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)

Although glycogen synthase kinase-3 (GSK-3) is but one of more than a thousand distinct serine/threonine kinases present in the mammalian genome, this enzyme has attracted attention for its role in a diverse range of cellular processes and its positioning at a nexus of several signaling pathways that are important in cancer and other human diseases. The association of GSK-3 with widely different functions, from glycogen metabolism to fruit fly segmentation and slime mold differentiation, was initially perplexing. However, as the context of the biological processes involving this enzyme has been clarified, unifying themes have emerged that begin to explain its pleiotropic nature. Unlike most protein kinases involved in signaling, GSK-3 is active in unstimulated, resting cells. Its activity is inactivated during cellular responses and its substrates therefore tend to be dephosphorylated. As more of these targets have been identified and the effects of their modification by GSK-3 determined, most have been found to be functionally inhibited by GSK-3. Hence, this kinase appears to act as a general repressor, keeping its targets switched off or inaccessible under resting conditions. The rarity of this form of regulation is perhaps related to the diversity of its targets. Over the past decade, the importance of GSK-3 has been established by three significant properties: its remarkable evolutionary conservation, allowing analysis in genetically tractable organisms; its involvement in the Wnt/wingless signaling pathway; and its inhibition by agonists of the prosurvival phosphatidylinositol 3' kinase (P13'K) pathway. This review covers recent advances in understanding the physiological roles of this enzyme, particularly in the context of cancer.
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PMID:Role of glycogen synthase kinase-3 in cancer: regulation by Wnts and other signaling pathways. 1188 28

Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). Here we describe another Axin-associated kinase, whose phosphorylation of beta-catenin precedes and is required for subsequent GSK-3 phosphorylation of beta-catenin. This "priming" kinase is casein kinase Ialpha (CKIalpha). Depletion of CKIalpha inhibits beta-catenin phosphorylation and degradation and causes abnormal embryogenesis associated with excessive Wnt/beta-catenin signaling. Our study uncovers distinct roles and steps of beta-catenin phosphorylation, identifies CKIalpha as a component in Wnt/beta-catenin signaling, and has implications to pathogenesis/therapeutics of human cancers and diabetes.
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PMID:Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. 1195 36

Beta-catenin plays a key role in the Wnt signaling cascade. The levels of beta-catenin within a cell are regulated via phosphorylation of the N terminus of beta-catenin by GSK-3beta. The phosphorylation leads to ubiquitination and subsequent degradation of the protein. Thus far three serines (S33, 37, 45) and one threonine (T41) are considered to be the substrates for GSK-3beta phosphorylation. Indeed, these amino acids are regularly mutated in tumors, resulting in beta-catenin molecules with enhanced transcriptional activity. Aligning N-terminal sequences of beta-catenin homologues of different species revealed two other highly conserved serines (S23, 29), which have also been found mutated in tumors. We show that these serines are modified in the same fashion as that of the known regulatory residues. During embryogenesis, the phosphorylation status of S23 and S29 appears to be actively regulated. Nevertheless, constructs harboring the mutations found in tumors fail to show enhanced transcriptional activity or transforming properties.
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PMID:Identification of two novel regulated serines in the N terminus of beta-catenin. 1202 56

Glycogen synthase kinase-3alpha and -3beta (GSK-3alpha and -3beta) are multi-substrate, serine/threonine-specific kinases that can phosphorylate microtubule-associated protein tau and other neuronal proteins. In this study, the expression level and mRNA distribution of two GSK-3 isoforms, GSK-3alpha and -3beta in mice were investigated. Northern blot analyses indicated that GSK-3alpha mRNA is encoded by a 2.5-kb transcript in adult tissues, whereas a 4.1-kb transcript was found in neonatal tissues. The GSK-3beta mRNA is encoded by a 1.6-kb transcript in the testis and a 7.6-kb transcript in the brain, and in many other adult tissues, but not neonatal tissues. Western blot analyses demonstrated that GSK-3beta protein was mainly expressed in the brain and heart, whereas GSK-3alpha was highly expressed in the brain, heart, and testis. A non-radioactive in situ hybridization study using specific digoxigenin-labeled RNA probes showed that GSK-3alpha and -3beta mRNAs were found in many brain regions, and were especially abundant in the hippocampus, cerebral cortex, and the Purkinje cells of the cerebellum. This implies the importance of GSK-3alpha and -3beta for brain function. The differential expression of GSK-3alpha and -3beta mRNAs as well as proteins in other tissues indicate that they play different roles in cellular functions and the developmental process.
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PMID:Expression of glycogen synthase kinase-3 isoforms in mouse tissues and their transcription in the brain. 1204 12

Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of beta-catenin. In the absence of a Wnt signal, beta-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in beta-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of three of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has recently been shown that the GSK-3 dependent phosphorylation of beta-catenin requires prior priming through phosphorylation of Ser45. However, it is not known whether phosphorylation of Ser45 is carried out by GSK-3 itself or by an alternative kinase. In this study, the phosphorylation of beta-catenin at Ser45 was characterised using a phospho-specific antibody. GSK-3beta was found to be unable to phosphorylate beta-catenin at Ser45 in vitro and in intact cells. However, inhibition of GSK-3 in intact cells reduced Ser45 phosphorylation, suggesting that GSK-3 kinase activity is required for the phosphorylation event. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1varepsilon, a known positive regulator of Wnt signalling, as overexpression of this kinase leads to decreased phosphorylation levels. In conclusion, phosphorylation of beta-catenin at the GSK-3 priming site Ser45 is not mediated by GSK-3 itself, but by an alternative kinase, indicating that beta-catenin is not an unprimed substrate for GSK-3 in vivo. Priming of GSK-3 dependent phosphorylation of beta-catenin by a different kinase could have important implications for the regulation of Wnt signalling.
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PMID:Characterisation of the phosphorylation of beta-catenin at the GSK-3 priming site Ser45. 1205 14

To investigate the contribution of beta-catenin to the development of carcinoma of the ampulla of Vater, genetic alterations of beta-catenin gene, CTNNB-1 were searched. Mutational analysis of exon3 in CTNNB-1, which encodes the serine/threonine residues for GSK-3beta phosphorylation sites, was performed on 21 cases of carcinoma of the ampulla of Vater, by means of polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) followed by nucleotide sequencing. We found one deleted mutation at codon 32 to approximately 65 in one case of carcinoma of the ampulla of Vater. We also analyzed subcellular localization of beta-catenin protein in all cases immunohistochemically, and confirmed its accumulation in the nucleus in four cases including in a CTNNB-1 mutated one. This is the first study to show CTNNB-1 mutation and beta-catenin expression in carcinoma of the ampulla of Vater. These results suggested that abnormal Wnt-wingless signaling and in particular beta-catenin alteration caused accumulation of beta-catenin, which might partially contribute to the development of carcinoma of the ampulla of Vater.
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PMID:beta-Catenin alteration in cancer of the ampulla of Vater. 1207 24

B -Catenin is closely associated with carcinoma invasion/metastasis and poor survival. Recent studies have demonstrated that abnormal expression of B -catenin, especially its nuclear accumulation, also plays an important role in wingless/Wnt signaling pathway. In this study, we evaluated immunohistochemically the nuclear localization of B -catenin in a total of 93 human-endocrine-related tumors including 1 medullary carcinoma (thyroid gland), 12 parathyroid tumors, 22 carcinoid tumors (digestive tract and liver), 7 islet cell tumors, 26 adrenocortical tumors, 13 neuroblastoma (adrenal gland), and 12 pheochromocytoma (adrenal gland), and also studied genetic alterations of the B -catenin gene. Nuclear accumulation of B -catenin was frequently detected in 8 of 22 (36%) carcinoid tumors and 2 of 7 (29%) islet cell tumors. No genetic alteration in exon 3 of the B -catenin gene encoding serine/threonine rich domain, which was phosphorylated by GSK-3 B, was detected in any groups of the endocrine tumors. However, nuclear accumulation of B -catenin in carcinoid tumors was significantly correlated with the proliferative marker Ki-67 (MIB-1) labeling index (p <0.001). Our findings suggest that nuclear transfer and accumulation of the B -catenin may contribute in the tumorigenesis of carcinoid tumor as an oncoprotein.
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PMID:Nuclear Accumulation of B-Catenin in Human Endocrine Tumors: Association with Ki-67 (MIB-1) Proliferative Activity. 1211 96

