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)

Glycogen synthase kinase 3beta (GSK-3beta) negatively regulates cardiac hypertrophy. A potential target mediating the antihypertrophic effect of GSK-3beta is eukaryotic translation initiation factor 2Bepsilon (eIF2Bepsilon). Overexpression of GSK-3beta increased the cellular kinase activity toward GST-eIF2Bepsilon in neonatal rat cardiac myocytes, whereas LiCl (10 mmol/L) or isoproterenol (ISO) (10 micromol/L), a treatment known to inhibit GSK-3beta, decreased it. Immunoblot analyses using anti-S535 phosphospecific eIF2Bepsilon antibody showed that S535 phosphorylation of endogenous eIF2Bepsilon was decreased by LiCl or ISO, suggesting that GSK-3beta is the predominant kinase regulating phosphorylation of eIF2Bepsilon-S535 in cardiac myocytes. Decreases in eIF2Bepsilon-S535 phosphorylation were also observed in a rat model of cardiac hypertrophy in vivo. Overexpression of wild-type eIF2Bepsilon alone moderately increased cell size (+31+/-11%; P<0.05 versus control), whereas treatment of eIF2Bepsilon-transduced myocytes with LiCl (+73+/-22% versus eIF2Bepsilon only; P<0.05) or ISO (+84+/-33% versus eIF2Bepsilon only; P<0.05) enhanced the effect of eIF2Bepsilon. Overexpression of eIF2Bepsilon-S535A, which is not phosphorylated by GSK-3beta, increased cell size (+107+/-35%) as strongly as ISO (+95+/-25%), and abolished antihypertrophic effects of GSK-3beta, indicating that S535 phosphorylation of eIF2Bepsilon critically mediates antihypertrophic effects of GSK-3beta. Furthermore, expression of eIF2Bepsilon-F259L, a dominant-negative mutant, inhibited ISO-induced hypertrophy, indicating that eIF2Bepsilon is required for beta-adrenergic hypertrophy. Interestingly, expression of eIF2Bepsilon-S535A partially increased cytoskeletal reorganization, whereas it did not increase expression of atrial natriuretic factor gene. These results suggest that GSK-3beta is the predominant kinase mediating phosphorylation of eIF2Bepsilon-S535 in cardiac myocytes, which in turn plays an important role in regulating cardiac hypertrophy primarily through protein synthesis.
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PMID:Phosphorylation of eukaryotic translation initiation factor 2Bepsilon by glycogen synthase kinase-3beta regulates beta-adrenergic cardiac myocyte hypertrophy. 1500 29

Glycogen synthase kinase-3beta (GSK-3beta) can be associated with several proteins in cell. We analyzed the immunoprecipitates by an anti-GSK-3beta antibody from cell lysate of human fibroblasts and found that this protein was co-precipitated with mitogen-activated protein kinase kinase (MEK1/2). U0126, a MEK1/2 inhibitor, inhibited tyrosine phosphorylation of GSK-3beta, suggesting that MEK1/2 was involved in the phosphorylation of Tyr(216) in GSK-3beta. In vitro kinase assay was carried out using a recombinant human active MEK1 and we found that GSK-3beta was phosphorylated on Tyr(216) by this kinase in a dose- and time-dependent manner. Further, the pretreatment of fibroblasts with U0126 inhibited serum-induced nuclear translocation of GSK-3beta. These results suggested that MEK1/2 induces tyrosine phosphorylation of GSK-3beta and this cellular event might induce nuclear translocation of GSK-3beta. This is the first report to suggest that MEK1/2 phosphorylates not only ERK1/2 but also GSK-3beta.
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PMID:Glycogen synthase kinase-3beta is tyrosine-phosphorylated by MEK1 in human skin fibroblasts. 1502 Feb 33

Worldwide increasing resistance of Plasmodium falciparum to common anti-malaria agents calls for the urgent identification of new drugs. Glycogen synthase kinase-3 (GSK-3) represents a potential screening target for the identification of such new compounds. We have cloned PfGSK-3, the P. falciparum gene homologue of GSK-3 beta. It encodes a 452-amino-acid, 53-kDa protein with an unusual N-terminal extension but a well-conserved catalytic domain. A PfGSK-3 tridimensional homology model was generated on the basis of the recently crystallised human GSK-3 beta. It illustrates how the regions involved in the active site, in substrate binding (P+4 phosphate binding domain) and in activity regulation are highly conserved. Recombinant PfGSK-3 phosphorylates GS-1, a GSK-3-specific peptide substrate, glycogen synthase, recombinant axin and the microtubule-binding protein tau. Neither native nor recombinant PfGSK-3 binds to axin. Expression and intracellular localisation of PfGSK-3 were investigated in the erythrocytic stages. Although PfGSK-3 mRNA is present in similar amounts at all stages, the PfGSK-3 protein is predominantly expressed at the early trophozoite stage. Once synthesized, PfGSK-3 is rapidly transported to the erythrocyte cytoplasm where it associates with vesicle-like structures. The physiological functions of PfGSK-3 for the parasite remain to be elucidated. A series of GSK-3 beta inhibitors were tested on both PfGSK-3 and mammalian GSK-3beta. Remarkably these enzymes show a partially divergent sensitivity to the compounds, suggesting that PfGSK-3 selective compounds might be identified.
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PMID:Plasmodium falciparum glycogen synthase kinase-3: molecular model, expression, intracellular localisation and selective inhibitors. 1502 60

