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

Lysophosphatidic acid (LPA) is a natural phospholipid with multiple biological functions. We show here that LPA induces phosphorylation and inactivation of glycogen synthase kinase 3 (GSK-3), a multifunctional serine/threonine kinase. The effect of LPA can be reconstituted by expression of Edg-4 or Edg-7 in cells lacking LPA responses. Compared to insulin, LPA stimulates only modest phosphatidylinositol 3-kinase (PI3K)-dependent activation of protein kinase B (PKB/Akt) that does not correlate with the magnitude of GSK-3 phosphorylation induced by LPA. PI3K inhibitors block insulin- but not LPA-induced GSK-3 phosphorylation. In contrast, the effect of LPA, but not that of insulin or platelet-derived growth factor (PDGF), is sensitive to protein kinase C (PKC) inhibitors. Downregulation of endogenous PKC activity selectively reduces LPA-mediated GSK-3 phosphorylation. Furthermore, several PKC isotypes phosphorylate GSK-3 in vitro and in vivo. To confirm a specific role for PKC in regulation of GSK-3, we further studied signaling properties of PDGF receptor beta subunit (PDGFRbeta) in HEK293 cells lacking endogenous PDGF receptors. In clones expressing a PDGFRbeta mutant wherein the residues that couple to PI3K and other signaling functions are mutated with the link to phospholipase Cgamma (PLCgamma) left intact, PDGF is fully capable of stimulating GSK-3 phosphorylation. The process is sensitive to PKC inhibitors in contrast to the response through the wild-type PDGFRbeta. Therefore, growth factors, such as PDGF, which control GSK-3 mainly through the PI3K-PKB/Akt module, possess the ability to regulate GSK-3 through an alternative, redundant PLCgamma-PKC pathway. LPA and potentially other natural ligands primarily utilize a PKC-dependent pathway to modulate GSK-3.
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PMID:Convergence of multiple signaling cascades at glycogen synthase kinase 3: Edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase C-dependent intracellular pathway. 1188 98

To determine the mechanism(s) for insulin resistance induced by fatty acids, we measured the ability of insulin to activate phosphoinositide 3-kinase (PI3K) and multiple distal pathways in rats. Following a 5-h infusion of lipid or glycerol (control), rats underwent a euglycemic hyperinsulinemic clamp. Insulin stimulated IRS-1-associated PI3K activity in muscle of glycerol-infused rats 2.4-fold but had no effect in lipid-infused rats. IRS-2- and phosphotyrosine-associated PI3K activity were increased 3.5- and 4.8-fold, respectively, by insulin in glycerol-infused rats but only 1.6- and 2.3-fold in lipid-infused rats. Insulin increased Akt1 activity 3.9-fold in glycerol-infused rats, and this was impaired 41% in lipid-infused rats. Insulin action on Akt2 and p70S6K were not impaired, whereas activation of protein kinase C lambda/zeta activity was reduced 47%. Insulin inhibited glycogen synthase kinase 3alpha (GSK-3alpha) activity by 30% and GSK-3beta activity by approximately 65% and increased protein phosphatase-1 activity by 40-47% in both glycerol- and lipid-infused rats. Insulin stimulated glycogen synthase activity 2.0-fold in glycerol-infused rats but only 1.4-fold in lipid-infused rats. Thus, 1) elevation of fatty acids differentially affects insulin action on pathways distal to PI3K, impairing activation of Akt1 and protein kinase C lambda/zeta and 2) insulin action on glycogen synthase can be regulated independent of effects on GSK-3 and protein phosphatase-1 activity in vivo.
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PMID:Fatty acid infusion selectively impairs insulin action on Akt1 and protein kinase C lambda /zeta but not on glycogen synthase kinase-3. 1209 90

