosphorylated in vitro by cAMP-dependent protein kinase, protein kinase C and casein kinase-2. Phosphorylation affected preferentially sites located in the amino-terminal half of the protein and did not alter the activity of the phosphatase.
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PMID:Biochemical characterization of recombinant yeast PPZ1, a protein phosphatase involved in salt tolerance. 761 85

The activity of protein phosphatase-1 in rat liver nuclei (PP-1N) was decreased by up to 97% by associated inhibitory polypeptides, depending on the assay and extraction conditions. These inhibitors were rapidly degraded by endogenous proteases, resulting in the accumulation of active heat-stable intermediates. Two major species of PP-1N could be differentiated by fractionation of a nuclear extract. PP-1NR111 contained, besides the delta-isoform of the catalytic subunit, an inhibitory polypeptide of 111 kDa. PP-1NR41 was found to be an inactive heterodimer between the delta-isoform of the catalytic subunit and NIPP-1, a nuclear inhibitor of PP-1, which in its undegraded form is heat labile and migrates during SDS-polyacrylamide gel electrophoresis as a polypeptide of 41 kDa. Native hepatic NIPP-1 displayed a reduced affinity for the catalytic subunit after phosphorylation by protein kinase A in vitro and after glucagon-induced phosphorylation in vivo.
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PMID:Subunit structure and regulation of protein phosphatase-1 in rat liver nuclei. 761 25

Microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated in affected neurons of Alzheimer disease brain. This hyperphosphorylated tau can be dephosphorylated at some of the abnormal phosphorylated sites by purified protein phosphatase-1, 2A, and 2B in vitro. In the present study, we have developed an assay to measure protein phosphatase activity toward tau-1 sites (Ser199/Ser202) using the hyperphosphorylated tau isolated from Alzheimer disease brain as substrate. Using this assay, we have identified that in normal brain, protein phosphatase-2A and 2B and, to a lesser extent, 1 are involved in the dephosphorylation of tau. The Km values of dephosphorylation of the hyperphosphorylated tau by protein phosphatase-2A and 2B are similar. The tau phosphatase activity is decreased by approximately 30% in brain of Alzheimer disease patients compared with those of age-matched controls. These findings suggest that a defect of protein phosphatase could be the cause of the abnormal hyperphosphorylation of tau in Alzheimer disease.
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PMID:Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. 761 30

The crystal structure of mammalian protein phosphatase-1, complexed with the toxin microcystin and determined at 2.1 A resolution, reveals that it is a metalloenzyme unrelated in architecture to the tyrosine phosphatases. Two metal ions are positioned by a central beta-alpha-beta-alpha-beta scaffold at the active site, from which emanate three surface grooves that are potential binding sites for substrates and inhibitors. The carboxy terminus is positioned at the end of one of the grooves such that regulatory sequences following the domain might modulate function. The fold of the catalytic domain is expected to be closely preserved in protein phosphatases 2A and 2B (calcineurin).
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PMID:Three-dimensional structure of the catalytic subunit of protein serine/threonine phosphatase-1. 765 33

The form of protein phosphatase-1 associated with hepatic glycogen (PP1G) was purified to near homogeneity from rat liver by affinity chromatography on microcystin-Sepharose and gel-filtration. The enzyme is a heterodimer consisting of the catalytic subunit of PP1 (the alpha and beta isoforms) complexed to a 33 kDa glycogen-binding (GL) subunit. The GL subunit binds phosphorylase a with high affinity, and is responsible for the enhanced dephosphorylation of glycogen synthase by PP1G and its allosteric inhibition by phosphorylase a.
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PMID:Purification of the hepatic glycogen-associated form of protein phosphatase-1 by microcystin-Sepharose affinity chromatography. 772 Aug 53


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