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)

Protein kinases of the Akt and related serum- and glucocorticoid-regulated kinase (SGK) families are major downstream mediators of phosphatidylinositol (PI) 3-kinase signaling to many cellular processes including metabolic flux, membrane trafficking, and apoptosis. Activation of these kinases is thought to occur at the plasma membrane through their serine and threonine phosphorylation by the phosphoinositide-dependent kinase 1 (PDK1) protein kinase, which interacts with membrane 3'-polyphosphoinositides through its pleckstrin homology (PH) domain. Here, we demonstrate that the SGK family member cytokine-independent survival kinase (CISK) binds strongly and selectively to the monophosphoinositide PI(3)P through its phox homology (PX) domain. Comparing native green fluorescent protein-CISK (EGFP-CISK) to a mutant EGFP-CISK (Y51A) that displays attenuated binding to PI(3)P reveals that this interaction is both necessary and sufficient for its localization to early endosome antigen (EEA1)-positive endosomes. Furthermore, early endosome association of expressed epitope-tagged CISK in COS cells directed by binding of its PX domain to PI(3)P is required for activation of the CISK protein kinase by both insulin-like growth factor-1 and epidermal growth factor. Taken together, these results reveal a critical role of endosomal PI(3)P in the signal transmission mechanism whereby this survival kinase is activated in response to PI3-kinase stimulation by growth factors.
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PMID:Activation of the Akt-related cytokine-independent survival kinase requires interaction of its phox domain with endosomal phosphatidylinositol 3-phosphate. 1160 32

The insulin/insulin-like growth factor-1 signaling pathway promotes growth in invertebrates and vertebrates by increasing the levels of phosphatidylinositol 3,4,5-triphosphate through the activation of p110 phosphatidylinositol 3-kinase. Two key effectors of this pathway are the phosphoinositide-dependent protein kinase 1 (PDK1) and Akt/PKB. Although genetic analysis in Caenorhabditis elegans has implicated Akt as the only relevant PDK1 substrate, cell culture studies have suggested that PDK1 has additional targets. Here we show that, in Drosophila, dPDK1 controls cellular and organism growth by activating dAkt and S6 kinase, dS6K. Furthermore, dPDK1 genetically interacts with dRSK but not with dPKN, encoding two substrates of PDK1 in vitro. Thus, the results suggest that dPDK1 is required for dRSK but not dPKN activation and that it regulates insulin-mediated growth through two main effector branches, dAkt and dS6K.
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PMID:PDK1 regulates growth through Akt and S6K in Drosophila. 1175 51

Insulin inhibits the expression of the hepatic insulin-like growth factor-binding protein-1 (IGFBP-1) and glucose-6-phosphatase (G6Pase) genes. The signaling pathway that mediates these events requires the activation of phosphatidylinositol 3-kinase, whereas transfection studies have suggested an involvement of Akt (protein kinase B) and FKHR, a transcription factor regulated by Akt. We now demonstrate that insulin repression of endogenous IGFBP-1 gene transcription was blocked by rapamycin or by amino acid starvation. Rapamycin inhibited the mammalian target of rapamycin (mTOR) and the subsequent activation of p70/p85 S6 protein kinase-1 (S6K1) by insulin, whereas amino acid depletion prevented insulin induction of these signaling molecules. Importantly, we demonstrate that insulin regulation of the thymine-rich insulin response element of the IGFBP-1 promoter was also inhibited by rapamycin. However, sustained activation of S6K1 did not repress this promoter. In addition, rapamycin did not affect insulin regulation of G6Pase expression or Akt activation. We propose that these observations indicate that an mTOR-dependent, but S6K-independent mechanism regulates the suppression of IGFBP-1 (but not G6Pase) gene expression by insulin. Therefore, although the insulin-responsive sequence of the G6Pase gene promoter is related to that of the IGFBP-1 promoter, the signaling pathways that mediate suppression of these genes are distinct.
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PMID:Insulin regulation of insulin-like growth factor-binding protein-1 gene expression is dependent on the mammalian target of rapamycin, but independent of ribosomal S6 kinase activity. 1178 21

