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)

The phosphorylation of insulin receptor substrate 1 (IRS-1) on tyrosine residues by the insulin receptor (IR) tyrosine kinase is involved in most of the biological responses of insulin. IRS-1 mediates insulin signaling by recruiting SH2 proteins through its multiple tyrosine phosphorylation sites. The phosphorylation of IRS-1 on serine/threonine residues also occurs in cells; however, the particular protein kinase(s) promoting this type of phosphorylation are unknown. Here we report that glycogen synthase kinase 3 (GSK-3) is capable of phosphorylating IRS-1 and that this modification converts IRS-1 into an inhibitor of IR tyrosine kinase activity in vitro. Expression of wild-type GSK-3 or an "unregulated" mutant of the kinase (S9A) in CHO cells overexpressing IRS-1 and IR, resulted in increased serine phosphorylation levels of IRS-1, suggesting that IRS-1 is a cellular target of GSK-3. Furthermore, insulin-induced tyrosine phosphorylation of IRS-1 and IR was markedly suppressed in cells expressing wild-type or the S9A mutant, indicating that expression of GSK-3 impairs IR tyrosine kinase activity. Taken together, our studies suggest a new role for GSK-3 in attenuating insulin signaling via its phosphorylation of IRS-1 and may provide new insight into mechanisms important in insulin resistance.
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PMID:Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action. 927 79

When serum-starved A431 cells were treated with 200 nM phorbol ester TPA for 15 min, the cellular activity of protein kinase FA/glycogen synthase kinase-3alpha (kinase FA/GSK-3alpha) could be decreased to approximately 25% of control. Conversely, when treated with 1 microM TPA for 24 hr, the activity could be reversibly increased to approximately 200% of Control. The naturally occurring protein kinase C (PKC) inhibitor sphingosine at a concentration of 27 microM could also induce activation of kinase FA/GSK-3alpha to approximately 200% of control within 60 min. Further, when cells were chronically treated with 1 microM TPA for 24 hr and then with 27 microM sphingosine for 60 min, the activity of kinase FA/GSK-3alpha could only be increased to approximately 200% of control. Furthermore, when cells were pretreated with sphingosine and then acutely treated with TPA, the acute TPA effect on kinase FA/GSK-3alpha activity could be abolished by genistein or tyrosine phosphorylation, which could be blocked by genistein or tyrosine phosphatase, but could be reversed by orthovanadate. Taken together, the results demonstrate that TPA/sphingosine induce tyrosine phosphorylation and concurrent activation of kinase FA/GSK-3alpha in a common signalling pathway. Since TPA and sphingosine are potent PKC modulators, the results further suggest a potential role of PKC in modulating tyrosine phosphorylation/activation of kinase FA/GSK-3alpha. Kinetic studies on seven subtypes of PKC further demonstrate a specific involvement of PKCE in this tyrosine phosphorylation/activation process. This provides a new mode of signal transduction between these two important serine/threonine kinases in cells.
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PMID:The naturally occurring PKC inhibitor sphingosine and tumor promoter phorbol ester potentially induce tyrosine phosphorylation/activation of oncogenic proline-directed protein kinase FA/GSK-3alpha in a common signalling pathway. 949 24

The cell undergoes a diverse range of stimulations including growth factor activation and signal transduction from adhesion receptors, such as cadherins. In the absence of a mitogenic signal from outside the cell, beta catenin is sequestered in complexes with the product of the adenomatous polyposis coli (APC) gene and a serine threonine glycogen kinase (GSK 3 beta) enabling degradation of free beta catenin. Residual catenins hold cells together by binding to cadherins both at adherens junctions and the actin cytoskeleton. When a mitotic signal is delivered by the wnt pathway, GSK 3 beta is antagonised so that beta catenin can no longer be degraded. Cytosolic concentrations rise and binding to other newly synthesised proteins occurs, especially transcription factors that are transported to the nucleus, such as lymphocyte enhancing factor and T cell factor. This article discusses the signalling between mitogenic and adhesion pathways and suggests that it is a global mechanism for development, differentiation, and disease. These changes in catenin and APC biology may not be sufficient alone to transform cells fully but they appear to be a necessary final common pathway for several cancers of the mucous secreting crypts (including Barrett's oesophageal lesions and colorectal cancer) or stratified secreting epithelium (melanoma) before invasion.
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PMID:Cadherin and catenin biology represent a global mechanism for epithelial cancer progression. 953 77

