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)

The polypeptide with a mobility of the tryptophanyl-tRNA-synthetase subunit can be labeled in bovine pancreas extracts from [gamma-32P]ATP. Immunoprecipitation analysis with monospecific polyclonal antibodies against the enzyme as well as identification of [32P]phosphoamino acids in the immunoprecipitate revealed that in bovine pancreas extracts tryptophanyl-tRNA-synthetase undergoes phosphorylation at serine residues. The level of phosphorylation does not change in the presence of activity modulators of cAMP-, cGMP- and Ca2(+)-dependent protein kinases, decreases after addition of phosphoseryl/phosphothreonyl-protein phosphatase inhibitors and increases in the presence of their activators. It was supposed that phosphorylation of tryptophanyl-tRNA-synthetase catalyzed by seryl/threonyl-specific protein kinase depends on the activity of phosphoseryl/phosphothreonyl-phosphatase.
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PMID:[Phosphorylation of tryptophanyl-tRNA-synthase in extracts of bovine pancreas]. 212 Dec 90

We have previously reported that the enzymic activity of rat liver-3-hydroxy-3-methyl-glutaryl-CoA reductase (NADPH) (HMG-CoA reductase) is modulated in vitro by a phosphorylation-dephosphorylation reaction sequence. The in vitro phosphorylation of HMG-CoA reductase was further studied by utilizing purified HMG-CoA reductase and reductase kinase. Analysis of 32P-labeled HMG-CoA reductase revealed 1 mol of phosphate per subunit. Purified [32P]HMG-CoA reductase could be dephosphorylated with phosphoprotein phosphatase. To demonstrate the in vivo phosphorylation, rats were injected with 32P and hepatic HMG-CoA reductase was isolated by immunoprecipitation and also by purification of the enzyme to homogeneity. Analysis of [32P]HMG-CoA reductase by sodium dodecyl sulfate gel electrophoresis revealed a single peak of radioactivity comigrating with HMG-CoA reductase. Administration of glucagon enhances the in vivo phosphorylation of both HMG-CoA reductase and reductase kinase. In response to glucagon, HMG-CoA reductase activity is decreased whereas reductase kinase activity is increased. These results support our concept that the enzymic activity of HMG-CoA reductase is modulated by a bicyclic cascade system involving phosphorylation-dephosphorylation. The enzymic activity of HMG-CoA reductase has also been shown to be modulated by cholesterol and mevalonolactone by both short-term and long-term mechanisms. The effects of cholesterol and mevalonolactone are twofold. Rapid inhibition of HMG-CoA reductase activity is due to increased phosphorylation of the enzyme; the long-term effect of HMG-CoA reductase is achieved by reduction in enzyme concentration by modulation of enzyme synthesis and/or degradation. Regulation of HMG-CoA reductase by mevalonolactone is of major importance in cellular metabolism because mevalonate serves as precursor for four separate metabolic pathways, including the formation of cholesterol, ubiquinone, dolichols, and isopentenyl tRNA.
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PMID:Modulation of rat liver 3-hydroxy-3-methylglutaryl-CoA reductase activity by reversible phosphorylation. 628 63

Initiation factor eIF-2 (a trimer of subunits alpha, beta and gamma) attaches the initiator Met-tRNA to the ribosome during the initiation of translation in eukaryotic cells. Both the alpha and beta subunits can be phosphorylated although the sites in the beta-subunit have not previously been fully identified. Here we identify the sites at which eIF-2 beta is phosphorylated in vitro by three well-characterised protein kinases, casein kinase-2 (which phosphorylates serine residues-2 and -67), protein kinase C (serine-13) and cAMP-dependent protein kinase (serine-218). This constitutes an essential prerequisite for studying the phosphorylation of eIF-2 beta in vivo. Indeed, we present evidence that at least one of these sites (serine-67) is phosphorylated in reticulocytes. The major kinase activity against eIF-2 beta in reticulocyte lysates appears in CK-2 and protein phosphatase-2A is the principal enzyme responsible for dephosphorylation of eIF-2 beta phosphorylated by this kinase.
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PMID:Identification of novel phosphorylation sites in the beta-subunit of translation initiation factor eIF-2. 802 72

A 6.8 kbp DNA fragment localized to the left arm of chromosome XI from Saccharomyces cerevisiae was sequenced and analysed (EMBL accession no. X69765). Two genes involved in protein phosphatase activity were identified: YCN2 and an open reading frame encoding a protein that shares 46% amino acid identity with the sds22+ protein from Schizosaccharomyces pombe. A comparison of the genomic YCN2 sequence with the published cDNA sequence suggests the presence of an intron near the 5' end of the gene. Further sequence analysis suggests the presence of three additional genes near YCN2: a mitochondrial acyl-carrier protein, a gene encoding a putative hydrophobic protein, and a new gene coding for a tRNA(Leu) (UAA) isoacceptor located near a delta sequence.
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PMID:DNA sequence analysis of the YCN2 region of chromosome XI in Saccharomyces cerevisiae. 839 42