We have investigated the role of protein kinase C (PKC) signal transduction pathways in parathyroid hormone (PTH) regulation of insulin-like growth factor-binding protein-5 (IGFBP-5) gene expression in the rat osteoblast-like cell line UMR-106-01. Involvement of the PKC pathway was determined by the findings that bisindolylmaleimide I inhibited 40% of the PTH effect, and 1 microM bovine PTH-(3-34) stimulated a 10-fold induction of IGFBP-5 mRNA. PTH-(1-34) and PTH-(3-34) (100 nM) both stimulated PKC-delta translocation from the membrane to the nuclear fraction. Rottlerin, a PKC-delta-specific inhibitor, and a dominant negative mutant of PKC-delta were both able to significantly inhibit PTH-(1-34) and PTH-(3-34) induction of IGFBP-5 mRNA, suggesting a stimulatory role for PKC-delta in the effects of PTH. Phorbol 12-myristate 13-acetate (PMA) stimulated PKC-alpha translocation from the cytosol to the membrane and inhibited approximately 50% of the PTH-(1-34), forskolin, and 8-bromoadenosine 3',5'-cyclic monophosphate-stimulated IGFBP-5 mRNA levels, suggesting that PKC-alpha negatively regulates protein kinase A (PKA)-mediated induction of IGFBP-5 mRNA. These results suggest that the induction of IGFBP-5 by PTH is both PKA and PKC dependent and PKC-delta is the primary mediator of the effects of PTH via the PKC pathway.
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PMID:The role of protein kinase C-delta in PTH stimulation of IGF-binding protein-5 mRNA in UMR-106-01 cells. 1183 54

The action of growth hormone (GH) on the production of hormones, growth factors, growth factor binding protein and the occurrence of apoptosis in porcine ovarian granulosa cells, as well as the role of cAMP-stimulated protein kinase A (PKA) in the mediation of these effects, were studied. For this purpose, the effects of exogenous pGH (1-10,000 ng/ml), PKA blockers KT5720 (100 ng/ml) and Rp-cAMPS (1micromol), alone and in combination, on insulin-like growth factor type I (IGF-I), insulin-like binding protein 3 (IGFBP-3), oxytocin (OT) and prostaglandin F alpha (PGF) secretion, PKA and cAMP response element binding transcription factor (CREB) content and the occurrence of apoptosis were investigated. It was found (using RIA/IRMA) that GH addition to culture medium significantly stimulated IGF-I and PGF release and inhibited IGFBP-3 and OT secretion. GH significantly decreased the incidence of apoptosis (TUNEL method) in cultured cells. Immunocytochemical study and Western immunoblotting showed, that addition of GH caused a dramatic increase in the accumulation of immunoreactive PKA within the cells, whilst Western blotting did not reveal marked influence of GH on content of CREB in cell lysates. PKA blockers, given alone, were able to decrease IGFBP-3 output (Rp-cAMPS, but not KT5720), reduce basal OT release (either Rp-cAMPS and KT5720) and increase PGF accumulation (KT5720, but not Rp-cAMPS). Furthermore, PKA blockers were able to prevent stimulatory effects of GH on IGF-I and PGF release, and inhibitory effect of GH on IGFBP-3, OT output and on apoptosis. These observations suggest the involvement of GH and a PKA-dependent intracellular mechanism in the control of IGF-I, IGFBP-3, OT, PGF, cAMP and apoptosis in porcine ovarian granulosa cells. Stimulation of PKA by GH and the prevention of GH-induced effects by PKA blockers suggest that both stimulatory and inhibitory effects of GH on porcine ovarian cells are probably mediated by the cAMP/PKA system.
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PMID:Growth hormone can regulate functions of porcine ovarian granulosa cells through the cAMP/protein kinase A system. 1184 11

