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

Immotile bovine caput epididymal sperm contain levels of protein phosphatase activity twofold higher than do mature motile caudal sperm. Comparison of the inhibition profiles of endogenous phosphatase activities detected by okadaic acid (OA) and calyculin A (CA) revealed a pattern consistent with the predominance of a type 1 protein phosphatase (PP1). Immunoblot analysis identified PP1 gamma 2 (the testis-specific isoform of PP1) as the only PP1 isoform in sperm and showed little protein phosphatase 2A (PP2A). In addition, of the known PP1 inhibitors, i.e., DARPP-32, inhibitor 1 (I1), and inhibitor 2 (I2), only I2-like activity was detected in sperm. Inhibition of PP1 by the heat-stable I2-like activity purified from sperm could be reversed with purified glycogen synthase kinase-3 (GSK-3). Furthermore, sperm extracts contain an inactive complex of PP1 and I2 (termed PP1I) that could also be activated by purified GSK-3. The presence of GSK-3 in sperm was demonstrated by activation of purified PP1I, and quantitation revealed that immotile caput sperm contained sixfold higher GSK-3 activity than motile caudal sperm. Immunoblot analysis confirmed the expression of GSK-3 in sperm and revealed the occurrence of both the alpha and beta isoforms. Our findings suggest that the higher PP1 activity measured in immotile sperm, presumably due to higher GSK-3 activity, is responsible for holding motility in check. This conclusion was supported by the observation that the phosphatase inhibitors OA and CA, at micromolar and nanomolar levels, respectively, were able to induce motility in completely immotile bovine caput epididymal sperm and to stimulate the kinetic activity of mature caudal sperm. The intrasperm levels of cAMP, pH, and calcium were unaltered by treatment with these inhibitors. The results suggest a biochemical basis for the development and regulation of sperm motility and a possible physiological role for the PP1/I2/GSK-3 system.
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PMID:Sperm motility development in the epididymis is associated with decreased glycogen synthase kinase-3 and protein phosphatase 1 activity. 883 95

TPK-IIB is a protein kinase that is predominant in the cytosol of spleen and is characterized by a high specific activity toward acidic peptide substrates and a low auto-phosphorylation activity. A prominent 52-kDa component purifies with the kinase [Marin, O., Donella-Deana, A., Brunati, A. M., Fischer, S. & Pinna, L. A. (1991) J. Biol. Chem. 266, 17798-17803]. Here we demonstrate that the 52-kDa protein displays sequence identity with the Miller-Dieker lissencephaly protein (LIS 1). The protein is not related to any known protein kinase and lacks an ATP-binding motif. The ATP binding and phosphotransferase activities of TPK-IIB can be fully accounted for by a minor 38-kDa protein band (p38/TPK-IIB) which can be separated from the 52-kDa protein by Mono-Q/FPLC in the presence of EDTA. Sequence analysis of p38/TPK-IIB reveals a high level of similarity, if not identity, with the catalytic domain of p72syk, a protein-tyrosine kinase implicated in the activation of hematopoietic cells. Antibodies raised against the catalytic domain of p72syk, but not antibodies raised against its N-terminal segment, cross-react with p38/TPK-IIB. The peptide substrate specificity of p72syk is almost identical to that of p38/TPK-IIB, which also supports the classification of TPK-IIB as a close relative (possibly a proteolytic or alternative spliced form) of p72syk. p38/TPK-IIB, however, exhibits a specific activity which is sixfold higher than that of p72syk and appears to be 50-fold more sensitive to inhibition by heparin. Thus, the observation that Ca(2+)-dependent degradation of p72syk by particulate fraction of rat spleen is accompanied by increased catalytic activity and increased sensitivity to heparin would be consistent with the possibility that hyperactive p38/TPK-IIB might be proteolytically generated from p72syk in response to an increase of intracellular Ca2+.
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PMID:The spleen protein-tyrosine kinase TPK-IIB is highly similar to the catalytic domain of p72syk. 884 5

Using immunohistochemistry, we examined the localization of four types of proline-directed kinases in the brains of control rats and in the brains of non-demented aged human subjects, subjects with Alzheimer's disease and those with Down's syndrome. The four kinases were: cyclin-dependent kinase (cdk) 5, a component of tau protein kinase (TPK) II; TPK I/glycogen synthase kinase (GSK)-3 beta; GSK-3 alpha; and mitogen-activated protein kinase (MAPK/ERK2). Each of these kinases has been reported to promote the hyperphosphorylation of tau protein in vitro. The kinases were located essentially in neurons, although the intensity and distribution of labeling varied. Antiserum for cdk5 showed the most preferential and consistent labeling of intraneuronal neurofibrillary tangles (NFT). Antiserum for TPK I/GSK-3 beta also labeled intraneuronal NFT. Double immunolabeling for TPK I/GSK-3 beta and tau 1 showed that TPK I/GSK-3 beta was closely associated with NFT. Antiserum for GSK-3 alpha labeled neurons weakly, and the intensity of labeling did not differ between neurons with and without NFT. Antiserum for MAPK labeled neurons in superficial cortical layers, but NFT appeared in both superficial and deep cortical layers. These findings suggest that cdk5 and TPK I/GSK-3 beta are the critically important kinases for the generation in vivo of hyperphosphorylated tau, the main component of the paired helical filaments in NFT.
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PMID:Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II. 887 Aug 24