The Arabidopsis thaliana AtSK sub-family of serine threonine protein kinases groups 10 homologues of SHAGGY/GSK-3. Previous results obtained with different plant members of the SHAGGY/GSK-3 family strongly suggest that these proteins are involved in cell differentiation and stress responses. In order to gain further insight into the biological functions of this family in A. thaliana, polyclonal antibodies were raised against specific domains of the AtSKtheta protein. The antibodies were purified and used in immunolocalization studies in various tissues of A. thaliana. Our results show that the protein is located in the cell nuclei of various developing organs. Differential protein localization profiles were found in some of the observed tissues, notably during gametophyte and embryo development. Based on this protein location pattern, and on what is known about the mammalian members of the GSK-3 family, we suggest that AtSKtheta may have a role in the regulation of transcription factors.
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PMID:AtSKtheta, a plant homologue of SGG/GSK-3 marks developing tissues in Arabidopsis thaliana. 1217 18

To understand the nature and roles of mutated beta-catenin in human hepatocellular carcinomas (HCCs), 57 cases of surgically resected HCCs were studied. DNAs extracted from each tumor were examined for somatic mutations of exon 3, and the protein expressions of beta-catenin, cyclin D1, and Ki-67 were observed by immunohistochemical staining. beta-catenin mutations in exon 3 were detected in 10 (17.5%) out of 57 HCCs, including nine missense mutations and one deletion mutation. All of the cases with gene alterations had the anti-HCV antibody, and tested negative for the HBs antigen in the sera. All of the mutations occurred at the serine/threonine phosphorylation sites of glycogen synthase kinase-3beta (GSK-3beta) or their neighboring residues. Significant correlation with intracellular expression (p=0.00055) was shown in the HCCs harboring beta-catenin mutations. The intracellular accumulation of beta-catenin showed significant correlation with the cyclin D1 expression (p=0.00858), and with a higher proliferation index (p=0.00072). In addition, the beta-catenin mutations showed significant association with the cyclin D1 expression (p=0.0424). These results suggest that accumulated beta-catenin proteins may bind to the lymphocyte enhancer binding factor-1 (LEF-1), form the beta-catenin/LEF-1 complex, and stimulate such promoters regulating the cell cycle as the cyclin D1 gene. This is the first report to demonstrate a significant correlation between beta-catenin and the cyclin D1 expression in human HCCs.
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PMID:Beta-catenin and cyclin D1 expression in human hepatocellular carcinoma. 1237 19

Intracellular regulation of oocyte meiosis is not completely understood. However, reversible phosphorylation, which involves serine/threonine protein kinases and phosphatases (PP), is an important mediator. Glycogen synthase kinase-3 (GSK-3) is a highly conserved serine/threonine protein kinase. Currently no reports exist on presence or function of GSK-3 in mammalian oocytes. The aim of this study was to determine GSK-3 presence/absence, transcript and protein expression, intracellular protein distribution, and to investigate the functional importance of GSK-3 in mouse oocyte meiosis. Germinal vesicle-intact (GVI) oocytes contained both GSK-3 transcript and protein. Although GSK-3 beta-isoform is the only transcript identifiable in GVI oocytes, both alpha- and beta-isoforms were recognized by Western blot analysis. In growing, meiotic-incompetent oocytes GSK-3 was present, diffusely located throughout the cytoplasm and absent in the nucleus, whereas in meiotic-competent oocytes this cytoplasmic GSK-3 displays a predominant peri-oolemma staining. Treatment of mouse GVI oocytes with lithium chloride (LiCl), which inhibits both inositol monophosphatase (IMPase) and GSK-3, had no significant influence on oocyte viability, morphology, or development to metaphase II (MII). However, LiCl caused abnormal spindle formation and significantly increased incidence of abnormal homologue segregation during the first meiotic division. L690,330, which is a specific IMPase inhibitor, had no significant effect on oocyte viability, morphology, MII development, or homologue segregation. This is the first report of GSK-3 in mammalian oocytes. LiCl inhibition of mouse oocyte GSK-3 modified organization of microtubules and/or function of meiotic spindles thus compromising segregation of condensed bivalent chromosomes.
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PMID:Glycogen synthase kinase-3 regulates mouse oocyte homologue segregation. 1242 Mar 4


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