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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the role of 3-phosphoinositide-dependent protein kinase 1 (PDK1) in the insulin-signaling pathway for glucose metabolism, wild-type (wt), the kinase-dead (kd), or the plecstrin homology (PH) domain deletion (DeltaPH) mutant of PDK1 was expressed using an adenovirus gene transduction system in 3T3-L1 adipocytes. wt-PDK1 and kd-PDK1 were found in both membrane and cytosol fractions, whereas DeltaPH-PDK1, which exhibited PDK1 activity similar to that of wt-PDK1, was detected exclusively in the cytosol fraction. Insulin dose dependently activated protein kinase B (PKB) but did not change atypical protein kinase C (aPKC) activity in control cells. aPKC activity was not affected by expression of wt-, kd-, or DeltaPH-PDK1 in either the presence or the absence of insulin. Overexpression of wt-PDK1 enhanced insulin-induced activation of PKB as well as insulin-induced phosphorylation of glycogen synthase kinase (GSK)3alpha/beta, a direct downstream target of PKB, although insulin-induced glycogen synthesis was not significantly enhanced by wt-PDK1 expression. Neither DeltaPH-PDK1 nor kd-PDK1 expression affected PKB activity, GSK3 phosphorylation, or glycogen synthesis. Thus membrane localization of PDK1 via its PH domain is essential for insulin signaling through the PDK1-PKB-GSK3alpha/beta pathway. Glucose transport activity was unaffected by expression of wt-PDK1, kd-PDK1, or DeltaPH-PDK1 in either the presence or the absence of insulin. These findings suggest the presence of a signaling pathway for insulin-stimulated glucose transport in which PDK1 to PKB or aPKC is not involved.
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PMID:Role of PDK1 in insulin-signaling pathway for glucose metabolism in 3T3-L1 adipocytes. 1200 70

Lithium, carbamazepine and valproic acid are effective mood-stabilizing treatments for bipolar affective disorder. The molecular mechanisms underlying the actions of these drugs and the illness itself are unknown. Berridge and colleagues suggested that inositol depletion may be the way that lithium works in bipolar affective disorder, but others have suggested that glycogen synthase kinase (GSK3) may be the relevant target. The action of valproic acid has been linked to both inositol depletion and to inhibition of histone deacetylase (HDAC). We show here that all three drugs inhibit the collapse of sensory neuron growth cones and increase growth cone area. These effects do not depend on GSK3 or HDAC inhibition. Inositol, however, reverses the effects of the drugs on growth cones, thus implicating inositol depletion in their action. Moreover, the development of Dictyostelium is sensitive to lithium and to valproic acid, but resistance to both is conferred by deletion of the gene that codes for prolyl oligopeptidase, which also regulates inositol metabolism. Inhibitors of prolyl oligopeptidase reverse the effects of all three drugs on sensory neuron growth cone area and collapse. These results suggest a molecular basis for both bipolar affective disorder and its treatment.
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PMID:A common mechanism of action for three mood-stabilizing drugs. 1201 4

Proteolytic processing of Ci requires phosphorylation by the kinases Sgg/GSK3 and CK1. The newly identified phosphorylation sites form clusters with previously described PKA sites in which phosphorylation by PKA acts to prime subsequent phosphorylation by Sgg/GSK3 and CK1.
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PMID:Ci proteolysis: regulation by a constellation of phosphorylation sites. 1212 92

Eukaryotic initiation factor (eIF) 2B is a guanine-nucleotide exchange factor that plays a key role in the regulation of protein synthesis. It is activated by insulin, serum and other agents that stimulate general protein synthesis. The largest (epsilon) subunit of eIF2B is a substrate for glycogen synthase kinase (GSK)-3 in vitro, and phosphorylation by GSK3 inhibits the activity of eIF2B. The site of phosphorylation has previously been identified as Ser(535). GSK3 is inactivated by phosphorylation in response to insulin or serum. In Chinese-hamster ovary cells, insulin and serum bring about the dephosphorylation of Ser(535) in vivo, concomitantly with the phosphorylation of GSK3, and these effects are mediated through signalling via phosphoinositide 3-kinase. We have made use of inhibitors of GSK3 to determine whether GSK3 is responsible for phosphorylation of Ser(535) in vivo and to explore the role of phosphorylation of Ser(535) in the regulation of eIF2B. Treatment of cells with LiCl or with either of two recently developed GSK3 inhibitors, SB-415286 and SB-216763, brought about the dephosphorylation of Ser(535), which strongly indicates that this site is indeed a target for GSK3 in vivo. However, these compounds did not elicit significant activation of eIF2B, indicating, consistent with conclusions from one of our previous studies, that additional inputs are required for the activation of eIF2B. Our results also show that each of the inhibitors used affects overall protein synthesis and have additional effects on translation factors or signalling pathways apparently unrelated to their effects on GSK3, indicating that caution must be exercised when interpreting data obtained using these compounds.
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PMID:Evidence that the dephosphorylation of Ser(535) in the epsilon-subunit of eukaryotic initiation factor (eIF) 2B is insufficient for the activation of eIF2B by insulin. 1213