Alteration in ganglioside composition in F-11 cells by suppression of GD3-synthase gene expression resulted in greatly reduced tumor growth and metastasis when the cells were injected into nude mice. To identify genes whose expression is correlated with the decreased level of ganglioside GD3, we analyzed gene expression profiles of the GD3-suppressed F-11 cells and the control F-11 cells using DNA microarrays. We identified a set of GD3-related genes, most of which are involved in tumor growth and development. The genes that define the proliferation-transformation signature are down-regulated, such as creatine kinase-B (CKB), upstream stimulation factor 1 (USF-1), type II cAMP-dependent protein kinase regulatory subunit (RII PKA), and tyrosine hydroxylase (TH). On the other hand, the genes that define the differentiation-reverse transformation signature are up-regulated, including p160 myb-binding protein (P160), brain factor-2, insulin-like growth factor-binding protein (IGFBP), and growth/differentiation factor 11. Transcriptional levels of the genes that showed the most distinct GD3-related expression change were validated by reverse transcription-polymerase chain reaction (RT-PCR). Defining GD3-related genes may lead to identification of clinically relevant therapeutics and to understanding of the mechanism(s) by which ganglioside GD3 affects tumor growth and metastasis.
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PMID:Variations in gene expression patterns correlated with phenotype of F-11 tumor cells whose expression of GD3-synthase is suppressed. 1184 46

Transforming growth factor (TGF)-alpha- and epidermal growth factor (EGF)-induced signal transduction was directly compared with that of glucose and insulin-like growth factor-1 (IGF-1) in INS-1 cells. TGF-alpha/EGF transiently (<20 min) induced phosphorylation of extracellular-regulated kinase (Erk)-1/2 (>20-fold), glycogen synthase kinase (GSK)-3 (>10-fold), and protein kinase B (PKB) (Ser(473) and Thr(308)), but did not increase [(3)H]thymidine incorporation. In contrast, phosphorylation of Erk1/2, GSK-3, and PKB in response to glucose and IGF-1 was more prolonged (>24 h) and, though not as robust as TGF-alpha/EGF, did increase beta-cell proliferation. Phosphorylation of p70(S6K) was also increased by IGF-1/glucose, but not by TGF-alpha/EGF, despite upstream PKB activation. It was found that IGF-1 induced phosphatidylinositol 3-kinase (PI3K) association with insulin receptor substrate (IRS)-1 and -2 in a glucose-dependent manner, whereas TGF-alpha/EGF did not. The importance of specific IRS-2-mediated signaling events was emphasized in that adenoviral-mediated overexpression of IRS-2 further increased glucose/IGF-1-induced beta-cell proliferation (more than twofold; P < 0.05) compared with control or adenoviral-mediated IRS-1 overexpressing INS-1 cells. Neither IRS-1 nor IRS-2 overexpression induced a beta-cell proliferative response to TGF-alpha/EGF. Thus, a prolonged activation of Erk1/2 and PI3K signaling pathways is important in committing a beta-cell to a mitogenic event, and it is likely that this sustained activation is instigated by signal transduction occurring specifically through IRS-2.
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PMID:Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-alpha or EGF, augments pancreatic beta-cell proliferation. 1191 14

Hepatic expression of insulin-like growth factor-binding protein-1 (IGFBP-1) is rapidly and completely inhibited by insulin. The signalling pathway that mediates this effect of insulin requires the activation of phosphoinositide 3-kinase (PI 3-kinase). Many of the cellular actions of insulin, including activation of PI 3-kinase, can be 'mimicked' by oxidative stresses, such as H(2)O(2). In the present study, we demonstrate that H(2)O(2) does not 'mimic' but rather antagonizes insulin repression of IGFBP-1 gene expression in H4IIE cells. This effect is accompanied by a decrease in the insulin-induced activation of mammalian target of rapamycin (mTOR)-dependent signalling. However, insulin-induced phosphorylation and regulation of protein kinase B, glycogen synthase kinase-3 and FKHR (forkhead in rhabdomyosarcoma) are not affected by H(2)O(2) in the same cells. In addition, H(2)O(2) strongly activates the p42/p44 mitogen-activated protein kinases, but the presence of PD184352 (an inhibitor of this pathway) does not block the effect of H(2)O(2) on IGFBP-1 gene expression. Our results support the view that the insulin-mediated repression of IGFBP-1 gene expression is partly mTOR-dependent, and demonstrate that H(2)O(2) selectively antagonizes mTOR-dependent insulin action. The implications for the use of H(2)O(2)-generating agents as therapeutics for the treatment of insulin resistance, as well as the role of oxidative stress in the development of insulin resistance, are discussed.
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PMID:Insulin regulation of hepatic insulin-like growth factor-binding protein-1 (IGFBP-1) gene expression and mammalian target of rapamycin (mTOR) signalling is impaired by the presence of hydrogen peroxide. 1194 57

