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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The major phosphorylation site for both casein kinase-2 (CK2) and casein kinase-1 (CK1) in protein phosphatase-1 (PP-1) inhibitor-2 (I-2) is Ser86. Minor phosphorylation sites affected by either CK2 or CK1 are Ser120/Ser121 and Ser174, respectively. A synthetic peptide of 25 amino acids encompassing residues 67-93 of I-2 is phosphorylated by either CK2 or CK1 at its seryl residue corresponding to Ser86 with higher Vmax and Km values similar to those of the intact protein (9 vs 7.2 microM and 14.2 vs 5.3 microM with CK2 and CK1, respectively). No detectable phosphorylation of this peptide which also includes the glycogen synthase kinase-3 (GSK-3) site (Thr72), could be observed with either GSK-3 or p34cdc2 kinase whether or not its seryl residue equivalent to Ser86 had been previously phosphorylated by CK2. Shorter derivatives of I-2(67-93), encompassing residues 72-93 and 78-93, are also readily phosphorylated by both CK1 and CK2, with phosphorylation efficiencies similar to those of the parent peptide. A synthetic heptadecapeptide reproducing the phosphoacceptor site around Ser120/Ser121 is phosphorylated by CK2, but not to any detectable extent by CK1, with a Km value fivefold higher than that of the corresponding pentadecapeptide including Ser86 (78-93). A synthetic pentadecapeptide (166-180) reproducing the phosphoacceptor site around Ser174 is phosphorylated by CK1 less efficiently than the pentadecapeptide including its main phosphorylation site (78-93) (Km 280 microM vs 33 microM). This peptide is readily phosphorylated by CK2 as well, although it lacks the canonical consensus sequence for CK2 and its Ser174 is almost unaffected by CK2 in intact I-2. These data provide the clear-cut demonstration that the consensus sequence with N-terminal prephosphorylated residue(s), SerP/ThrP-Xaa-Xaa-Ser/Thr, [Flotow, H., Graves, P. R., Wang, A., Fiol, C. J., Roeske, R. W. & Roach, P. J. (1990) J. Biol. Chem. 265, 14264-14269; Meggio, F., Perich, J. W., Reynolds, E. C. & Pinna, L. A. (1991) FEBS Lett. 283, 303-306] is not always required to achieve efficient and high-affinity phosphorylation by CK1. They also show that the specificity determinants for I-2 phosphorylation by either CK2 or CK1, but not by GSK3, are entirely grounded on local structural features of the phosphoacceptor site, being only marginally affected by the overall structure of I-2.
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PMID:Phosphorylation of synthetic fragments of inhibitor-2 of protein phosphatase-1 by casein kinase-1 and -2. Evidence that phosphorylated residues are not strictly required for efficient targeting by casein kinase-1. 805 35

The beta-isoform of glycogen synthase kinase-3 (GSK3 beta) isolated from rabbit skeletal muscle was inactivated 90-95% following incubation with MgATP and either MAP kinase-activated protein kinase-1 (MAPKAP kinase-1, also termed RSK-2) or p70 S6 kinase (p70S6K), and re-activated with protein phosphatase 2A. MAPKAP kinase-1 and p70S6K phosphorylated the same tryptic peptide on GSK3 beta, and the site of phosphorylation was identified as the serine located nine residues from the N-terminus of the protein. The inhibitory effect of Ser-9 phosphorylation on GSK3 beta activity was observed with three substrates, (inhibitor-2, c-jun and a synthetic peptide), and also with glycogen synthase provided that 0.15 M KCl was added to the assays. The results suggest that Ser-9 phosphorylation underlies the reported inhibition of GSK3 beta by insulin and that GSK3 may represent a point of convergence of two major growth-factor-stimulated protein kinase cascades.
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PMID:Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. 825 Aug 35

Phosphorylation of inhibitor 2, the regulatory subunit of the ATP-Mg-dependent protein phosphatase, by glycogen synthase kinase 3 (GSK-3) causes activation of the phosphatase. Prior phosphorylation by casein kinase II has been shown to enhance both phosphorylation and activation of the phosphatase by GSK-3 (DePaoli-Roach, A. A. (1984) J. Biol. Chem. 259, 12144-12152). Reported here is a comparison of the phosphorylation of inhibitor 2 by two defined isoforms of GSK-3, GSK-3 alpha and GSK-3 beta. GSK-3 beta was a significantly better inhibitor 2 kinase than was GSK-3 alpha. The Vmax/Km value for GSK-3 beta was approximately 10-fold higher than that for GSK-3 alpha. GSK-3 beta phosphorylated inhibitor 2 to a stoichiometry of approximately 1.0 mol of phosphate/mol of inhibitor 2. The phosphorylation by GSK-3 beta was determined to be exclusively at Thr-72 on the basis of the inability of the enzyme to modify a mutant inhibitor 2 in which Thr-72 was changed to alanine. Prior phosphorylation by casein kinase II promoted the action of GSK-3 alpha in keeping with earlier reports using undefined GSK-3 preparations. Phosphorylation by GSK-3 beta, in contrast, was unaffected by the previous action of casein kinase II. These results suggest that there can be important differences in substrate recognition by different isoforms of the same protein kinase and may help explain why some reported GSK-3 substrates require prior phosphorylation whereas other do not.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isoform differences in substrate recognition by glycogen synthase kinases 3 alpha and 3 beta in the phosphorylation of phosphatase inhibitor 2. 828 31

