Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ATP-Mg-dependent phosphoprotein phosphatase is believed to consist of a catalytic subunit and a regulatory component identified as phosphatase inhibitor-2. It was found in this study that isolated inhibitor-2 was phosphorylated in serine residues by casein kinase II to at least 3 mol of phosphate per mol of inhibitor-2 while another protein kinase, F A/GSK-3, introduced no more than 0.3 mol of phosphate per mol exclusively in threonine residues. Analysis of tryptic digests by high performance liquid chromatography indicated that casein kinase II action resulted in two major (peaks 1 and 2) and two minor phosphopeptides whereas F A/GSK-3 action generated only peak 2. Combined action of the two protein kinases introduced an additional 0.4-0.6 mol of phosphate per mol over that predicted for simple additive behavior. This synergistic phosphorylation was associated with increased phosphate in peak 2 and correlated with unchanged phosphoserine but increased phosphothreonine, to a level approaching 1 mol/mol. ATP-Mg-dependent protein phosphatase was either reconstituted from purified inhibitor-2 and low molecular weight type 1 phosphatase or isolated as an inactive complex (Fc). Both phosphatase complexes were activated by F A/GSK-3 which caused a transient phosphorylation of the inhibitor-2 component. Casein kinase II alone phosphorylated the inhibitor-2 in both phosphatase complexes without affecting the enzyme activity. Exposure to the combination of F A/GSK-3 and casein kinase II resulted in a synergistic phosphorylation. Furthermore, the combined action of the two protein kinases caused a synergistic activation of the phosphatase at submaximal F A/GSK-3 levels. The results suggest that interactions between phosphorylation sites may play a role in the activation of the ATP-Mg-dependent phosphatase, in particular that phosphorylation by casein kinase II at serine can potentiate the phosphorylation of threonine by F A/GSK-3 with subsequent influence on phosphatase activation.
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PMID:Synergistic phosphorylation and activation of ATP-Mg-dependent phosphoprotein phosphatase by F A/GSK-3 and casein kinase II (PC0.7). 609 Apr 57

A protein kinase, able to phosphorylate casein, phosvitin, and glycogen synthase, was purified approximately 9000-fold from rabbit liver, and appeared analogous to an enzyme studied by Itarte and Huang (Itarte, E., and Huang, K.-P. (1979) J. Biol. Chem. 254, 4052-4057). This enzyme, designated here casein kinase-1, was shown to be a distinct glycogen synthase kinase and in particular to be different from the protein kinase GSK-3 (Hemmings, B.A., Yellowlees, D., Kernohan, J.C., and Cohen, P. (1981) Eur. J. Biochem. 119, 443-451). Casein kinase-1 had native molecular weight of 30,000 as judged by gel filtration. The enzyme phosphorylated beta-casein A or B better than kappa-casein or alpha s1-casein, and modified only serine residues in beta-casein B and phosvitin. The apparent Km for ATP was 11 microM, and GTP was ineffective as a phosphoryl donor. The phosphorylation of glycogen synthase by casein kinase-1 was inhibited by glycogen, half-maximally at 2 mg/ml, and by heparin, half-maximally at 0.5-1.0 microgram/ml, but was unaffected by Ca2+ and/or calmodulin, or by cyclic AMP. Phosphorylation of muscle glycogen synthase proceeded to a stoichiometry of at least 6 phosphates/subunit with reduction in the +/- glucose-6-P activity ratio to less than 0.4. Phosphate was introduced into both a COOH-terminal CNBr fragment (CB-2) as well as a NH2-terminal fragment (CB-1). At a phosphorylation stoichiometry of 6 phosphates/subunit, 84% of the phosphate was associated with CB-2 and 6.5% with CB-1. The remainder of the phosphate was introduced into another CNBr fragment of apparent molecular weight 16,500. Phosphorylation by casein kinase-1 correlated with reduced electrophoretic mobilities, as analyzed on polyacrylamide gels in the presence of sodium dodecyl sulfate, of the intact glycogen synthase subunit, as well as the CNBr fragments CB-1 and CB-2.
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PMID:Glycogen synthase kinases. Classification of a rabbit liver casein and glycogen synthase kinase (casein kinase-1) as a distinct enzyme. 632 24

The conservation in evolution of fundamental signal transduction modules offers a means of isolating genes likely to be involved in plant development. We have amplified by PCR Arabidopsis cDNA and genomic sequences related to the product of the shaggy/zeste-white 3 (sgg) segment polarity gene of Drosophila. This regulatory protein is functionally homologous to glycogen synthase kinase-3 in mammals (GSK-3), which regulates, among others, the DNA-binding activity of the c-jun/AP1 transcription factor. Analysis of PCR products led to the identification of five genes; for two of which, corresponding full-length cDNAs, ASK-alpha and gamma (for Arabidopsis shaggy-related protein kinase), were characterized. The encoded proteins were 70% identical to GSK-3 and sgg over the protein kinase catalytic domain and, after production in Escherichia coli, autophosphorylated mainly on threonine and serine residues, but phosphotyrosine was also detected. ASK-alpha and ASK-gamma also phosphorylated phosphatase inhibitor-2 and myelin basic protein, on threonine and serine, respectively. The high conservation of the protein kinases of GSK-3 family, and their action at the transcriptional level, suggest that the ASK proteins have important functions in higher plants.
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PMID:Arabidopsis homologs of the shaggy and GSK-3 protein kinases: molecular cloning and functional expression in Escherichia coli. 750 23

