Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The intestinal mucosa is a rapidly-renewing tissue characterized by cell proliferation, differentiation, and eventual apoptosis with progression up the vertical gut axis. The inhibition of phosphatidylinositol (PI) 3-kinase by specific chemical inhibitors or overexpression of the lipid phosphatase PTEN enhances enterocyte-like differentiation in human colon cancer cell models of intestinal differentiation. In this report, we examined the role of PI 3-kinase inhibition in the regulation of apoptotic gene expression in human colon cancer cell lines HT29, HCT-116, and Caco-2. Inhibition of PI 3-kinase with the chemical inhibitor wortmannin increased TNF-related apoptosis-inducing ligand (TRAIL; Apo2) mRNA and protein expression. Similarly, overexpression of the tumor suppressor protein PTEN, an antagonist of PI 3-kinase signaling, resulted in the increased expression of TRAIL. Activation of PI 3-kinase by pretreatment with IGF-1, a gut trophic factor, markedly attenuated the induction of TRAIL by wortmannin. Moreover, overexpression of active Akt, a downstream target of PI 3-kinase, or inhibition of GSK-3, a downstream target of active Akt, completely blocked the induction of TRAIL by wortmannin. Consistent with findings that TRAIL is induced by agents that enhance intestinal cell differentiation, TRAIL expression was specifically localized to the differentiated cells of the colon and small bowel. Adenovirus-mediated overexpression of TRAIL increased DNA fragmentation of HCT-116 cells, demonstrating the functional activity of TRAIL induction. Taken together, our findings demonstrate induction of the TRAIL by inhibition of PI 3-kinase in colon cancer cell lines. These results identify TRAIL, a novel TNF family member, as a downstream target of the PI 3-kinase/Akt/GSK-3 pathway and may have important implications for better understanding the role of the PI 3-kinase pathway in intestinal cell homeostasis.
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PMID:Regulation of TRAIL expression by the phosphatidylinositol 3-kinase/Akt/GSK-3 pathway in human colon cancer cells. 1214 Feb 94

Stress of the endoplasmic reticulum (ER), which is associated with many neurodegenerative conditions, can lead to the elimination of affected cells by apoptosis through only partially understood mechanisms. Thapsigargin, which causes ER stress by inhibiting the ER Ca(2+)-ATPase, was found to not only activate the apoptosis effector caspase-3 but also to cause a large and prolonged increase in the activity of glycogen synthase kinase-3beta (GSK3beta). Activation of GSK3beta was obligatory for thapsigargin-induced activation of caspase-3, because inhibition of GSK3beta by expression of dominant-negative GSK3beta or by the GSK3beta inhibitor lithium blocked caspase-3 activation. Thapsigargin treatment activated GSK3beta by inducing dephosphorylation of phospho-Ser-9 of GSK3beta, a phosphorylation that normally maintains GSK3beta inactivated. Caspase-3 activation induced by thapsigargin was blocked by increasing the phosphorylation of Ser-9-GSK3beta with insulin-like growth factor-1 or with the phosphatase inhibitors okadaic acid and calyculin A, but the calcineurin inhibitors FK506 and cyclosporin A were ineffective. Insulin-like growth factor-1, okadaic acid, calyculin A, and lithium also protected cells from two other inducers of ER stress, tunicamycin and brefeldin A. Thus, ER stress activates GSK3beta through dephosphorylation of phospho-Ser-9, a prerequisite for caspase-3 activation, and this process is amenable to pharmacological intervention.
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PMID:Central role of glycogen synthase kinase-3beta in endoplasmic reticulum stress-induced caspase-3 activation. 1222 24

