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)

GskA, the Dictyostelium GSK-3 orthologue, is modified and activated by the dual-specificity tyrosine kinase Zak1, and the two kinases form part of a signaling pathway that responds to extracellular cyclic AMP. We identify potential cellular effectors for the two kinases by analyzing the corresponding null mutants. There are proteins and mRNAs that are altered in abundance in only one or the other of the two mutants, indicating that each kinase has some unique functions. However, proteomic and microarray analyses identified a number of proteins and genes, respectively, that are similarly misregulated in both mutant strains. The positive correlation between the array data and the proteomic data is consistent with the Zak1-GskA signaling pathway's functioning by directly or indirectly regulating gene expression. The discoidin 1 genes are positively regulated by the pathway, while the abundance of the H5 protein is negatively regulated. Two of the targets, H5 and discoidin 1, are well-characterized markers for early development, indicating that the Zak1-GskA pathway plays a role in development earlier than previously observed.
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PMID:Proteomic and microarray analyses of the Dictyostelium Zak1-GSK-3 signaling pathway reveal a role in early development. 1708 34

Recently we demonstrated that IGF-1 expression is increased in the diabetic kidney and that it may involve in renal hypertrophy and extracellular matrix protein (ECM) accumulation in mesangial cells as seen in diabetic glomerulopathy. The present study investigates the molecular mechanism(s) of IGF-1 and Akt/glycogen synthase kinase-3beta (GSK-3beta) signaling pathway in the regulation of fibronectin and cyclin D1 expression and survival of renal mesangial cells. A proteomic approach is also employed to identify protein targets of IGF-1 signaling via GSK-3beta inhibition in mesangial cells. We show that IGF-1 (100 ng/ml) significantly increases the protein kinase Akt/PKB activity (1.5-2-fold, p<0.05) within 1-5 minutes, which is completely blocked by the presence of 100 nM Wortmannin (phosphatidyl-inositol 3-kinase inhibitor). Akt activation is coupled with Ser9 phosphorylation and inactivation of its down-stream target GSK-3beta. IGF-1 increases the cyclic AMP-responsive element (CRE) binding transcription factor CREB phosphorylation at Ser 133 and CRE-binding activity in mesangial cells, which parallels cyclin D1 and fibronectin expressions. Both proteins are known to have CRE-sequences in their promoter regions upstream of the transcription start site. Suppression of GSK-3beta by SB216763 (100 nM) increases CREB phosphorylation, cyclin D1 and fibronectin levels. Two dimensional gel electrophoresis followed by MALDI-TOF mass spectrometric analysis of mesangial proteins reveals that IGF-1 treatment or an inhibition of GSK-3beta increases the expression of the phosphorylated Ser/Thr binding signal adapter protein 14-3-3zeta. Immuno-precipitation of 14-3-3zeta followed by Western blotting validates the association of phosphorylated GSK-3beta with 14-3-3zeta in renal mesangial cells. Stable expression of a constitutively active GSK-3beta(Ser9Ala) induces cell death while overexpression of HA-tagged 14-3-3zeta increases cell viability as measured by MTT assays. These results indicate that the Akt/GSK-3beta pathway and the adapter protein 14-3-3zeta may play an important role in IGF-1 signaling and survival of mesangial cells in diabetic nephropathy.
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PMID:Proteomic identification of 14-3-3zeta as an adapter for IGF-1 and Akt/GSK-3beta signaling and survival of renal mesangial cells. 1720 Jun 89

Lithium is a therapeutic agent commonly used to treat bipolar disorder and its beneficial effects are thought to be due to a combination of activation of the Wnt/beta-catenin pathway via inhibition of glycogen synthase kinase-3beta and depletion of the inositol pool via inhibition of the inositol monophosphatase-1. We demonstrated that lithium in primary endothelial cells induced an increase in mitochondrial mass leading to an increase in ATP production without any significant change in mitochondrial efficiency. This increase in mitochondrial mass was associated with an increase in the mRNA levels of mitochondrial biogenesis transcription factors: nuclear respiratory factor-1 and -2beta, as well as mitochondrial transcription factors A and B2, which lead to the coordinated upregulation of oxidative phosphorylation components encoded by either the nuclear or mitochondrial genome. These effects of lithium on mitochondrial biogenesis were independent of the inhibition of glycogen synthase kinase-3beta and independent of inositol depletion. Also, expression of the coactivator PGC-1alpha was increased, whereas expression of the coactivator PRC was not affected. Lithium treatment rapidly induced a decrease in activating Akt-Ser473 phosphorylation and inhibitory Forkhead box class O (FOXO1)-Thr24 phosphorylation, as well as an increase in activating c-AMP responsive element binding (CREB)-Ser133 phosphorylation, two mechanisms known to control PGC-1alpha expression. Together, our results show that lithium induces mitochondrial biogenesis via CREB/PGC-1alpha and FOXO1/PGC-1alpha cascades, which highlight the pleiotropic effects of lithium and reveal also novel beneficial effects via preservation of mitochondrial functions.
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PMID:Lithium increases PGC-1alpha expression and mitochondrial biogenesis in primary bovine aortic endothelial cells. 1745 29