The Drosophila gene product Wingless (Wg) is a secreted glycoprotein and a member of the Wnt gene family. Genetic analysis of Drosophila epidermal development has defined a putative paracrine Wg signalling pathway involving the zeste-white 3/shaggy (zw3/sgg) gene product. Although putative components of Wg- (and by inference Wnt-) mediated signalling pathways have been identified by genetic analysis, the biochemical significance of most factors remains unproven. Here we show that in mouse 10T1/2 fibroblasts the activity of glycogen synthase kinase-3 (GSK-3), the murine homologue of Zw3/Sgg, is inactivated by Wg. This occurs through a signalling pathway that is distinct from insulin-mediated regulation of GSK-3 in that Wg signalling to GSK-3 is insensitive to wortmannin. Additionally, Wg-induced inactivation of GSK-3 is sensitive to both the protein kinase C (PKC) inhibitor Ro31-8220 and prolonged pre-treatment of 10T1/2 fibroblasts with phorbol ester. These findings provide the first biochemical evidence in support of the genetically defined pathway from Wg to Zw3/Sgg, and suggest a previously uncharacterized role for a PKC upstream of GSK-3/Zw3 during Wnt/Wg signal transduction.
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PMID:Wingless inactivates glycogen synthase kinase-3 via an intracellular signalling pathway which involves a protein kinase C. 888 44

Computer analysis of protein phosphorylation-sites sequence revealed that most transcriptional factors and viral oncoproteins are prime targets for regulation of proline-directed protein phosphorylation, suggesting an association of proline-directed protein kinase (PDPK) family with neoplastic transformation and tumorigenesis. In this report, an immunoprecipitate activity assay of protein kinase FA/glycogen synthase kinase-3alpha (kinase FA/GSK-3alpha) (a particular member of PDPK family) has been optimized for human cervical tissue and used to demonstrate for the first time significantly increased (P < 0.001) activity in poorly differentiated cervical carcinoma (82.8 +/- 6.6 U/mg of protein), moderately differentiated carcinoma (36.2 +/- 3.4 U/mg of protein), and well-differentiated carcinoma (18.3 +/- 2.4 U/mg of protein) from 36 human cervical carcinoma samples when compared to 12 normal controls (4.9 +/- 0.6 U/mg of protein). Immunoblotting analysis further revealed that increased activity of kinase FA/GSK-3alpha in cervical carcinoma is due to overexpression of protein synthesis of the kinase. Taken together, the results provide initial evidence that overexpression of protein synthesis and cellular activity of kinase FA/GSK-3alpha may be involved in human cervical carcinoma dedifferentiation/progression, supporting an association of proline-directed protein kinase with neoplastic transformation and tumorigenesis. Since protein kinase FA/GSK-3alpha may function as a possible regulator of transcription factors/proto-oncogenes, the results further suggest that kinase FA/GSK-3alpha may play a potential role in human cervical carcinogenesis, especially in its dedifferentiation and progression.
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PMID:Association of protein kinase FA/GSK-3alpha (a proline-directed kinase and a regulator of protooncogenes) with human cervical carcinoma dedifferentiation/progression. 890 8

Dystrophin is a protein product of the gene responsible for Duchenne and Becker muscular dystrophy. The protein is localized to the inner surface of sarcolemma and is associated with a group of membrane (glyco)proteins. Dystrophin links cytoskeletal actins via the dystrophin-associated protein complex to extracellular matrix protein, laminin. This structural organization implicates the role of dystrophin in stabilizing the sarcolemma of muscle fibers. Precisely how dystrophin functions is far from clear. The presence of an array of isoforms of the C-terminal region of dystrophin suggests that dystrophin may have functions other than structural. In agreement, many potential phosphorylation sites are found in the C-terminal region of dystrophin, and the C-terminal region of dystrophin is phosphorylated both in vitro and in vivo by many protein kinases, including MAP kinase, p34cdc2 kinase, CaM kinase, and casein kinase, and is dephosphorylated by calcineurin. The C-terminal domain of dystrophin is also a substrate for hierarchical phosphorylation by casein kinase-2 and GSK-3. These observations, in accordance with the finding that the cysteine-rich region binds to Ca2+, Zn2+, and calmodulin, suggest an active involvement of dystrophin in transducing signals across muscle sarcolemma. Phosphorylation-dephosphorylation of the C-terminal region of dystrophin may play a role in regulating dystrophin-protein interactions and (or) transducing signal from the extracellular matrix via the dystrophin molecule to the cytoskeleton.
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PMID:Phosphorylation of the carboxyl-terminal region of dystrophin. 896 Mar 49

