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 naphthodianthrone hypericin causes a photosensitized inhibition of protein kinases involved in growth factor signalling pathways. Nanomolar concentrations of hypericin inhibit the protein tyrosine kinase activities (PTK) of the epidermal growth factor receptor and the insulin receptor, while being ineffective towards the cytosolic protein tyrosine kinases Lyn, Fgr, TPK-IIB and CSK. Photosensitized inhibition by hypericin is not restricted to receptor-PTKs since the Ser/Thr protein kinases (protein kinase CK-2, protein kinase C and mitogen-activated kinase) are also extremely sensitive to inhibition (IC50 value for protein kinase CK-2 = 6 nM). A comparison of the hypericin-mediated inhibition of the epidermal growth factor-receptor PTK and protein kinase CK-2 revealed that the inhibition is irreversible, strictly dependent upon irradiation of the enzyme-inhibitor complex with fluorescent light and likely mediated by the formation of radical intermediates (type I mechanism). Although the exact molecular basis for the selectivity of enzyme inhibition by hypericin remains unknown, our results suggest that distantly related protein kinases could still share common reactive domains for the interaction with hypericin.
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PMID:Photosensitized inhibition of growth factor-regulated protein kinases by hypericin. 778 2

The role of the p90 ribosomal protein S6 kinase/mitogen-activated protein kinase (RSK/MAPK) signaling pathway in regulating glycogen synthase kinase-3 (GSK-3) activity was investigated. In vitro studies showed that GSK-3 was inactivated by 50% upon incubation with RSK purified from epidermal growth factor (EGF)-stimulated NIH/3T3 cells. Subsequently, the effect of EGF on GSK-3 activity was measured in NIH/3T3 cells that stably overexpressed mutated forms of MAPK kinase (MAPKK). The activation of RSK by EGF was markedly decreased in cell lines expressing the dominant negative MAPKK mutants S222A and K97A and was increased in cells expressing the S222E mutant as compared with control cell lines. EGF induced a rapid decrease in GSK-3 beta activity (50%) in control and S222E cells; however, only 25 and 10% inhibition in GSK-3 beta activity was observed in cell lines expressing the dominant negative mutants K97A and S222A, respectively, suggesting that inhibition of GSK-3 was partially blocked in these cells. Taken together, these results suggest that the action of EGF on GSK-3 inactivation is mediated by the RSK/MAPK signaling pathway in NIH/3T3 cells and provide evidence for a mechanism regulating GSK-3 activity in intact cells.
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PMID:Inactivation of glycogen synthase kinase-3 by epidermal growth factor is mediated by mitogen-activated protein kinase/p90 ribosomal protein S6 kinase signaling pathway in NIH/3T3 cells. 783 18

Glycogen synthase kinase-3 (GSK-3) mediates epidermal growth factor, insulin and Wnt signals to various downstream events such as glycogen metabolism, gene expression, proliferation and differentiation. We have isolated here a GSK-3beta-interacting protein from a rat brain cDNA library using a yeast two-hybrid method. This protein consists of 832 amino acids and possesses Regulators of G protein Signaling (RGS) and dishevelled (Dsh) homologous domains in its N- and C-terminal regions, respectively. The predicted amino acid sequence of this GSK-3beta-interacting protein shows 94% identity with mouse Axin, which recently has been identified as a negative regulator of the Wnt signaling pathway; therefore, we termed this protein rAxin (rat Axin). rAxin interacted directly with, and was phosphorylated by, GSK-3beta. rAxin also interacted directly with the armadillo repeats of beta-catenin. The binding site of rAxin for GSK-3beta was distinct from the beta-catenin-binding site, and these three proteins formed a ternary complex. Furthermore, rAxin promoted GSK-3beta-dependent phosphorylation of beta-catenin. These results suggest that rAxin negatively regulates the Wnt signaling pathway by interacting with GSK-3beta and beta-catenin and mediating the signal from GSK-3beta to beta-catenin.
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PMID:Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. 948 34

The regulation of glycogen synthesis and associated enzymes was studied in human myoblasts and myotubes maintained in culture. Both epidermal growth factor (EGF) and insulin stimulated glycogen synthesis approximately 2-fold, this stimulation being accompanied by a rapid and stable activation of the controlling enzyme glycogen synthase (GS). EGF also caused inhibition of glycogen synthase kinase 3 (GSK-3) and activation of the alpha isoform of protein kinase B (PKB) with the time-course and magnitude of its effects being similar to those induced by insulin. An inhibitor of the mitogen-activated protein (MAP) kinase pathway did not prevent stimulation of GS by EGF, suggesting that this pathway is not essential for the effect. A partial decrease in the fold activation of GS was, however, observed when p70(S6k) activation was blocked with rapamycin, suggesting a contribution of this pathway to the control of GS by either hormone. Wortmannin, a selective inhibitor of phosphatidylinositol 3'-kinase (PI-3 kinase) completely blocked the effects of both EGF and insulin in these cells. These results demonstrate that EGF, like insulin, activates glycogen synthesis in muscle, acting principally via the PKB/GSK-3 pathway but with a contribution from a rapamycin-sensitive component that lies downstream of PI-3 kinase.
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PMID:Control of glycogen synthesis in cultured human muscle cells. 987 15