Glycogen synthase kinase 3 (GSK-3) in the 21(st) century emerged as one of the most attractive therapeutic target for the development of selective inhibitors as new promising drugs for unmet pathologies including Alzheimer's disease, stroke, bipolar disorders, chronic inflammatory processes, cancer and diabetes type II. The full potential of GSK-3 inhibitors is just starting to be realized but the number of candidates in development provided by both academic centres and pharmaceutical companies have increased exponentially in the last two years. This review discloses recent discoveries and developments on peptides and small molecules targeting GSK-3. Focusing attention on this exciting target could thus reap considerable clinical and economic rewards.
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PMID:GSK-3 inhibitors: discoveries and developments. 1503 29

Glycogen synthase kinase-3beta (GSK-3beta) is a key component of several signaling pathways. We found that a short variant of 'TNF-like weak inducer of apoptosis' (shortTWEAK) formed a complex with GSK-3beta in a yeast two-hybrid system. We demonstrate that shortTWEAK and GSK-3beta colocalize in the nucleus of human neuroblastoma cells. We also show that TWEAK is internalized in different cell lines and that it translocates to the nucleus. This event causes the degradation of IkappaBalpha, the nuclear translocation of both GSK-3beta and p65, and the induction of NF-kappaB-driven gene expression. We demonstrate that the induction of IL-8 expression by TWEAK can be counteracted by LiCl. Taken together, these data suggest that GSK-3beta plays an important role in the signal transduction pathway between TWEAK and NF-kappaB.
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PMID:Involvement of GSK-3beta in TWEAK-mediated NF-kappaB activation. 1514 69

Glycogen synthase kinase-3 (GSK-3) is a downstream component of the Wnt pathway and recent studies have reported abnormal levels of GSK-3beta in schizophrenia. In a sample of 147 schizophrenic patients and 212 healthy individuals, we analyzed two common SNPs at position -1727 A/T and -50 C/T and a (CAA)(n) repeat polymorphism localized in intron 1 of the gene. The results showed that the allele, genotype and haplotype distributions for the three polymorphisms investigated do not differ between schizophrenic patients in general and control subjects. However, in the subtype of paranoid schizophrenic patients, we found that the (CAA)(3)/(CAA)(5) heterozygotes were more often represented. Although taken from a small sample, our results support the reports that GSK-3beta appears to be involved in a subtype of schizophrenic patients, but not in schizophrenia in general. In conclusion, we would speculate that this gene may be linked to some features of psychotic disorders rather than to schizophrenia itself.
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PMID:Association study of -1727 A/T, -50 C/T and (CAA)n repeat GSK-3beta gene polymorphisms with schizophrenia. 1517 15

Glycogen synthase kinase 3 regulates glycogen synthase, the rate-determining enzyme for glycogen synthesis. Liver and muscle glycogen synthesis is defective in type 2 diabetics, resulting in elevated plasma glucose levels. Inhibition of GSK-3 could potentially be an effective method to control plasma glucose levels in type 2 diabetics. Structure-activity studies on a N-phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine series have led to the identification of potent and selective compounds with good cellular efficacy. Molecular modeling studies have given insights into the mode of binding of these inhibitors. Since the initial leads were also potent inhibitors of CDK-2/CDK-4, an extensive SAR was performed at various positions of the pyrazolo[1,5-b]pyridazin core to afford potent GSK-3 inhibitors that were highly selective over CDK-2. In addition, these inhibitors also exhibited very good cell efficacy and functional response. A representative example was shown to have good oral exposure levels, extending their utility in an in vivo setting. These inhibitors provide a viable lead series in the discovery of new therapies for the treatment of type 2 diabetes.
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PMID:N-Phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amines as potent and selective inhibitors of glycogen synthase kinase 3 with good cellular efficacy. 1534 87