The sequence and characterization of the KlGSK-3 gene in chromosome VI [corrected] from Kluyveromyces lactis is presented. The deduced amino-acid sequence predicts a protein of 415 amino acids and an Mr of 47 kDa. A computer search reveals significant homology to serine/threonine protein kinases closely related to members of the GSK-3 subfamily. The Klgsk-3::URA3 disrupted strain is unable to grow in glucose at 37 C but KlGSK-3 is not essential for vegetative growth at 30 C or 14 C. The KlGSK-3 gene presents the highest homology with the Saccharomyces cerevisiae MDS1 gene. Expression studies show an increase of mRNA levels caused both by carbon starvation and when diploids are shifted from rich to sporulation media. The data reported show that KlGSK-3, like MCK1 from S. cerevisiae, is related to glycogen storage.
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PMID:The Kluyveromyces lactis gene KLGSK-3 combines functions which in Saccharomyces cerevisiae are performed by MCK1 and MSD1. 956 Apr 33

One of the histopathological markers in Alzheimer's disease is the accumulation of hyperphosphorylated tau in neurons called neurofibrillary tangles (NFT) composing paired helical filaments (PHF). Combined tau protein kinase II (TPK II), which consists of CDK5 and its activator (p23), and glycogen synthase kinase-3beta (GSK-3beta) phosphorylate tau to the PHF-form in vitro. To investigate tau phosphorylation by these kinases in intact cells, the phosphorylation sites were examined in detail using well-characterized phosphorylation-dependent anti-tau antibodies after overexpressing the kinases in COS-7 cells with a human tau isoform. The overexpression of tau in COS-7 cells showed extensive phosphorylation at Ser-202 and Ser-404. The p23 overexpression induced a mobility shift of tau, but most of the phosphorylation sites overlapped the endogenous phosphorylation sites. GSK-3beta transfection showed the phosphorylation at Ser-199, Thr-231, Ser-396, and Ser-413. Triplicated transfection resulted in phosphorylation of tau at 8 observed sites (Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-396, Ser-404, and Ser-413).
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PMID:Characterization of tau phosphorylation in glycogen synthase kinase-3beta and cyclin dependent kinase-5 activator (p23) transfected cells. 956 82

In Alzheimer disease brain the microtubule associated protein (MAP) tau is abnormally hyperphosphorylated. The role of protein phosphatases (PP) in the regulation of phosphorylation of tau was studied in undifferentiated SY5Y cells. In cells treated with 10 nM okadaic acid (OA), a PP-2A/PP-1 inhibitor, the PP-1 and -2A activities decreased by 60% and 100% respectively and the activities of MAPKs, cdc2 kinase and cdk5, but not of GSK-3, increased. OA increased the phosphorylation of tau at Thr-231/Ser-235 and Ser-3961404, but not at Ser-262/356 or Ser-199/202. An increase in tyrosinated/detyrosinated tubulin ratio, a decrease in the microtubule binding activities of tau, MAP1b and MAP2, and cell death were observed. Treatment with 1 microm taxol partially inhibited the cell death. These data suggest (1) that OA induced hyperphosphorylation of tau is probably the result of activated MAPK and cdks in addition to decreased PP-2A and PP-1 activities and (2) that in SY5Y cells the OA induced cell death is associated with a decrease in stable microtubules.
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PMID:The regulation of phosphorylation of tau in SY5Y neuroblastoma cells: the role of protein phosphatases. 959 18

Transcriptional activation by the glucocorticoid receptor (GR) is regulated by both glucocorticoid binding and phosphorylation. The rat GR N-terminal transcriptional regulatory domain contains four major phosphorylation sites: threonine 171 (Thr171), serine 224 (Ser224), serine 232 (Ser232), and serine 246 (Ser246). We have previously demonstrated that Ser224 and Ser232 are phosphorylated by cyclin-dependent kinases, while Ser246 is phosphorylated by the c-Jun N-terminal kinase. We report here that the remaining GR phosphorylation site, Thr171, is a target for glycogen synthase kinase-3 (GSK-3) in vitro and in cultured mammalian cells. Increasing GSK-3 activity through its overexpression in cultured cells inhibits GR transcriptional enhancement, an effect dependent upon Thr171. Correspondingly, overexpression of a constitutively active form of the GSK-3 inhibitor, protein kinase B/Akt, increases GR transcriptional enhancement. Overexpression of GSK-3 had no effect on GR-mediated transcriptional repression of AP1-dependent gene expression. Importantly, transcriptional activation by the human GR (hGR), which contains an alanine (Ala150) at the position equivalent to Thr171 in rat GR, is not affected by GSK-3 overexpression. Introduction of a threonine residue at this position (A150T) establishes GSK-3-mediated inhibition of hGR transcriptional activation. These findings demonstrate species-specific differences in GR signaling, as revealed through GSK-3 phosphorylation, which suggests that GR function in rodents may not fully recapitulate receptor action in humans and that hGR is capable of adopting the GSK-3 signaling pathway through a somatic mutation.
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PMID:Phosphorylation and inhibition of rat glucocorticoid receptor transcriptional activation by glycogen synthase kinase-3 (GSK-3). Species-specific differences between human and rat glucocorticoid receptor signaling as revealed through GSK-3 phosphorylation. 960 39