In a previous study, protein kinase FA/glycogen synthase kinase-3 (FA/GSK-3) was identified as a myelin basic protein (MBP) kinase associated with intact brain myelin. In this report, the phosphorylation sites of MBP by kinase FA/GSK-3 were further determined by two-dimensional electrophoresis/TLC, phosphoamino acid analysis, tryptic peptide mapping, Edman degradation, and direct sequencing. Kinase FA/GSK-3 phosphorylates MBP on both threonine and serine residues. Three tryptic phosphopeptide peaks were resolved by C18 reverse-phase HPLC. Sequential manual Edman degradation together with direct sequence analysis revealed that T(p)PPPSQGK is the phosphorylation site sequence for the first major phosphopeptide peak. When mapping with the bovine brain MBP sequence, we finally demonstrate Thr97-Pro, one of the in vivo phosphorylation sites in MBP, as the major site phosphorylated by kinase FA/GSK-3, implicating a physiologically relevant role of FA/GSK-3 in the regulation of brain myelin function. By using the same approach, we also identified NIVT94(p)PR as the phosphorylation site sequence in the second major tryptic phosphopeptide derived from [32P]MBP phosphorylated by kinase FA/GSK-3, further indicating that kinase FA/GSK-3 represents a Thr-Pro motif-directed MBP kinase involved in the phosphorylation of brain myelin.
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PMID:Protein kinase FA/glycogen synthase kinase-3 predominantly phosphorylates the in vivo site Thr97-Pro in brain myelin basic protein: evidence for Thr-Pro and Ser-Arg-X-X-Ser as consensus sequence motifs. 751 Jul 85

Spleen TPK-IIB is an acidophilic protein tyrosine kinase, devoid of autophosphorylation activity, whose phosphorylation of the src-peptide NEYTA is crucially specified by Glu-2[(1991) J. Biol. Chem. 266, 17798-17803]. We show that phosphothreonine, phosphotyrosine and phosphoserine are, in this order, specificity determinants even more effective than glutamic acid if they are replacing Glu-2, to give the phosphopeptides NTpYTA, NYpYTA, NSpYTA, respectively. Non-phosphorylated threonine, tyrosine and serine are conversely ineffective. Consequently also the heptapeptide GEGTYGV reproducing the phosphoacceptor and inhibitory site of p34cdc2 is not appreciably affected by TPK-IIB, unless its threonyl residue is previously phosphorylated, the phosphoderivative GEGTpYGV being readily phosphorylated at its tyrosyl residue. Such a behaviour is unique for TPK-IIB among the protein tyrosine kinases tested (lyn-TPK, fgr-TPK and EGF-receptor, besides TPK-IIB). These data provide the first evidence that, in some instances, the targeting by protein tyrosine kinases can be specifically determined by the previous phosphorylation of the peptide substrate, thus extending the concept of 'hierarchal phosphorylation' [(1991) J. Biol. Chem. 266, 14139-14142] to tyrosyl residues as well.
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PMID:Phosphorylated residues as specificity determinants for an acidophilic protein tyrosine kinase. A study with src and cdc2 derived phosphopeptides. 768 79

The cAMP-dependent protein kinase (PKA) phosphorylates CREB327/341 at a single serine residue, Ser119/133, respectively. Phosphorylation at this site creates the sequence motif SXXXS(P), a consensus site of the glycogen synthase kinase-3 (GSK-3) enzyme (Fiol, C.J., Mahrenholz, A.M., Wang, Y., Roeske, R.W., and Roach, P.J. (1987) J. Biol. Chem. 262, 14042-14048). We examined the phosphorylation of CREB at the SXXXS(P) consensus site and its role in CREB transactivation to cAMP induction. Neither isoform of the GSK-3 enzyme (GSK-3 alpha or beta) utilizes CREB as its substrate unless CREB is already phosphorylated at Ser119/133. A 13-amino acid peptide containing the sequence surrounding Ser119/133 was phosphorylated by GSK-3, at Ser115/129, only after the primary phosphorylation of the peptide by PKA (at Ser119/133), suggesting that Ser115/129 is a GSK-3 phosphoacceptor site. Mutant CREB327/341 proteins containing Ser-->Ala substitutions confirmed Ser115/129 as the only GSK-3 phosphorylation site. Transfection assays of wild type and mutant Gal4-CREB fusion proteins in PC12 cells demonstrated that Ser-->Ala substitution of residue 129 of CREB341 impairs the transcriptional response to cAMP induction. Analogous mutation in CREB327 results in 70% decrease in its transactivation response to cAMP. In undifferentiated F9 cells, which are refractory to cAMP induction, transfected GSK-3 beta kinase induces a 60-fold increase in cyclic AMP response element-dependent transcription, mediated via the endogenous CREB protein. We propose that the hierarchical phosphorylation at the PKA and GSK-3 sites of CREB are essential for cAMP control of CREB.
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PMID:A secondary phosphorylation of CREB341 at Ser129 is required for the cAMP-mediated control of gene expression. A role for glycogen synthase kinase-3 in the control of gene expression. 779 17