Brain-derived neurotrophic factor (BDNF) and insulin promote the survival of 6-7 day old post-natal rat cerebellar granule cells. Previous studies using the PI3 kinase inhibitor, wortmannin and the over-expression of protein kinase B (PKB) have indicated that both PI3 kinase and PKB activation are central for insulin-stimulated survival of these neurones. Here we report that BDNF, insulin and epidermal growth factor (EGF) all cause the phosphorylation and stimulation of endogenous PKB activity, though with differing profiles. The addition of BDNF, or insulin resulted in a rapid and sustained phosphorylation and stimulation of PKB activity, whilst EGF stimulation, which does not promote survival, caused a more transient phosphorylation and stimulation of PKB activity. We also investigated the involvement of the PKB substrate, glycogen synthase kinase 3 (GSK 3). All three growth factors caused the inactivation of GSK-3beta, suggesting that the inactivation of GSK-3beta does not correlate with survival.
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PMID:Sustained phosphorylation and activation of protein kinase B correlates with brain-derived neurotrophic factor and insulin stimulated survival of cerebellar granule cells. 1032 30

Cripto-1 (CR-1), a member of the epidermal growth factor-CFC peptide family, activates the ras/raf/mitogen-activated protein/extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. In the present study, the role of CR-1 in the phosphatidylinositol 3'-kinase (PI3K)/AKT (protein kinase B)/glycogen synthase kinase 3beta (GSK-3beta)-dependent signaling pathway was evaluated in human SiHa cervical carcinoma cells. Our data demonstrate that CR-1 can enhance the tyrosine phosphorylation of the p85 regulatory subunit of PI3K and transiently induce the phosphorylation of AKT in a time- and dose-dependent manner. In addition, CR-1 was found to induce the phosphorylation of GSK-3beta. Phosphorylation of AKT and GSK-3beta by CR-1 can be blocked by LY294002, a specific inhibitor of PI3K, thus leading to apoptosis. Finally, the apoptotic effect of LY294002 can be partially rescued by exogenous CR-1. In summary, our data suggest that human CR-1 may function as a survival factor through a PI3K-dependent signaling pathway involving AKT and GSK-3beta.
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PMID:Cripto-1 induces phosphatidylinositol 3'-kinase-dependent phosphorylation of AKT and glycogen synthase kinase 3beta in human cervical carcinoma cells. 1049 95

The regulatory influences of glycogen synthase kinase-3 beta (GSK3 beta) and lithium on the activity of cyclic AMP response element binding protein (CREB) were examined in human neuroblastoma SH-SY5Y cells. Activation of Akt (protein kinase B) with serum-increased phospho-serine-9-GSK3 beta (the inactive form of the enzyme), inhibited GSK3 beta activity, and increased CREB DNA binding activity. Inhibition of GSK3 beta by another paradigm, treatment with the selective inhibitor lithium, also increased CREB DNA binding activity. The inhibitory regulation of CREB DNA binding activity by GSK3 beta also was evident in differentiated SH-SY5Y cells, indicating that this regulatory interaction is maintained in non-proliferating cells. These results demonstrate that inhibition of GSK3 beta by serine-9 phosphorylation or directly by lithium increases CREB activation. Conversely, overexpression of active GSK3 beta to 3.5-fold the normal levels completely blocked increases in CREB DNA binding activity induced by epidermal growth factor, insulin-like growth factor-1, forskolin, and cyclic AMP. The inhibitory effects due to overexpressed GSK3 beta were reversed by treatment with lithium and with another GSK 3beta inhibitor, sodium valproate. Overall, these results demonstrate that GSK3 beta inhibits, and lithium enhances, CREB activation.
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PMID:CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium. 1157 31