It has been suggested that the rate of queuine uptake into cultured human fibroblasts is controlled by phosphorylation levels within the cell. We show that the uptake of queuine is stimulated by activators of protein kinase C (PKC) and inhibitors of protein phosphatase; while inhibitors of PKC, and down-regulation of PKC by chronic exposure to phorbol esters inhibit the uptake of queuine into cultured human fibroblasts. Activators of cAMP- and cGMP-dependent kinases exert no effect on the uptake of queuine into fibroblast cell cultures. These studies suggest that PKC directly supports the activity of the queuine uptake mechanism, and that protein phosphatase activity in the cell acts to reverse this. Regardless of the modulation of uptake rate, the level of intracellular queuine base saturates in 6 h. However, there is still an effect on the incorporation rate of queuine into tRNA of fibroblast cultures even after 24 h. We now show that the incorporation of queuine into tRNA in cultured human fibroblasts by tRNA-guanine ribosyltransferase (TGRase) is also stimulated by activators of PKC and inhibitors of protein phosphatase; while inhibitors of PKC decrease the activity of this enzyme. These studies suggest that PKC supports both the cellular transport of queuine and the activity of TGRase in cultured human fibroblasts, and that protein phosphatase activity in fibroblasts acts to reverse this phenomenon. A kinase-phosphatase control system, that is common to controlling both intracellular signal transduction and many enzyme systems, appears to be controlling the availability of the queuine substrate and the mechanism for its incorporation into tRNA. Since hypomodification of transfer RNA with queuine is commonly observed in undifferentiated, rapidly growing and neoplastically transformed cells, phosphorylation of the queuine modification system may be a critical regulatory mechanism for the modification of tRNA and subsequent control of cell growth and differentiation.
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PMID:Modulation of queuine uptake and incorporation into tRNA by protein kinase C and protein phosphatase. 863 Mar 30

A continuous 75627 bp segment of the Mycobacterium leprae chromosome spanning the oriC region was sequenced. The gene order at this locus was similar to that found in the replication origin region of many other prokaryotes, particularly Mycobacterium tuberculosis and Streptomyces coelicolor. As in the case of several Gram-positive bacteria, essential genes involved in basic cellular functions, such as DNA or RNA metabolism (dnaA, dnaB, dnaN, gyrB, gyrA, pcnB, recF, rnpA, ssb), cell wall synthesis (ponA, pbpA) and probably cell division (gidB, rodA) were found. Strikingly, the gidA gene was absent from this part of the genome and there was no rRNA operon near oriC. The gyrA gene harbours an intein coding sequence indicating that protein splicing is required to produce the mature A subunit of DNA gyrase. Among the many other noteworthy features were ORFs encoding putative serine/threonine protein kinases and a protein phosphatase, three tRNA genes, one M. leprae-specific repetitive element and a glnQ pseudogene.
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PMID:Gene arrangement and organization in a approximately 76 kb fragment encompassing the oriC region of the chromosome of Mycobacterium leprae. 896 12

We report a study of 10 candidate genes presumably involved in diabetes or insulin resistance or obesity among Pondicherian Tamil Indians, an isolated population with a high prevalence of diabetes. Forty-nine families with at least two affected patients in the sibship (567 individuals) were selected and tested by PCR-RFLP techniques for reported mutations in 10 diabetes or obesity candidate genes: glucagon receptor, insulin receptor substrate 1, insulin receptor, human beta 3 adrenergic receptor, fatty acid binding protein 2, mitochondrial tRNA(Leu(UUR)), sulphonylurea receptor, human uncoupling protein and the glycogen-associated regulatory subunit of protein phosphatase-1. Glucokinase gene was also screened for mutations. No mutations were found in glucokinase, glucagon receptor and mitochondrial genes in any of the 49 probands. Frequencies of polymorphisms at other loci were similar to those reported in Caucasian populations, except for 4 of the loci at which a higher frequency of variants was observed: human beta 3 adrenergic receptor, human uncoupling type 1 protein, fatty acid binding protein 2 and the glycogen-associated regulatory subunit of protein phosphatase-1. However, no evidence of association between any of these gene variants and non-insulin-dependent diabetes mellitus (NIDDM) or quantitative traits related to NIDDM (including body mass index, waist/hip ratio, insulinaemia, glycaemia, triglycerides and total cholesterol) was found in our sample. These results suggest that none of these gene variants commonly found in the Pondicherian Tamil population of South India is a major NIDDM predisposing locus, although it cannot be excluded that they may contribute to the polygenic background of the metabolic syndrome in Pondichery.
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PMID:Genetic studies of polymorphisms in ten non-insulin-dependent diabetes mellitus candidate genes in Tamil Indians from Pondichery. 969 58