We report here the isolation of the Arabidopsis thaliana gene AtK-1. The predicted protein sequence of AtK-1 shows 70% identity to the Arabidopsis ASK and alfalfa MsK kinases that are homologs of the Drosophila shaggy and rat GSK-3 serine/threonine protein kinases playing an important role in signal transduction processes in animals. Northern analysis of different organs revealed exclusive expression in inflorescences suggesting an involvement of the AtK-1 kinase in reproduction-specific processes.
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PMID:Inflorescence-specific expression of AtK-1, a novel Arabidopsis thaliana homologue of shaggy/glycogen synthase kinase-3. 786 93

To identify consensus sequence motif for a new family of protein kinase termed autophosphorylation-dependent protein serine/threonine kinase (auto-kinase), we have tested several synthetic peptides. The well established protein serine/threonine kinases such as cAMP-dependent protein kinase, Ca2+/calmodulin-dependent protein kinase (CaM-kinase), and protein kinase C were found to be inactive toward phosphorylation of syntide-3 (RPRPASVPPSPSLSRHA), which turned out to be an excellent substrate only for auto-kinase, indicating that syntide-3 is a specific substrate for auto-kinase. Modification of syntide-3 to become RPRPASVPPS/T did not affect the activity of auto-kinase. By contrast, autokinase became rather or almost inactive when the peptide was modified to become RPRPASVPPA/G/F/K/R/D/E/Y, indicating that amino acid number 10 in syntide-3 is crucial to the sequence motif recognized by auto-kinase. Phosphorylation of myelin basic protein (MBP) by autokinase revealed that auto-kinase predominantly phosphorylates MBP on one particular site with RT-T(p)HYGS as the phosphorylation site sequence, which could not be phosphorylated by any other reported MBP kinases including cAMP-dependent protein kinase, CaM-kinase, protein kinase C, mitogen-activated protein kinase, and kinase FA/GSK-3. Taken together, the results provide initial evidence that -Arg-X-(X)-Ser/Thr-X3-Ser/Thr- may represent a unique consensus sequence motif specifically recognized by autophosphorylation-dependent protein kinase, a new family of multi-substrate/multifunctional protein serine/threonine kinase.
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PMID:Identification of -R-X-(X)-S/T-X3-S/T- as consensus sequence motif for autophosphorylation-dependent protein kinase. 785 32

Glycogen synthase kinase 3 (GSK-3) is involved in the regulation of several metabolic enzymes and transcription factors in response to extracellular signals. Here we report the use of a synthetic peptide derived from the sequence of the cyclic AMP responsive element binding protein (CREB) as a specific substrate for GSK-3 isoforms. The 13-amino acid peptide, KRREILSRRPSYR, was phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PKA) and purified on a C18 cartridge. Phosphorylation of the COOH-terminal serine of the peptide by PKA creates a phosphorylation site for GSK-3 since GSK-3 recognizes the consensus motif -S-X-X-X-S(P)-. Although the COOH-terminal serine of the peptide can be phosphorylated by PKA and several other kinases, the phospho-CREB peptide is specific for GSK-3 with Kms of 140 and 200 microM for GSK-3 alpha and GSK-3 beta isoforms, respectively. Using the phospho-CREB peptide, we have successfully purified GSK-3 activity from rabbit skeletal muscle and Escherichia coli cells transformed with a GSK-3 expression vector. The assay described provides a convenient and specific determination of GSK-3 activity.
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PMID:Use of a synthetic peptide as a selective substrate for glycogen synthase kinase 3. 797 84

Glycogen synthase kinase-3 (GSK-3), a protein-serine kinase implicated in cell-fate determination and differentiation, phosphorylates several regulatory proteins that are activated by dephosphorylation in response to hormones or growth factors. GSK-3 beta is phosphorylated in vitro at serine 9 by p70 S6 kinase and p90rsk-1, resulting in its inhibition [Sutherland, Leighton, and Cohen (1993) Biochem. J. 296, 15-19]. Using HeLa cells expressing GSK-3 beta or a mutant containing alanine at residue 9, we demonstrate that serine 9 is modified in intact cells and is targeted specifically by p90rsk-1, and that phosphorylation leads to loss of activity. Since p90rsk-1 is directly activated by mitogen-activated protein kinases, agonists of this pathway, such as insulin, repress GSK-3 function.
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PMID:Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. 798 Apr 35


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