T cells resistant to the immunosuppressive drug cyclosporin A (CsA) may be important mediators of chronic graft rejection. We previously reported that T cells activated in the presence of endothelial cells (EC) develop resistance to CsA, and initiate IL-2 secretion within 8-12 h of triggering. CsA normally blocks the phosphatase, calcineurin, thus preventing nuclear translocation of the transcription factor, NFAT. We find that in the presence but not the absence of EC, NFAT1 can be detected in the nuclei of CsA-treated T cells within 8 h of triggering, reaching a maximal level of 60% of control by 24 h. Glycogen synthase kinase-3beta (GSK-3beta), which rephosphorylates NFAT and promotes nuclear export, is inhibited by EC costimulation. GSK-3beta is a component of the wnt signaling pathway, and EC express wnt-5a and T cells express frizzled-5, a wnt-5a receptor. Wnt-5a promotes T cell NFAT nuclear accumulation in the presence of CsA, an effect mimicked by Li(+), a potent inhibitor of GSK-3beta. The protein kinase C agonist PMA dramatically synergizes with both EC and wnt-5a in stimulating T cell IL-2 synthesis, and inhibition of either protein kinase C by Ro-31-8425 or G-proteins by pertussis toxin effectively blocks the actions of wnt-5a on T cells. Finally, a secreted, dominant-negative form of frizzled-5 blocks EC-mediated CsA resistance. Thus, EC promote CsA-resistant nuclear localization of NFAT and subsequent IL-2 synthesis through a noncanonical wnt-dependent pathway.
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PMID:Endothelial cells stimulate T cell NFAT nuclear translocation in the presence of cyclosporin A: involvement of the wnt/glycogen synthase kinase-3 beta pathway. 1224 65

The nuclear localization and transcriptional activity of the NF-ATc family of transcription factors, essential to many developmental, differentiation, and adaptation processes, are determined by the opposing activities of the phosphatase calcineurin, which promotes nuclear accumulation of NF-ATc, and several kinases, which promote cytoplasmic accumulation. Many reports suggest that protein kinase A (PKA) negatively modulates calcineurin-mediated NF-ATc activation. Here we show that overexpression of PKA causes phosphorylation and cytoplasmic accumulation of NF-ATc1 in direct opposition to calcineurin by phosphorylating Ser-245, Ser-269, and Ser-294 in the conserved serine-proline repeat domain, and that mutation of these serines blocks the effect of PKA. Activation of endogenous PKA is similarly able to promote phosphorylation of these sites on NF-ATc1 in two lymphoid cell lines. We further show that a complete block of NF-ATc1 nuclear localization by PKA requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (GSK-3), and that mutation of either the PKA phosphorylation sites or the upstream GSK-3 sites prevents the effect of PKA. Thus, we propose that PKA functions cooperatively as a priming kinase for further phosphorylation by GSK-3 to oppose calcineurin-mediated nuclear accumulation and transcriptional activity of NF-ATc1 and that, through this mechanism, PKA may be an important modulator of many NF-ATc-dependent processes.
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PMID:Protein kinase A negatively modulates the nuclear accumulation of NF-ATc1 by priming for subsequent phosphorylation by glycogen synthase kinase-3. 1235 31

We reported that the inhibition of protein synthesis in skeletal muscle during sepsis correlated with reduced eukaryotic initiation factor eIF2B activity. The present studies define changes in eIF2Bepsilon phosphorylation in gastrocnemius of septic animals. eIF2B kinase activity was significantly elevated 175% by sepsis compared with sterile inflammation, whereas eIF2B phosphatase activity was unaffected. Phosphorylation of eIF2Bepsilon-Ser(535) was significantly augmented over 2-fold and 2.5-fold after 3 and 5 days and returned to control values after 10 days of sepsis. Phosphorylation of glycogen synthase kinase-3 (GSK-3), a potential upstream kinase responsible for the elevated phosphorylation of eIF2Bepsilon, was significantly reduced over 36 and 41% after 3 and 5 days and returned to control values after 10 days of sepsis. The phosphorylation of PKB, a kinase thought to directly phosphorylate and inactivate GSK-3, was significantly reduced approximately 50% on day 3, but not on days 5 or 10, postinfection compared with controls. Treatment of septic rats with TNF-binding protein prevented the sepsis-induced changes in eIF2Bepsilon and GSK-3 phosphorylation, implicating TNF in mediating the effects of sepsis. Thus increased phosphorylation of eIF2Bepsilon via activation of GSK-3 is an important mechanism to account for the inhibition of skeletal muscle protein synthesis during sepsis. Furthermore, the study presents the first demonstration of changes in eIF2Bepsilon phosphorylation in vivo.
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PMID:Phosphorylation of eukaryotic initiation factor eIF2Bepsilon in skeletal muscle during sepsis. 1237 32