Human alveolar macrophages, central to immune responses in the lung, are unique in that they have an extended life span in contrast to precursor monocytes. We have shown previously that the ERK MAPK (ERK) pathway is constitutively active in human alveolar macrophages and contributes to the prolonged survival of these cells. We hypothesized that ERK maintains survival, in part, by positively regulating protein translation. In support of this hypothesis, we have found novel links among ERK, JNK, protein phosphatase 1 (PP1), and the eukaryotic initiation factor (eIF) 2alpha. eIF2alpha is active when hypophosphorylated and is essential for initiation of protein translation (delivery of initiator tRNA charged with methionine to the ribosome). Using [(35)S]methionine labeling, we found that ERK inhibition significantly decreased protein translation rates in alveolar macrophages. Decreased protein translation resulted from phosphorylation (and inactivation) of eIF2alpha. We found that ERK inhibition increased JNK activity. JNK in turn inactivated (via phosphorylation) PP1, the phosphatase responsible for maintaining the hypophosphorylated state of eIF2alpha. As a composite, our data demonstrate that in human alveolar macrophages, constitutive ERK activity positively regulates protein translation via the following novel pathway: active ERK inhibits JNK, leading to activation of PP1alpha, eIF2alpha dephosphorylation, and translation initiation. This new role for ERK in alveolar macrophage homeostasis may help to explain the survival characteristic of these cells within their unique high oxygen and stress microenvironment.
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PMID:Active ERK contributes to protein translation by preventing JNK-dependent inhibition of protein phosphatase 1. 1684 72

The mammalian amino acid response (AAR) pathway is up-regulated by protein or amino acid depletion. This pathway involves detection of uncharged tRNA by the GCN2 kinase, phosphorylation of the translation initiation factor eIF2alpha (eukaryotic initiation factor 2alpha), and, through subsequent translational control, enhanced de novo synthesis of the transcription factor ATF4. The present studies demonstrate that inhibition of MEK activation in HepG2 human hepatoma cells by PD98059 or U0126 blocked the increased phosphorylation of eIF2alpha and ATF4 synthesis triggered by amino acid limitation, showing that the AAR requires activation of the MEK-ERK pathway. Inhibitors of the JNK or p38 MAPK pathways were ineffective. Consequently, inhibition of MEK activation blocked transcriptional induction of ATF4 target genes, but the induction was rescued by overexpression of ATF4 protein. Furthermore, the enhanced ERK phosphorylation following amino acid deprivation required GCN2 kinase activity and eIF2alpha phosphorylation. Inhibition of protein phosphatase 1 action on phospho-eIF2alpha by knockdown of GADD34 did not block the sensitivity to PD98059, suggesting that MEK functions to enhance GCN2-dependent eIF2alpha phosphorylation rather than suppressing dephosphorylation. Collectively, these results document a critical interdependence between the MEK-ERK MAPK signaling pathway and the amino acid stress-activated pathway.
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PMID:MEK signaling is required for phosphorylation of eIF2alpha following amino acid limitation of HepG2 human hepatoma cells. 1828 93

In yeast, the role for the Elongator complex in tRNA anticodon modification is affected by phosphorylation of Elongator subunit Elp1. Thus, hyperphosphorylation of Elp1 due to inactivation of protein phosphatase Sit4 correlates with Elongator-minus phenotypes including resistance towards zymocin, a tRNase cleaving anticodons of Elongator-dependent tRNAs. Here we show that zymocin resistance of casein kinase hrr25 mutants associates with hypophosphorylation of Elp1 and that nonsense suppression by the Elongator-dependent SUP4 tRNA is abolished in hrr25 or sit4 mutants. Thus changes that perturb the evenly balanced ratio between hyper- and hypophosphorylated Elp1 forms present in wild-type cells lead to Elongator inactivation. Antagonistic roles for Hrr25 and Sit4 in Elongator function are further supported by our data that Sit4 inactivation is capable of restoring both zymocin sensitivity and normal ratios between the two Elp1 forms in hrr25 mutants. Hrr25 binds to Elongator in a fashion dependent on Elongator partner Kti12. Like sit4 mutants, overexpression of Kti12 triggers Elp1 hyperphosphorylation. Intriguingly, this effect of Kti12 is blocked by hrr25 mutations, which also show enhanced binding of Kti12 to Elongator. Collectively, our data suggest that rather than directly targeting Elp1, the Hrr25 kinase indirectly affects Elp1 phosphorylation states through control of Sit4-dependent dephosphorylation of Elp1.
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PMID:Elongator function depends on antagonistic regulation by casein kinase Hrr25 and protein phosphatase Sit4. 1965 97


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