The AGC family of protein kinases, which includes isoforms of protein kinase B (also known as Akt), ribosomal S6 protein kinase (S6K), and serum- and glucocorticoid-induced protein kinase (SGK) are activated in response to many extracellular signals and play key roles in regulating diverse cellular processes. They are activated by the phosphorylation of the T loop of their kinase domain by the 3-phosphoinositide-dependent protein kinase-1 and by phosphorylation of a residue located C-terminal to the kinase domain in a region termed the hydrophobic motif. Recent work has implicated the NIMA (never in mitosis, gene A)-related kinase-6 (NEK6) as the enzyme that phosphorylates the hydrophobic motif of S6K1 in vivo. Here we demonstrate that in addition to phosphorylating S6K1 and SGK1 at their hydrophobic motif, NEK6 also phosphorylates S6K1 at two other sites and phosphorylates SGK1 at one other site in vitro. Employing the Jerini pepSTAR method in combination with kinetic analysis of phosphorylation of variant peptides, we establish the key substrate specificity determinants for NEK6. Our analysis indicates that NEK6 has a strong preference for Leu 3 residues N-terminal to the site of phosphorylation. Its mutation to either Ile or Val severely reduced the efficacy with which NEK6-phosphorylated peptide substrates, and moreover, mutation of the equivalent Leu residue in S6K1 or SGK1 prevented phosphorylation of their hydrophobic motifs by NEK6 in vitro. However, these mutants of S6K1 or SGK1 still became phosphorylated at their hydrophobic motif following insulin-like growth factor-1 stimulation of transfected 293 cells. This study provides the first description of the basis for the substrate specificity of NEK6 and indicates that NEK6 is unlikely to be responsible for the IGF1-induced phosphorylation of the hydrophobic motif of S6K, SGK, and protein kinase B isoforms in vivo.
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PMID:Molecular basis for the substrate specificity of NIMA-related kinase-6 (NEK6). Evidence that NEK6 does not phosphorylate the hydrophobic motif of ribosomal S6 protein kinase and serum- and glucocorticoid-induced protein kinase in vivo. 1202 60

A growing body of information suggests antigonadotropic and atretogenic roles for granulosa cell-derived insulin-like growth factor binding proteins (IGFBPs) 4 and 5 during ovarian folliculogenesis. Activation of protein kinase-A (PKA) in rat granulosa cells has been shown to modulate the relative expression of IGFBP-4 and -5 transcripts and proteins. In this article, we assess the role of protein kinase-C (PKC) in this regard. Provision of granulosa cells with phorbol 12-myristate 13-acetate (PMA) (but not 4alphaPMA, an inert analogue), a tumor-promoting phorbol ester and an established activator of PKC, was without significant effect on the expression of IGFBP-4 transcripts but resulted in biphasic dose-dependent alterations in IGFBP-5 transcripts and in the accumulation of the IGFBP-4 and -5 proteins. Comparable effects were noted for GnRH, an established PKC agonist. Provision of staurosporine, a potent inhibitor of the catalytic subunit of PKC, produced significant dose-dependent decrements in the relative expression of IGFBP-5 transcripts. Treatment with FSH (presumptively PKA-mediated) markedly attenuated the ability of PMA or GnRH to upregulate the accumulation of the IGFBP-5 (but not IGFBP-4) protein. Taken together, our present findings indicate that the modulation of rat ovarian IGFBP-4 and -5 is PKC as well as PKA dependent and that these two signaling pathways interact in a diametrically opposed and antagonistic fashion.
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PMID:Regulation of granulosa cell-derived insulin-like growth factor binding proteins (IGFBPs): role for protein kinase-C in the pre- and posttranslational modulation of IGFBP-4 and IGFBP-5. 1219 14


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