Three coagulase-negative Staphylococcus species (CNS) (Staphylococcus epidermidis, Staphylococcus xylosus and Staphylococcus hyicus), from the milk of cows with mastitis, were used to evaluate adherence to and internalization by bovine mammary epithelial cells, and to investigate involvement of host cell signal transduction and host cell cytoskeleton rearrangement on internalization of CNS. S. xylosus showed highest adherence and internalization values of the species evaluated. Host cell cytoskeleton polymerization and protein kinase (PK) phosphorylation were required for internalization of CNS. Both protein kinase C (PKC) and tyrosine kinase (TPK) pathways were involved, but internalization of S. xylosus occurred preferentially through epidermal growth factor TPK activity. S. epidermidis and S. hyicus seemed to exploit other TPK pathways. Results of this study showed that S. xylosus, S. hyicus and S. epidermidis were able to adhere and internalize bovine mammary cells in a process that appeared to be receptor(s) mediated and exploited host signal transduction and cytoskeleton to induce an uptake signal.
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PMID:Interaction of coagulase-negative Staphylococcus species with bovine mammary epithelial cells. 1171 Aug 40

During wound healing, keratinocytes initiate migration from the wound edge by extending lamellipodia into a fibronectin-rich provisional matrix. While lamellipodia-like structures are also found in cultured keratinocytes exposed to epidermal growth factor (EGF), the signaling pathway that regulates the formation of these structures is not defined. In cultured human keratinocytes seeded on fibronectin, we found that protein-serine/threonine kinase inhibitors including staurosporine, induced concentration-dependent formation of extended lamellipodia (E-lams). The formation of E-lams was inhibited by the proteintyrosine kinase inhibitors herbimycin A and genistein and augmented by the protein-tyrosine phosphatase inhibitor sodium orthovanadate. Staurosporine treatment induced relocation of tyrosine phosphorylated phospholipase C-gamma1 (PLC-gamma1) to the tips of lamellipodia where actin assembly was initiated. Consistent with an involvement of PLC-gamma1 in E-lam formation, intracellular free calcium (Ca2+) was elevated during the formation of E-lams and conversely, E-lam formation was blocked by intracellular Ca2+ chelation with BAPTA/AM, but not by extracellular reduction of Ca2+ by EGTA. Notably, glycogen synthase kinase-3alpha/beta (GSK-3alpha/beta) was activated by staurosporine as evidenced by reduced phosphorylation on Ser-21/9. Suppression of GSK-3 activity by LiCl2 or by a specific chemical inhibitor, SB-415286, blocked E-lam formation but without altering cell spreading. Furthermore, GSK-3 inhibitors blocked both staurosporine- and EGF-induced keratinocyte migration in scratch-wounded cultures. We propose that GSK-3 plays a crucial role in the formation of long lamellipodia in human keratinocytes and is potentially a central regulatory molecule in epithelial cell migration during wound healing.
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PMID:Glycogen synthase kinase-3 regulates formation of long lamellipodia in human keratinocytes. 1289 Jul 58

Occupational exposure to asphalt fumes may pose a health risk. Experimental studies using animal and in vitro models indicate that condensates from asphalt fumes are genotoxic and can promote skin tumorigenesis. Enhanced activity of activator protein-1 (AP-1) is frequently associated with the promotion of skin tumorigenesis. The current study investigated the effect of exposure to asphalt fumes on AP-1 activation in mouse JB6 P+ epidermal cells and the skin of transgenic mice expressing the AP-1 luciferase reporter gene. Asphalt fumes were generated from a dynamic generation system that simulated road-paving conditions. Exposure to asphalt fumes significantly increased AP-1 activity in JB6 P+ cells as well as in cultured keratinocytes isolated from transgenic mice expressing AP-1 reporter. In addition, topical application of asphalt fumes by painting the tail skin of mice increased AP-1 activity by 14-fold. Exposure to asphalt fumes promoted basal as well as epidermal growth factor-stimulated anchorage-independent growth of JB6 P+ cells in soft agar. It activated phosphatidylinositol 3-kinase and induced phosphorylation of Akt at Ser-473/Thr-308, and concurrently activated downstream p70 S6 kinase as well as glycogen synthase kinase-3beta. Asphalt fumes transiently activated c-Jun NH2-terminal kinases without affecting extracellular signal-regulated kinases and p38 mitogen-activated protein kinases. Further study indicated that blockage of phosphatidylinositol 3-kinase activation eliminated asphalt fume-stimulated AP-1 activation and formation of anchorage-independent colonies in soft agar. This is the first report showing that exposure to asphalt fumes can activate AP-1 and intracellular signaling that may promote skin tumorigenesis, thus providing important evidence on the potential involvement of exposure to asphalt fumes in skin carcinogenesis.
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PMID:Exposure to asphalt fumes activates activator protein-1 through the phosphatidylinositol 3-kinase/Akt signaling pathway in mouse epidermal cells. 1294


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