Glycogen synthase kinase-3 (GSK-3) is a multifaceted enzyme involved in development, neurogenesis, and survival at the CNS. We investigated nucleotides signaling to GSK-3 in cerebellar granule neurons and found that the metabotropic agonist 2-methyl-thio-ADP (2MeSADP) was able to induce GSK-3 phosphorylation and inhibition of its catalytic activity. 2MeSADP could be acting through several P2Y-ADP receptors expressed in granule neurons, as RT-PCR expression was found for P2Y(1), P2Y(12), and P2Y(13) receptors, but the pharmacological data fitted well with a Gi-coupled P2Y(13) receptor: the effect was sensitive to pertussis toxin, was unaffected by specific antagonists of P2Y(1) and P2Y(12) receptors, such as 2'-deoxy-N(6)-methyl-adenosine 3',5'-diphosphate and 2-methyl-thio-AMP, respectively, and the EC(50) values for 2MeSADP and ADP were in the same low nanomolar range. 2MeSADP was able to phosphorylate and activate extracellular signal-regulated kinase (ERK)-1,2 and Akt proteins, but its effect on GSK-3 phosphorylation was primarily dependent on the phosphatidyl inositol-3 kinase (PI3-K)/Akt pathway, as it was abolished by the PI3-K inhibitor wortmannin. GSK-3 inactivation by 2MeSADP in granule neurons resulted in nuclear translocation of its substrate beta-catenin, which functions as a transcriptional regulator, this effect being lost with wortmaninn. The present study first describes the coupling of a Gi-coupled P2Y(13)-like receptor to GSK-3 and beta-catenin through PI3-K/Akt signaling.
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PMID:Gi-coupled P2Y-ADP receptor mediates GSK-3 phosphorylation and beta-catenin nuclear translocation in granule neurons. 1798 31

The bipartite transcription factor beta-catenin/TCF (cat/TCF) has been recognized as the major effector of the Wnt signaling pathway for more than a decade, and its over-activation has been associated with malignancy such as colon and breast cancer. Extensive examination in different cell lineages has shown that the activity of cat/TCF can be stimulated by mechanisms other than via the Wnt glycoproteins, including the stimulation of beta-cat nuclear translocation and enhanced binding of cat/TCF to the Wnt target gene promoters by insulin and insulin-like growth factor-1 (IGF-1). In addition, the heterotrimeric G proteins of the G(12) subfamily can interact with the cytoplasmic domain of cadherins, resulting in the release of the transcriptional activator beta-cat. Furthermore, certain peptide hormones may stimulate cat/TCF-mediated gene transcription via activation of their corresponding G-protein coupled receptors. Recently, the serine/threonine kinase GSK-3 has been recognized to coordinate with AMP activated protein kinase (AMPK) in phosphorylation and activation of TSC2, the major component of the tumor suppressor complex TSC1/2. Thus, Wnt activation can stimulate protein translation via GSK-3 and TSC1/2 inactivation, followed by mTOR activation. Finally, beta-cat also functions as a pivotal molecule in defense against oxidative stress via serving as a partner of forkhead box O (FOXO) transcription factors. Thus, FOXO proteins, which mainly mediate aging and stress signaling, and TCF factors, which mainly mediate developmental and proliferation signaling, compete for a limited pool of free beta-cat. Insulin and growth factors, on the other hand, control the balance between TCF- and FOXO-mediated gene transcription via phosphorylation and nuclear exclusion of FOXO proteins. These observations provide new insight to understand how Wnt, insulin/growth factors, and FOXOs are involved in versatile physiological events and the development and progression of various human diseases.
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PMID:Wnt and beyond Wnt: multiple mechanisms control the transcriptional property of beta-catenin. 1855 64