Glycogen synthase kinase-3 (GSK-3) protein levels and activity are elevated in skeletal muscle in type 2 diabetes, and inversely correlated with both glycogen synthase activity and insulin-stimulated glucose disposal. To explore this relationship, we have produced transgenic mice that overexpress human GSK-3beta in skeletal muscle. GSK-3beta transgenic mice were heavier, by up to 20% (P < .001), than their age-matched controls due to an increase in fat mass. The male GSK-3beta transgenic mice had significantly raised plasma insulin levels and by 24 weeks of age became glucose-intolerant as determined by a 50% increase in the area under their oral glucose tolerance curve (P < .001). They were also hyperlipidemic with significantly raised serum cholesterol (+90%), nonesterified fatty acids (NEFAs) (+55%), and triglycerides (+170%). At 29 weeks of age, GSK-3beta protein levels were 5-fold higher, and glycogen synthase activation (-27%), glycogen levels (-58%) and insulin receptor substrate-1 (IRS-1) protein levels (-67%) were significantly reduced in skeletal muscle. Hepatic glycogen levels were significantly increased 4-fold. Female GSK-3beta transgenic mice did not develop glucose intolerance despite 7-fold overexpression of GSK-3beta protein and a 20% reduction in glycogen synthase activation in skeletal muscle. However, plasma NEFAs and muscle IRS-1 protein levels were unchanged in females. We conclude that overexpression of human GSK-3beta in skeletal muscle of male mice resulted in impaired glucose tolerance despite raised insulin levels, consistent with the possibility that elevated levels of GSK-3 in type 2 diabetes are partly responsible for insulin resistance.
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PMID:Development of glucose intolerance in male transgenic mice overexpressing human glycogen synthase kinase-3beta on a muscle-specific promoter. 1537 89

Glycogen synthase kinase-3 is an unusual protein serine/threonine kinase that, unlike most of its 500-odd relatives in the genome, is active under resting conditions and is inactivated upon cell stimulation. The two mammalian isoforms, GSK-3alpha and beta, play largely overlapping roles and have been implicated in a variety of human pathologies, including Type II diabetes, Alzheimer's disease, bipolar disorder and cancer. Recently, the modes of regulation of this enzyme have been elucidated through a combination of structural and cell biological studies. A series of relatively selective small molecules have facilitated chemical manipulation of the enzyme in intact cells and tissues, and new roles for the protein kinase in embryonic stem cell differentiation and motility have emerged. Despite these advances, the therapeutic value of this enzyme as a drug target remains clouded by uncertainty over the potential of antagonists to promote tumorigenesis. This article describes the state of understanding of this intriguing enzyme, and weighs current evidence regarding whether there is a therapeutic window for amelioration of diseases in which it is implicated, in the absence of inducing new pathologies.
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PMID:Glycogen synthase kinase-3 in insulin and Wnt signalling: a double-edged sword? 1549 20

Glycogen synthase kinase-3beta (GSK-3beta) is a critical activator of neuronal apoptosis induced by a diverse array of neurotoxic insults. However, the downstream substrates of GSK-3beta that ultimately induce neuronal death are unknown. Here, we show that GSK-3beta phosphorylates and regulates the activity of Bax, a pro-apoptotic Bcl-2 family member that stimulates the intrinsic (mitochondrial) death pathway by eliciting cytochrome c release from mitochondria. In cerebellar granule neurons undergoing apoptosis, inhibition of GSK-3beta suppressed both the mitochondrial translocation of an expressed green fluorescent protein (GFP)-Bax(alpha) fusion protein and the conformational activation of endogenous Bax. GSK-3beta directly phosphorylated Bax(alpha) on Ser163, a residue found within a species-conserved, putative GSK-3beta phosphorylation motif. Coexpression of GFP-Bax(alpha) with a constitutively active mutant of GSK-3beta, GSK-3beta(Ser9Ala), enhanced the in vivo phosphorylation of wild-type Bax(alpha), but not a Ser163Ala mutant of Bax(alpha), in transfected human embryonic kidney 293 (HEK293) cells. Moreover, cotransfection with constitutively active GSK-3beta promoted the localization of Bax(alpha) to mitochondria and induced apoptosis in both transfected HEK293 cells and cerebellar granule neurons. In contrast, neither a Ser163Ala point mutant of Bax(alpha) nor a naturally occurring splice variant that lacks 13 amino acids encompassing Ser163 (Bax(sigma)) were driven to mitochondria in HEK293 cells coexpressing constitutively active GSK-3beta. In a similar manner, either mutation or deletion of the identified GSK-3beta phosphorylation motif prevented the localization of Bax to mitochondria in cerebellar granule neurons undergoing apoptosis. Our results indicate that GSK-3beta exerts some of its pro-apoptotic effects in neurons by regulating the mitochondrial localization of Bax, a key component of the intrinsic apoptotic cascade.
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PMID:Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. 1552 85


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