To study phenotype-genotype correlations, ErbB/Ras pathway tumors (transgenic for ErbB2, c-Neu, mutants of c-Neu, polyomavirus middle T antigene (PyV-mT), Ras, and bi-transgenic for ErbB2/Neu with ErbB3 and with progesterone receptor) from four different institutions were histopathologically compared with Wnt pathway tumors [transgenes Wnt1, Wnt10b, dominant-negative glycogen synthase kinase 3-beta, beta-Catenin, and spontaneous mutants of adenomatous polyposis coli gene (Apc)]. ErbB/Ras pathway tumors tend to form solid nodules consisting of poorly differentiated cells with abundant cytoplasm. ErbB/Ras pathway tumors also have scanty stroma and lack myoepithelial or squamous differentiation. In contrast, Wnt pathway tumors exhibit myoepithelial, acinar, or glandular differentiation, and, frequently, combinations of these. Squamous metaplasia is frequent and may include transdifferentiation to epidermal and pilar structures. Most Wnt pathway tumors form caricatures of elongated, branched ductules, and have well-developed stroma, inflammatory infiltrates, and pushing margins. Tumors transgenic for interacting genes such as protein kinase CK2alpha (casein kinase IIalpha), and the fibroblast growth factors (Fgf) Int2/Fgf3 or keratinocyte growth factor (Kgf/Fgf7) also have the Wnt pathway phenotype. Because the tumors from the ErbB/Ras and the Wnt pathway are so distinct and can be readily identified using routine hematoxylin and eosin sections, we suggest that pathway pathology is applicable in both basic and clinical cancer research.
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PMID:Pathway pathology: histological differences between ErbB/Ras and Wnt pathway transgenic mammary tumors. 1221 37

Intracellular regulation of oocyte meiosis is not completely understood. However, reversible phosphorylation, which involves serine/threonine protein kinases and phosphatases (PP), is an important mediator. Glycogen synthase kinase-3 (GSK-3) is a highly conserved serine/threonine protein kinase. Currently no reports exist on presence or function of GSK-3 in mammalian oocytes. The aim of this study was to determine GSK-3 presence/absence, transcript and protein expression, intracellular protein distribution, and to investigate the functional importance of GSK-3 in mouse oocyte meiosis. Germinal vesicle-intact (GVI) oocytes contained both GSK-3 transcript and protein. Although GSK-3 beta-isoform is the only transcript identifiable in GVI oocytes, both alpha- and beta-isoforms were recognized by Western blot analysis. In growing, meiotic-incompetent oocytes GSK-3 was present, diffusely located throughout the cytoplasm and absent in the nucleus, whereas in meiotic-competent oocytes this cytoplasmic GSK-3 displays a predominant peri-oolemma staining. Treatment of mouse GVI oocytes with lithium chloride (LiCl), which inhibits both inositol monophosphatase (IMPase) and GSK-3, had no significant influence on oocyte viability, morphology, or development to metaphase II (MII). However, LiCl caused abnormal spindle formation and significantly increased incidence of abnormal homologue segregation during the first meiotic division. L690,330, which is a specific IMPase inhibitor, had no significant effect on oocyte viability, morphology, MII development, or homologue segregation. This is the first report of GSK-3 in mammalian oocytes. LiCl inhibition of mouse oocyte GSK-3 modified organization of microtubules and/or function of meiotic spindles thus compromising segregation of condensed bivalent chromosomes.
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PMID:Glycogen synthase kinase-3 regulates mouse oocyte homologue segregation. 1242 Mar 4

The potential role of a GSK3 protein kinase homolog, cggsk, was examined from Colletotrichum gloeosporioides f.sp. malvae, a fungal pathogen of Malva pusilla. A peak in cggsk expression relative to a constitutively expressed fungal actin gene occurred during host penetration and was followed by much lower expression levels during subsequent biotrophic and necrotrophic growth in host tissue. The peak level of cggsk expression observed during penetration was 21-fold greater than that during necrotrophic growth. Expression of cggsk showed small but reproducible changes during growth in culture; however, the levels were always similar to that during necrotrophic growth in the host. One possible role for cggsk could be to coordinate fungal development during host penetration.
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PMID:Expression of a glycogen synthase protein kinase homolog from Colletotrichum gloeosporioides f.sp. malvae during infection of Malva pusilla. 1255 31