Interferon-gamma (IFN-gamma) plays a crucial role in innate immunity and inflammation. It causes the synergistic effect on endotoxin lipopolysaccharide (LPS)-stimulated inducible nitric oxide synthase (iNOS)/NO biosynthesis; however, the mechanism remains unclear. In the present study, we investigated the effects of glycogen synthase kinase-3 (GSK-3)-mediated inhibition of anti-inflammatory interleukin-10 (IL-10). We found, in LPS-stimulated macrophages, that IFN-gamma increased iNOS expression and NO production in a time-dependent manner. In addition, ELISA analysis showed the upregulation of tumor necrosis factor-alpha and regulated on activation, normal T expressed and secreted, and the downregulation of IL-10. RT-PCR further showed changes in the IL-10 mRNA level as well. Treating cells with recombinant IL-10 showed a decrease in IFN-gamma/LPS-induced iNOS/NO biosynthesis, whereas anti-IL-10 neutralizing antibodies enhanced this effect, suggesting that IL-10 acts in an anti-inflammatory role. GSK-3-inhibitor treatment blocked IFN-gamma/LPS-induced iNOS/NO biosynthesis but upregulated IL-10 production. Inhibiting GSK-3 using short-interference RNA showed similar results. Additionally, treating cells with anti-IL-10 neutralizing antibodies blocked these effects. We further showed that inhibiting GSK-3 increased phosphorylation of transcription factor cyclic AMP response element binding protein. Inhibiting protein tyrosine kinase Pyk2, an upstream regulator of GSK-3beta, caused inhibition on IFN-gamma/LPS-induced GSK-3beta phosphorylation at tyrosine 216 and iNOS/NO biosynthesis. Taken together, these findings reveal the involvement of GSK-3-inhibited IL-10 on the induction of iNOS/NO biosynthesis by IFN-gamma synergized with LPS.
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PMID:IFN-gamma synergizes with LPS to induce nitric oxide biosynthesis through glycogen synthase kinase-3-inhibited IL-10. 1865 71

Bacillus anthracis edema toxin (ET) generates high levels of cyclic AMP and impacts a complex network of signaling pathways in targeted cells. In the current study, we sought to identify kinase signaling pathways modulated by ET to better understand how this toxin alters cell physiology. Using a panel of small-molecule inhibitors of mammalian kinases, we found that inhibitors of glycogen synthase kinase 3 beta (GSK-3beta) protected cells from ET-induced changes in the cell cycle. GSK-3beta inhibitors prevented declines in cellular levels of cyclin D1 and c-Jun following treatment of macrophages with ET. Strikingly, cell fractionation experiments and confocal immunofluorescence microscopy revealed that ET activates a compartmentalized pool of GSK-3beta residing in the nuclei, but not in the cytoplasm, of macrophages. To investigate the outcome of this event, we examined the cellular location and activation state of beta-catenin, a critical substrate of GSK-3beta, and found that the protein was inactivated within the nucleus following intoxication with ET. To determine if ET could overcome the effects of stimuli that inactivate GSK-3beta, we examined the impact of the toxin on the Wnt signaling pathway. The results of these experiments revealed that by targeting GSK-3beta residing in the nucleus, ET circumvents the upstream cytoplasmic inactivation of GSK-3beta, which occurs following exposure to Wnt-3A. These findings suggest ET arrests the cell cycle by a mechanism involving activation of GSK-3beta residing in the nucleus, and by using this novel mechanism of intoxication, ET avoids cellular systems that would otherwise reverse the effects of the toxin.
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PMID:Bacillus anthracis edema toxin activates nuclear glycogen synthase kinase 3beta. 1876 29