The alpha-isoform of glycogen synthase kinase-3 (GSK3 alpha) was inactivated by 80% towards a synthetic peptide substrate upon incubation with Mg-ATP and either MAP kinase-activated protein (MAPKAP) kinase-1 or p70 S6 kinase. Inactivation by either kinase resulted from the phosphorylation of Ser-21 and was reversed by treatment with protein phosphatase 2A1. Phosphorylation also decreased GSK3 alpha activity towards glycogen synthase, inhibitor-2 and c-jun. The specificity of GSK3 alpha was similar to GSK3 beta, but with the synthetic peptide substrate heparin stimulated the dephosphorylated form of GSK3 alpha (6-fold) more than GSK3 beta (1.8-fold). After phosphorylation, both isoforms were stimulated 15-20-fold by heparin.
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PMID:The alpha-isoform of glycogen synthase kinase-3 from rabbit skeletal muscle is inactivated by p70 S6 kinase or MAP kinase-activated protein kinase-1 in vitro. 830 53

Glycogen synthase kinase-3 (GSK-3) is a protein serine kinase implicated in the cellular response to insulin. The enzyme is the mammalian homologue of the zeste-white3 (shaggy) homeotic gene of Drosophila melanogaster and has been implicated in the regulation of the c-Jun/AP-1 transcription factor. In mammals this protein serine kinase is encoded by two related genes termed GSK-3 alpha and beta. Here, we demonstrate that these two proteins and the fruit fly protein are phosphorylated on tyrosine in vivo. Moreover, GSK-3 beta activity and function are shown to be dependent on tyrosine phosphorylation. The modified tyrosine residue is conserved in all members of the GSK-3 family and is equivalent to that required for activity by mitogen-activated protein (MAP) kinases. However, unlike MAP kinases, GSK-3 is highly phosphorylated on tyrosine and thus active in resting cells.
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PMID:Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. 838 13

During neurogenesis in Drosophila, groups of equipotential, neurally competent cells choose between epidermal and neural fates. Notch, a phylogenetically conserved transmembrane protein, may act as a receptor in a lateral signalling pathway in which a single neural precursor is chosen from each group and the neural fate of the other cells is inhibited, causing them to differentiate into epidermis. Possible intracellular transduction events mediating signals from Notch are, however, unknown. shaggy is also required for the lateral signal and encodes serine/threonine protein kinases with homology to the glycogen synthase kinase-3 (GSK-3) enzymes that act in signal transduction pathways in vertebrates. We report here that, in transgenic flies, GSK-3 beta can substitute for shaggy, and we also present a study of epistatic relationships between shaggy and gain and loss of function alleles of Notch. The results indicate that shaggy/GSK-3 is part of a signalling pathway downstream of Notch.
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PMID:Drosophila shaggy kinase and rat glycogen synthase kinase-3 have conserved activities and act downstream of Notch. 838 71

We examined the subcellular distribution of two glycogen synthase kinase-3 (GSK-3) isoforms in rat cerebellum. Results from immunoelectron microscopy and subcellular fractionation revealed that one isoform, tau protein kinase I/GSK-3 beta (TPKI/GSK-3 beta), was present in mitochondria, but GSK-3 alpha was not. Although the two GSK-3 isoforms seem to have similar properties, the difference of subcellular localization observed here suggests that TPKI/GSK-3 beta fulfills some specific function in mitochondria.
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PMID:Different localization of tau protein kinase I/glycogen synthase kinase-3 beta from glycogen synthase kinase-3 alpha in cerebellum mitochondria. 857 78

Exogenous application of synthetic amyloid beta protein (A beta) is known to induce neurotoxic effects in rat hippocampal culture. We report here that A beta (25-35) induces accumulation of amyloid precursor protein (APP) derivatives in the cytoplasm of neurons. At the same time, the level of the secreted form of APP released into the culture medium decreases. Tau protein kinase I/glycogen synthase kinase-3 beta (TPK I/GSK-3 beta) antisense oligonucleotide blocked APP accumulation and prevented neuronal death. These results provide evidence that APP accumulation after A beta treatment is regulated by TPK I/GSK-3 beta. A beta neurotoxicity is probably mediated via phosphorylation of tau by TPK I/GSK-3 beta, resulting in an impairment of axonal transport, and cytoplasmic accumulation of APP.
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PMID:Amyloid beta peptide induces cytoplasmic accumulation of amyloid protein precursor via tau protein kinase I/glycogen synthase kinase-3 beta in rat hippocampal neurons. 859 47


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