Inhibitor-2 (I-2) is a regulator of protein phosphatase type-1 (PP1), known to be phosphorylated in vitro by multiple kinases. In particular Thr72 is a Thr-Pro phosphorylation site conserved from yeast to human, but there is no evidence that this phosphorylation responds to any physiological signals. Here, we used electrophoretic mobility shift and immunoblotting with a site-specific phospho-Thr72 antibody to establish Thr72 phosphorylation in HeLa cells and show a 25-fold increase in phosphorylation during mitosis. Mass spectrometry demonstrated I-2 in actively growing HeLa cells was also phosphorylated at three other sites, Ser120, Ser121, and an additional Ser located between residues 70 and 90. In vitro kinase assays using recombinant I-2 as a substrate showed that the Thr72 kinase(s) was activated during mitosis, and sensitivity to kinase inhibitors indicated that the principal I-2 Thr72 kinase was not GSK3 but instead a member of the cyclin-dependent protein kinase family. Immunocytochemistry confirmed Thr72 phosphorylation of I-2 during mitosis, with peak intensity at prophase, and revealed subcellular concentration of the phospho-Thr72 I-2 at centrosomes. Together, the data show dynamic changes in I-2 phosphorylation during mitosis and localization of phosphorylated I-2 at centrosomes, suggesting involvement in mammalian cell division.
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PMID:Phosphorylation of phosphatase inhibitor-2 at centrosomes during mitosis. 1269 55

Hypoxia initiates an intracellular signaling pathway leading to the activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). HIF-1 activity is regulated through different mechanisms involving stabilization of HIF-1alpha, phosphorylations, modifications of redox conditions, and interactions with coactivators. However, it appears that some of these steps can be cell type-specific. Among them, the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in the regulation of HIF-1 by hypoxia remains controversial. Here, we investigated the activation state of PI3K/Akt/glycogen synthase kinase 3beta (GSK3beta) in HepG2 cells. Increasing incubation times in hypoxia dramatically decreased both the phosphorylation of Akt and the inhibiting phosphorylation of GSK3beta. The PI3K/Akt pathway was necessary for HIF-1alpha stabilization early during hypoxia. Indeed, its inhibition was sufficient to decrease HIF-1alpha protein level after 5-h incubation in hypoxia. However, longer exposure (16 h) in hypoxia resulted in a decreased HIF-1alpha protein level compared with early exposure (5 h). At that time, Akt was no longer present or active, which resulted in a decrease in the inhibiting phosphorylation of GSK3beta on Ser-9 and hence in an increased GSK3beta activity. GSK3 inhibition reverted the effect of prolonged hypoxia on HIF-1alpha protein level; more stabilized HIF-1alpha was observed as well as increased HIF-1 transcriptional activity. Thus, a prolonged hypoxia activates GSK3beta, which results in decreased HIF-1alpha accumulation. In conclusion, hypoxia induced a biphasic effect on HIF-1alpha stabilization with accumulation in early hypoxia, which depends on an active PI3K/Akt pathway and an inactive GSK3beta, whereas prolonged hypoxia results in the inactivation of Akt and activation of GSK3beta, which then down-regulates the HIF-1 activity through down-regulation of HIF-1alpha accumulation.
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PMID:Regulation of hypoxia-inducible factor-1alpha protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta pathway in HepG2 cells. 1276 43

Beta-catenin is a component of stable cell adherent complexes whereas its free form functions as a transcription factor that regulate genes involved in oncogenesis and metastasis. Free beta-catenin is eliminated by two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways regulated by glycogen synthase kinase 3beta (GSK3 beta) or p53-inducible Siah-1. Dysregulation of beta-catenin turnover consequent to mutations in critical genes of the APC-dependent pathways is implicated in cancers such as colorectal cancer. We have identified a novel retinoid X receptor (RXR)-mediated APC-independent pathway in the regulation of beta-catenin. In this proteasomal pathway, RXR agonists induce degradation of beta-catenin and RXR alpha and repress beta-catenin-mediated transcription. In vivo, beta-catenin interacts with RXR alpha in the absence of ligand, but RXR agonists enhanced the interaction. RXR agonist action was not impaired by GSK3 beta inhibitors or deletion of the GSK3 beta-targeted sequence from beta-catenin. In APC- and p53-mutated colorectal cancer cells, RXR agonists still inactivated endogenous beta-catenin via RXR alpha. Interestingly, deletion of the RXR alpha A/B region abolished ligand-induced beta-catenin degradation but not RXR alpha-mediated transactivation. RXR alpha-mediated inactivation of oncogenic beta-catenin paralleled a reduction in cell proliferation. These results suggest a potential role for RXR and its agonists in the regulation of beta-catenin turnover and related biological events.
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PMID:Adenomatous polyposis coli (APC)-independent regulation of beta-catenin degradation via a retinoid X receptor-mediated pathway. 1277 Nov 32


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