As an initial effort to dissect the signaling pathways responsible for pathogenesis of Toxoplasma gondii infection, we report the cloning and in vitro functional studies of TPK3 (Toxoplasma protein kinase-3), a homologue of shaggy/glycogen synthase kinase-3 (GSK-3) kinases. The shaggy/GSK-3 family of kinases are highly conserved protein kinases that play important roles in cell fate determination, nuclear signaling and hormonal regulation. The TPK3 gene was isolated by RT-PCR with degenerate primers corresponding to highly conserved regions of serine/threonine protein kinases. The complete sequences of genomic and cDNA clones indicated the open reading frame, 1185 bp in size, is interrupted by five introns. The predicted protein sequence of TPK3 shows 54% identity to shaggy/GSK-3 over the catalytic domains. Southern analysis revealed TPK3 is a single copy locus in the Toxoplasma genome. Antisera to other GSK-3 proteins from other species recognized GST-TPK3 and a protein of the predicted size in parasites lysates. In vitro kinase assays with GST-TPK3 indicated that TPK3 autophosphorylates and phosphorylates protein phosphatase inhibitor-2 (I-2), a specific substrate of GSK-3 kinase.
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PMID:Cloning and in vitro expression of TPK3, a Toxoplasma gondii homologue of shaggy/glycogen synthase kinase-3 kinases. 966 11

Beta-catenin forms complexes with Tcf and Lef-1 and functions as a transcriptional activator downstream of the Wnt signaling pathway. Activation of the pathway by stabilization of beta-catenin has been shown to be important in the development of colorectal carcinoma, which is mainly caused by inactivating mutations of the adenomatous polyposis coli tumor suppressor gene or by activating mutations in exon 3 of the beta-catenin gene. Here, we analyzed mutations in exon 3 of the beta-catenin gene in endometrial carcinoma cases in which loss of heterozygosity at the adenomatous polyposis coli tumor suppressor gene locus has been rarely reported. We found that 10 of 76 cases had beta-catenin gene mutations. All mutations identified were single-base missense mutations on serine/threonine residues (codons 33, 37, 41, and 45), altering the glycogen synthase kinase-3beta phosphorylation consensus motif, which participates in the degradation of beta-catenin. To determine whether these beta-catenin mutations actually led to stabilization of this protein, expression of beta-catenin was analyzed immunohistochemically, and 9 of 10 cases with the beta-catenin mutation and 20 of 66 cases without it showed accumulation of beta-catenin in the cytoplasm and/or nucleus. In total, 38% of cases showed accumulation of beta-catenin. These data indicate that stabilization of beta-catenin due to mutations in exon 3 of the beta-catenin gene and other mechanisms may have an important role in development of endometrial carcinomas.
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PMID:Beta-catenin mutation in carcinoma of the uterine endometrium. 972 53

The paired helical filaments (PHFs) found in Alzheimer's disease (AD) brains are composed primarily of the microtubule-associated protein tau. PHF-tau is in a hyperphosphorylated state and is unable to promote microtubule assembly. We investigated whether the inhibition of tau binding to microtubules is increased when tau is phosphorylated by different kinases in combination with GSK-3. We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II. From these observations we estimate that the phosphorylation of Thr 231, Ser 235, and Ser 262 contributes approximately 26, approximately 9, and approximately 33%, respectively, of the overall inhibition of tau binding to microtubules. Together, our results indicate that the binding of tau to microtubules is controlled by the phosphorylation of several sites, among which are Thr 231, Ser 235, and Ser 262.
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PMID:Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. 973 71


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