Glycogen synthase kinase-3 (GSK-3) is a highly conserved serine/threonine protein kinase that is involved in the signal transduction cascades of multiple cellular processes. GSK-3 has two isoforms, designated alpha and beta. GSK-3beta protein levels and GSK-3 enzyme activity have been reported to be reduced by over 40% in postmortem frontal cortex of schizophrenic patients. GSK-3 is also present in peripheral tissue such as lymphocytes. In this study we aimed to find whether the reduction in brain GSK-3beta measures is reflected in peripheral tissue of schizophrenic patients. Fresh lymphocytes from schizophrenic patients showed no difference in GSK-3 alpha and GSK-3beta mRNA levels, GSK-3beta protein levels, or total GSK-3 (alpha+beta) enzyme activity compared with findings in control subjects. In addition, lymphocyte-derived cell lines from schizophrenic patients did not differ in their GSK-3beta protein levels from levels in normal control subjects. The results rule out the use of lymphocyte GSK-3 as a marker for central GSK-3 abnormalities in schizophrenia.
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PMID:GSK-3 parameters in lymphocytes of schizophrenic patients. 1237 50

Pathological alterations in the microtubule-associated protein (MAP) tau are well-established in a number of neurodegenerative disorders, including Alzheimer's Disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and others. Tau protein and in some cases, neurofilament subunits exhibit abnormal phosphorylation on specific serine and threonine residues in these diseases. A large body of biochemical, genetic, and cell biological evidence implicate two major serine-threonine protein kinases, glycogen synthase kinase 3 (GSK-3) and cyclin-dependent kinase 5 (CDK5) as major kinases responsible for both normal and pathological phosphorylation of tau protein in vivo. What remains unclear is whether tau phosphorylation and/or neurofibrillary tangle (NFT) formation are causal or secondary to initiation of neuronal pathology. In fact, many studies have indicated that tau misphosphorylation is not the causal event. Interestingly, some of these kinase and phosphatase activities have recently merged as key regulators of fast axonal transport (FAT). Specifically, CDK5 and GSK-3 have been recently shown to regulate kinesin-driven motility. Given the essential role of FAT in neuronal function, an alternate model for pathogenesis can be proposed. In this model, misregulation of FAT induced by an imbalance in specific kinase-phosphatase activities within neurons represents an early and critical step for the initiation of neuronal pathology. Such a model may explain many of the unique characteristics of late onset of neurological diseases such as AD.
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PMID:Fast axonal transport misregulation and Alzheimer's disease. 1242 5

The yeast Saccharomyces cerevisiae has four genes, MCK1, MDS1 (RIM11), MRK1, and YOL128c, that encode homologues of mammalian glycogen synthase kinase 3 (GSK-3). A gsk-3 null mutant in which these four genes are disrupted showed growth defects on galactose medium. We isolated several multicopy suppressors of this growth defect. Two of them encoded Msn2p and phosphoglucomutase (PGM). Msn2p is a transcription factor that binds to the stress-response element (STRE). PGM is an enzyme that interconverts glucose-1 phosphate and glucose-6 phosphate and is regulated by Msn2p at the transcriptional level. Expression of the mRNAs of PGM2 and DDR2, whose promoter regions possess STRE sequences, on induction by heat shock or salt stress was reduced not only in an msn2 msn4 (msn2 homologue) double mutant but also in the gsk-3 null mutant. STRE-dependent transcription was greatly inhibited in the gsk-3 null mutant or mck1 mds1 double mutant, and this phenotype was suppressed by the expression of Mck1p but not of a kinase-inactive form of Mck1p. Although Msn2p accumulated in the nucleus of the gsk-3 null mutant as well as in the wild-type strain under various stress conditions, its STRE-binding activity was reduced in extracts prepared from the gsk-3 null mutant or mck1 mds1 double mutant. These results suggest that yeast GSK-3 promotes formation of a complex between Msn2p and DNA, which is required for the proper response to different forms of stress. Because neither Msn2p-GSK-3 complex formation nor GSK-3-dependent phosphorylation of Msn2p could be detected, the regulation of Msn2p by GSK-3 may be indirect.
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PMID:Yeast glycogen synthase kinase-3 activates Msn2p-dependent transcription of stress responsive genes. 1252 45