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 relationship between amyloid plaques and neurofibrillary tangles, the two pathologic hallmarks of Alzheimer's disease (AD), is an unknown and controversial subject. However, emerging evidence from genetic and biochemical studies suggests that accumulation of amyloid beta peptides may play a causative role in AD pathogenesis. This led to the amyloid hypothesis, which proposes that amyloid beta peptides disrupt neuronal metabolic and ionic homeostasis and cause aberrant activation of kinases and/or inhibition of phosphatases. The resulting alteration in kinase and phosphatase activities ultimately leads to hyperphosphorylation of tau and formation of neurofibrillary tangles. Cyclin-dependent kinase 5 (Cdk5) is a tau kinase whose activity is induced by amyloid beta peptides. Its deregulation may represent one of the signal transduction pathways that connect amyloid beta toxicity to tau hyperphosphorylation. This article reviews the functions and regulation of Cdk5. Evidence that suggests deregulation of Cdk5 activity in AD by virtue of calpain cleavage of its activator p35 to p25 will be discussed.
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PMID:Cdk5: one of the links between senile plaques and neurofibrillary tangles? 1271 30

Constitutive activation of the Wnt/beta-catenin pathway is thought to play a central role in colorectal carcinogenesis. A key output in this pathway is the nuclear level of beta-catenin, which determines the transcription of T-cell transcription factor (TCF)/lymphoid enhancer-binding factor-responsive target genes. In unstimulated cells, beta-catenin is continuously targeted for ubiquitin-dependent degradation, which depends on its NH(2)-terminal phosphorylation by glycogen synthase kinase-3beta (GSK-3beta) in association with a multiprotein complex. Previously, we have shown that the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin and indomethacin down-regulate beta-catenin/TCF signaling in colorectal cancer cells. Here, we demonstrate that the reduced signaling activity of beta-catenin in response to NSAIDs is a result of its enhanced phosphorylation. In SW948 and SW480 colorectal cancer cells, phosphorylation of NH(2)-terminal S/T residues time dependently increased in response to aspirin and indomethacin. In contrast, in 293 cells, NSAID treatment failed to induce detectable levels of beta-catenin phosphorylation but resulted in degradation of beta-catenin within 24 h in serum-deprived cells. The aspirin-induced beta-catenin phosphorylation in colon cancer cells preceded down-regulation of beta-catenin/TCF signaling, suggesting a causal relationship. Inhibition of this process by LiCl pointed to participation of GSK-3beta. Unexpectedly, GSK-3beta was also phosphorylated upon aspirin treatment in six colorectal cancer cell lines. We present evidence that inactivation of a phosphatase rather than stimulation of a kinase or interference with the ubiquitination machinery may be the cause of the stabilized phosphorylation. The data emphasize the importance of beta-catenin in the pathogenesis of colorectal cancer and define it as a key target for anticancer therapeutics.
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PMID:Reduction of beta-catenin/T-cell transcription factor signaling by aspirin and indomethacin is caused by an increased stabilization of phosphorylated beta-catenin. 1281 29

Despite considerable ongoing efforts at the epidemiological, genetic and molecular level, the etiology of bipolar disorder had not yet been elucidated. To study possible contributing components to the pathophysiology of this disorder, we have hypothesized that levels of enzymes inhibited by therapeutically relevant lithium ion concentrations in the brain of patients may differ from those in normal controls and may be involved in the etiology of the disorder. Three Li-inhibitable enzymes were studied in postmortem brain samples of bipolar patients and normal controls. The expression and function of the two enzymes that are obviously involved in signaling cascades, IMPase, involved in the second messenger system of the phosphatidylinositol cycle, and GSK-3, a mediator of an array of signaling cascades, were not found to be different in postmortem frontal and occipital cortex of bipolar patients and normal controls. Only PAP phosphatase protein levels, but not its mRNA levels or enzymatic activity, were found to be significantly decreased in frontal cortex of bipolar patients compared with normal controls.
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PMID:Lithium inhibitable enzymes in postmortem brain of bipolar patients. 1284 35

Phosphorylation of PTEN (phosphatase and tensin homologue) affects PTEN protein stability and function. In this study, phosphorylated PTEN (pPTEN) was observed in 45 (73.8%) of 61 cases with acute myeloid leukaemia (AML). Phosphorylation of Akt and its downstream molecules [FKHR; Forkhead (Drosophila) homologue 1; and GSK-3beta; glycogen synthase kinase 3 beta] was significantly associated with pPTEN (P < 0.001). The complete remission rates were not different with respect to pPTEN, but overall survival was significantly shorter in patients with pPTEN (P < 0.05). Constitutive PTEN phosphorylation may add insight into the molecular pathogenesis of AML, and may be a new parameter for an unfavourable outcome.
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PMID:Phosphatase and tensin homologue phosphorylation in the C-terminal regulatory domain is frequently observed in acute myeloid leukaemia and associated with poor clinical outcome. 1287 73


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