Several peptides derived from microtubule-associated tau protein, have been tested as substrates for glycogen synthase kinase 3 (GSK 3). In the absence of cofactors, GSK 3 can modify serines or threonines followed by prolines. In other cases, a phosphorylation in position +4 is required for the phosphorylation of threonine/serine residues. A third type of substrate can be modified by GSK 3 in the presence of heparin. The comparison of GSK 3 with other kinases suggests some similar features of this kinase with proline-directed protein kinases, such as cdc-2 or mitogen-activated protein kinase (MAP Kinases,) and also with casein kinase 2 (CK 2). Thus, all these kinases are specifically inhibited by 5,6-Dichloro-1-(beta-D-ribofuranosyl)-benzimidazole (DRB). However, heparin is an inhibitor of CK 2 whereas it activates the modification of certain substrates by GSK 3. A possible explanation for the obtained results is that the consensus sequence for GSK 3 phosphorylation is a serine/threonine adjacent to a proline or other beta-turn former residue and that such recognition could be favoured by the presence of adjacent negative charges or the addition of polyanions.
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PMID:Glycogen synthase kinase 3 phosphorylation of different residues in the presence of different factors: analysis on tau protein. 897 80

A number of studies have implicated a proline-directed protein kinase, glycogen synthase kinase-3 (GSK-3) in the hyperphosphorylation of tau in Alzheimer's disease (AD). Toward understanding the role of GSK-3 in the abnormal hyperphosphorylation of tau in AD we have found that GSK-3 is prominently present in neuronal cell bodies and their processes and co-localizes with neurofibrillary changes in AD brain. Furthermore, the levels of GSK-3 as determined by indirect ELISA are approximately 50% increased in the postsynaptosomal supernatant from AD brains as compared to the controls. However, no increase in GSK-3 enzyme activity was detected. In AD brain, with its reduced phosphatase activity, even normal levels of GSK-3 activity might be sufficient for the hyperphosphorylation of tau.
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PMID:Distribution, levels, and activity of glycogen synthase kinase-3 in the Alzheimer disease brain. 899 Jan 30

A key metabolic action of insulin is the stimulation of non-oxidative glucose utilization in skeletal muscle, by increasing both glucose uptake and glycogen synthesis. The molecular mechanism underlying this process has been investigated using a variety of experimental systems. We report here the use of cultured human myoblasts to study insulin control of glycogen synthesis in humans. In these cells insulin stimulates glycogen synthesis approx. 2.2-fold, associated with a similar activation of glycogen synthase (GS) which occurs within 5-10 min of the addition of insulin. Insulin also causes inactivation of glycogen synthase kinase-3 (GSK-3) and activation of protein kinase B, both processes being sufficiently rapid to account for the effects of insulin on GS. Activation by insulin of the protein kinases p70s6K, p90s6K and extracellular signal-regulated kinase 2 (ERK2) is observed, but is significantly slower than the activation of GS. Selective inhibitors of the p70s6K pathway (rapamycin), the ERK2/p90s6K pathway (PD98059) and phosphatidylinositol 3-kinase (wortmannin) have been used to probe the contribution of these components to insulin signalling in human muscle. Wortmannin blocks activation of both glycogen synthesis and GS and inactivation of GSK-3. PD98059 is without effect on these events, while rapamycin is without effect on inactivation of GSK-3 but partially blocks activation of glycogen synthesis and GS. Taken together, these findings suggest that protein kinase B is responsible for the inactivation of GSK-3, but that an additional rapamycin-sensitive mechanism may contribute to the activation of GS and stimulation of glycogen synthesis.
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PMID:Insulin action in cultured human myoblasts: contribution of different signalling pathways to regulation of glycogen synthesis. 900 74

In this study we describe the characterization and use of new peptide substrates for assaying glycogen synthase kinase-3 (GSK-3) which are based on the sequence around the single GSK-3 phosphorylation site in the translation factor eIF2B. The new peptides offer important advantages over previous substrates, which were based on the sequence around the multiple GSK-3 phosphorylation sites in glycogen synthase (GS), for the assay of GSK-3 in cell extracts. In particular, decreases in GSK-3 activity following, e.g., insulin treatment, are partially or completely masked when the GS-based peptides are used but are readily measured using the new, eIF2B-based, peptides. The new peptides, unlike those based on GS, are therefore suitable for the assay of changes in GSK-3 activity in cell extracts without the need for prior immunoprecipitation or ion-exchange chromatography.
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PMID:Peptide substrates suitable for assaying glycogen synthase kinase-3 in crude cell extracts. 902 1


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