It has been suggested that accumulation of beta-amyloid (Abeta) peptide triggers neurodegeneration, at least in part, via glutamate-mediated excitotoxicity in Alzheimer's disease (AD) brain. This is supported by observations that toxicity induced by Abeta peptide in cultured neurons and in adult rat brain is known to be mediated by activation of glutamatergic N-methyl-d-aspartate (NMDA) receptors. Additionally, recent clinical studies have shown that memantine, a noncompetitive NMDA receptor antagonist, can significantly improve cognitive functions in some AD patients. However, very little is currently known about the potential role of memantine against Abeta-induced toxicity. In the present study, we have shown that Abeta(1-42)-induced toxicity in rat primary cortical cultured neurons is accompanied by increased extracellular and decreased intracellular glutamate levels. We subsequently demonstrated that Abeta toxicity is induced by increased phosphorylation of tau protein and activation of tau kinases, i.e. glycogen synthase kinase-3beta and extracellular signal-related kinase 1/2. Additionally, Abeta treatment induced cleavage of caspase-3 and decreased phosphorylation of cyclic AMP response element binding protein, which are critical in determining survival of neurons. Memantine treatment significantly protected cultured neurons against Abeta-induced toxicity by attenuating tau-phosphorylation and its associated signaling mechanisms. However, this drug did not alter either conformation or internalization of Abeta(1-42) and it was unable to attenuate Abeta-induced potentiation of extracellular glutamate levels. These results, taken together, provide new insights into the possible neuroprotective action of memantine in AD pathology.
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PMID:Memantine protects rat cortical cultured neurons against beta-amyloid-induced toxicity by attenuating tau phosphorylation. 1904 81

Gap junction intercellular communication in osteocytes plays an important role in bone remodeling in response to mechanical loading; however, the responsible molecular mechanisms remain largely unknown. Here, we show that phosphoinositide-3 kinase (PI3K)/Akt signaling activated by fluid flow shear stress and prostaglandin E(2) (PGE(2)) had a stimulatory effect on both connexin 43 (Cx43) mRNA and protein expression. PGE(2) inactivated glycogen synthase kinase 3 (GSK-3) and promoted nuclear localization and accumulation of beta-catenin. Knockdown of beta-catenin expression resulted in a reduction in Cx43 protein. Furthermore, the chromatin immunoprecipitation (ChIP) assay demonstrated an association of beta-catenin with the Cx43 promoter, suggesting that beta-catenin could regulate Cx43 expression at the level of gene transcription. We have previously reported that PGE(2) activates cyclic AMP (cAMP)-protein kinase A (PKA) signaling and increases Cx43 and gap junctions. Interestingly, the activation of PI3K/Akt appeared to be independent of the activation of PKA, whereas both PI3K/Akt and PKA signaling inactivated GSK-3 and increased beta-catenin translocation. Together, these results suggest that shear stress, through PGE(2) release, activates both PI3K/Akt and cAMP-PKA signaling, which converge through the inactivation of GSK-3, leading to the increase in nuclear accumulation of beta-catenin. beta-Catenin binds to the Cx43 promoter, stimulating Cx43 expression and functional gap junctions between osteocytes.
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PMID:Prostaglandin promotion of osteocyte gap junction function through transcriptional regulation of connexin 43 by glycogen synthase kinase 3/beta-catenin signaling. 1984 Oct 66

Phencyclidine is an N-methyl d-aspartate receptor (NMDAR) blocker that has been reported to induce neuronal apoptosis during development and schizophrenia-like behaviors in rats later in life. Brain-derived neurotrophic factor (BDNF) has been shown to prevent neuronal death caused by NMDAR blockade, but the precise mechanism is unknown. This study examined the role of the phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways in BDNF protection of PCP-induced apoptosis in corticostriatal organotypic cultures. It was observed that BDNF inhibited PCP-induced apoptosis in a concentration-dependent fashion. BDNF effectively prevented PCP-induced inhibition of the ERK and PI-3K/Akt pathways and suppressed GSK-3beta activation. Blockade of either PI-3K/Akt or ERK activation abolished BDNF protection. Western blot analysis revealed that the PI-3K inhibitor LY294002 prevented the stimulating effect of BDNF on the PI-3K/Akt pathway, but had no effect on the ERK pathway. Similarly, the ERK inhibitor PD98059 prevented the stimulating effect of BDNF on the ERK pathway, but not the PI-3K/Akt pathway. Co-application of LY294002 and PD98059 had no additional effect on BDNF-evoked activation of Akt or ERK. However, concurrent exposure to PD98059 and LY294002 caused much greater inhibition of BDNF-evoked phosphorylation of GSK-3beta at serine 9 than did LY294002 alone. Finally, either BDNF or GSK-3beta inhibition prevented PCP-induced suppression of cyclic-AMP response element binding protein (CREB) phosphorylation. These data demonstrate that the protective effect of BDNF against PCP-induced apoptosis is mediated by parallel activation of the PI-3K/Akt and ERK pathways, most likely involves inhibition of GSK-3beta and activation of CREB.
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PMID:Brain-derived neurotrophic factor prevents phencyclidine-induced apoptosis in developing brain by parallel activation of both the ERK and PI-3K/Akt pathways. 1988 77


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