Prion diseases are characterized by neuronal cell death, glial proliferation and deposition of prion peptide aggregates. An abnormal misfolded isoform of the prion protein (PrP) is considered to be responsible for this neurodegeneration. The PrP 106-126, a synthetic peptide obtained from the amyloidogenic region of the PrP, constitutes a model system to study prion-induced neurodegeneration as it retains the ability to trigger cell death in neuronal cultures. In the present study, we show that the addition of this prion peptide to cultured neurons increases the activity of glycogen synthase kinase 3 (GSK-3), which is accompanied by the enhanced phosphorylation of some microtubule-associated proteins including tau and microtubule-associated protein 2. Prion peptide-treated neurons become progressively atrophic, and die ultimately. Both lithium and insulin, which inhibit GSK-3 activity, significantly decrease prion peptide-induced cell death both in primary neuronal cultures and in neuroblastoma cells. Finally, the overexpression of a dominant-negative mutant of GSK-3 in transfected neuroblastoma cells efficiently prevents prion peptide-induced cell death. These results are consistent with the view that the activation of GSK-3 is a crucial mediator of prion peptide-induced neurodegeneration.
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PMID:Prion peptide induces neuronal cell death through a pathway involving glycogen synthase kinase 3. 1257 63

Phosphatidylinositol 3-kinase (PI3K) activity is increased in aortae from deoxycorticosterone (DOCA)-salt rats and enhanced PI3K activity contributes to the arterial hyperreactivity in these animals. Because PI3K activity is increased in DOCA-salt hypertension, we postulated that phosphorylation of Akt and glycogen synthase kinase 3 (GSK-3), serine threonine kinases that are downstream of PI3K, would be increased in DOCA-salt hypertension. In this study, we focused on GSK-3. Because GSK-3 activity is reduced by phosphorylation, we expected that its activity would be reduced in DOCA-salt hypertensive arteries and that reduced GSK-3 activity could contribute to enhanced adrenergic signaling and vascular smooth muscle hypertrophy that augment the heightened contractile response in DOCA-salt hypertension. Surprisingly, we observed a decrease in phosphorylation of GSK-3, indicating an increase in GSK-3 activity. To determine whether increased GSK-3 activity contributes to altered arterial reactivity in DOCA-salt animals, we measured isometric contraction to norepinephrine (NE) in the presence and absence of PI3K or GSK-3 inhibition. Addition of LY294002 (20 micromol/L), a PI3K inhibitor, resulted in a rightward shift in response to NE and normalized the NE-induced contractions in the DOCA hypertensive vessels. SB415286, a GSK-3 inhibitor, resulted in a slight rightward shift in response to NE in the DOCA-salt vessels. Thus, enhanced GSK-3 activity modestly augments the effects of PI3K but does not appear to contribute greatly to the altered arterial reactivity in DOCA-salt hypertension.
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PMID:PI3-kinase-induced hyperreactivity in DOCA-salt hypertension is independent of GSK-3 activity. 1262 35

Glycogen synthase kinase-3 beta (GSK-3 beta) regulates cell metabolism, cell cycle, and cell fate through the phosphorylation of a diverse array of substrates. Herein, we provide evidence that supports a role for GSK-3 in mammalian meiosis and spermatogenesis. Immunostaining of testis sections showed that while GSK-3 alpha was ubiquitous in the seminiferous tubules, GSK-3 beta was expressed in premeiotic type B spermatogonia, in both meiotic preleptotene and leptotene spermatocytes, as well as in Sertoli cells in both the mouse and rat. Thus, GSK-3 beta is expressed in germ cells entering meiosis. In addition, intense immunoreactivity was detected in rat step 6 though 11 spermatids. In situ hybridization (ISH) in rat testis confirmed the immunostaining pattern in leptotene and spermatids and showed a GSK-3 beta messenger RNA (mRNA) signal in some pachytene spermatocytes. The restricted pattern of expression suggests cell-specific regulation of Gsk-3 beta mRNA. To determine whether GSK-3 is required for meiosis entry, rat stage VIIa seminiferous tubule segments were cultured with selective small-molecule GSK-3 inhibitors. These compounds markedly and dose-dependently suppressed meiotic synthesis (S)-phase DNA. Since a yeast GSK-3 homolog, Rim11p (regulator of inducer of meiosis), is pivotal to meiosis entry, we tested whether GSK-3 beta complements Rim11p function in meiosis. Rim11p phosphorylates transcription factors Ume6p (unscheduled meiotic gene expression) and Ime1p (inducer of meiosis) to induce meiosis entry. Overexpression of murine GSK-3 beta in a rim11 mutant yeast failed to rescue the sporulation defect. Our finding that GSK-3 beta interacted only with Ume6p but not with IME1 in a yeast 2-hybrid assay suggests that noncomplementation reflects partial divergence in substrate specificity. This work provides the basis for future studies of GSK-3 beta signaling in mammalian meiosis and spermatogenesis.
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PMID:Evidence for a role of glycogen synthase kinase-3 beta in rodent spermatogenesis. 1272 Dec 8

The latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) is expressed in all KSHV-associated malignancies. LANA is essential for replication and maintenance of the viral episomes during latent infection. However, LANA also has a transcriptional regulatory role and can affect gene expression both positively and negatively. A previously performed yeast two-hybrid screen identified glycogen synthase kinase 3 (GSK-3) as a LANA-interacting protein. Interaction with both GSK-3alpha and GSK-3beta was confirmed in transfected cells with coprecipitation assays. GSK-3beta also interacted with the herpesvirus saimiri homolog ORF73. GSK-3beta is an intermediate in the Wnt signaling pathway and a negative regulator of beta-catenin. In transfected cells, LANA was shown to overcome GSK-3beta-mediated degradation of beta-catenin. Examination of primary effusion lymphoma (PEL) cells found increased levels of beta-catenin relative to KSHV-negative B cells, and this translated into increased activity of a beta-catenin-responsive reporter containing Tcf/Lef binding sites. In tetradecanoyl phorbol acetate-treated PEL cells, loss of LANA expression correlated temporally with loss of detectable beta-catenin. LANA was found to alter the intracellular distribution of GSK-3beta so that nuclear GSK-3beta was more readily detectable in the presence of LANA. Mapping experiments with coimmunoprecipitation assays revealed that both N-terminal and C-terminal LANA sequences were required for efficient GSK-3beta interaction. LANA mutants that were defective for GSK-3beta interaction were unable to mediate GSK-3beta relocalization or activate a beta-catenin-responsive Tcf-luciferase reporter. This study identified manipulation of GSK-3beta activity as a mechanism by which LANA may modify transcriptional activity and contribute to the phenotype of primary effusion lymphoma.
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PMID:The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus manipulates the activity of glycogen synthase kinase-3beta. 1282 41

Lithium has been used as an effective mood-stabilizing drug for the treatment of manic episodes and depression for 50 years. More recently, lithium has been found to protect neurons from death induced by a wide array of neurotoxic insults. However, the molecular basis for the prophylactic effects of lithium have remained obscure. A target of lithium, glycogen synthase kinase 3 (GSK-3), is implicated in neuronal death after trophic deprivation. The mechanism whereby GSK-3 exerts its neurotoxic effects is also unknown. Here we show that lithium blocks the canonical c-Jun apoptotic pathway in cerebellar granule neurons deprived of trophic support. This effect is mimicked by the structurally independent inhibitors of GSK-3, FRAT1, and indirubin. Like lithium, these prevent the stress induced c-Jun protein increase and subsequent apoptosis. These events are downstream of c-Jun transactivation, since GSK-3 inhibitors block neuronal death induced by constitutively active c-Jun (Ser/Thr-->Asp) and FRAT1 expression inhibits AP1 reporter activity. Consistent with this, AP1-dependent expression of proapoptotic Bim requires GSK-3-like activity. These data suggest that a GSK-3-like kinase acts in tandem with c-Jun N-terminal kinase to coordinate the full execution of the c-Jun stress response and neuronal death in response to trophic deprivation.
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PMID:Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3. 1291 27


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