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)

Mitogen-activated protein (MAP) kinase plays crucial roles in cell growth and differentiation. It has recently been shown that the MAP kinase cascade in growth factor signaling diverges and cross-talks with other signaling pathways. In the present study, we examined the effects of wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3-kinase), on the activation of Ras, Raf-1 kinase, and MAP kinase by insulin and epidermal growth factor (EGF). The effect of LY294002, a structurally distinct PI3-kinase inhibitor, on the activation of Raf-1 kinase by both ligands was also examined. In 3T3-L1 adipocytes, 25 nmol/l wortmannin inhibited the insulin-induced activation of Raf-1 kinase to the basal level, whereas the same dose of wortmannin had little effect on the EGF-induced activation of Raf-1 kinase. One hundred micromol/l LY294002 blocked insulin-induced activation of Raf-1 kinase without affecting EGF-induced activation of this kinase. Twenty-five nmol/l wortmannin inhibited the insulin-induced activation of MAP kinase to the basal level with no effect on the EGF-induced activation of this kinase. But the same dose of wortmannin did not affect the formation of guanosine 5'-triphosphate (GTP)-bound Ras stimulated by either ligand. In KB cells, results similar to those in 3T3-L1 adipocytes were obtained. In contrast, in Chinese hamster ovary cells overexpressing the human insulin receptor (CHO-HIR cells), neither wortmannin nor LY294002 inhibited the insulin-induced activation of Raf-1 kinase, and wortmannin had little effect on the activation of MAP kinase by insulin. These results indicate that 1) PI3-kinase or wortmannin-sensitive molecules are involved in the interaction between activated Ras and Raf-1 kinase in the insulin signaling in 3T3-L1 adipocytes, 2) the involvement of PI3-kinase or wortmannin-sensitive molecules in the insulin-induced activation of MAP kinase appears to be cell-type specific, and 3) differential mechanisms to activate Raf-1 kinase and MAP kinase by insulin and EGF exist.
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PMID:Differential activation of mitogen-activated protein kinase by insulin and epidermal growth factor in 3T3-L1 adipocytes: a possible involvement of PI3-kinase in the activation of the MAP kinase by insulin. 913 38

The autosomal recessive human disorder ataxia-telangiectasia (A-T) was first described as a separate disease entity 40 years ago. It is a multisystem disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, radiosensitivity, predisposition to lymphoid malignancies and immunodeficiency, with defects in both cellular and humoral immunity. The pleiotropic nature of the clinical and cellular phenotype suggests that the gene product involved is important in maintaining stability of the genome but also plays a more general role in signal transduction. The chromosomal instability and radiosensitivity so characteristic of this disease appear to be related to defective activation of cell cycle checkpoints. Greater insight into the nature of the defect in A-T has been provided by the recent identification, by positional cloning, of the responsible gene, ATM. The ATM gene is related to a family of genes involved in cellular responses to DNA damage and/or cell cycle control. These genes encode large proteins containing a phosphatidylinositol 3-kinase domain, some of which have protein kinase activity. The mutations causing A-T completely inactivate or eliminate the ATM protein. This protein has been detected and localized to different subcellular compartments.
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PMID:The genetic defect in ataxia-telangiectasia. 914 86

Mast cells synthesize and secrete specific cytokines and chemokines which play an important role in allergic inflammation. Aggregation of the high-affinity Fc receptor (FcepsilonRI) for immunoglobulin E (IgE) in MC/9 mouse mast cells stimulates the synthesis and secretion of tumor necrosis factor alpha (TNF-alpha). FcepsilonRI aggregation activates several sequential protein kinase pathways, leading to increased activity of extracellular signal-regulated kinases (ERKs), c-Jun amino-terminal kinases (JNKs), and the p38 mitogen-activated protein (MAP) kinase. Inhibition of ERKs with the compound PD 098059 had little effect on FcepsilonRI-stimulated TNF-alpha production. Aggregation of FcepsilonRI stimulated MEK kinase 1 (MEKK1) activity, which activates JNK kinase (JNKK), the kinase that phosphorylates and activates JNKs. Expression of activated MEKK1 (DeltaMEKK1) in MC/9 cells strongly stimulated JNK activity but only weakly stimulated p38 activity, and it induced a large activation of TNF-alpha promoter-regulated luciferase gene expression. Inhibitory mutant JNK2 expressed in MC/9 cells significantly blunted FcepsilonRI stimulation of TNF-alpha promoter-driven luciferase expression. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, diminished FcepsilonRI-mediated TNF-alpha synthesis, significantly blunted JNK activation and TNF-alpha promoter-driven luciferase expression, and only weakly inhibited p38 kinase activation. Inhibition of NFkappaB activation resulting from DeltaMEKK1 expression or FcepsilonRI stimulation did not affect TNF-alpha promoter-driven luciferase expression. Our findings define a MEKK-regulated JNK pathway activated by FcepsilonRI that regulates TNF-alpha production in mast cells.
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PMID:Mast cell tumor necrosis factor alpha production is regulated by MEK kinases. 917 22

Many cytokines, hormones, and growth factors activate Janus kinases to tyrosine phosphorylate select members of the Stat transcription factors. For full transcriptional activation, Stat1 and Stat3 also require phosphorylation of a conserved serine residue within a mitogen-activated protein kinase phosphorylation consensus site. On the other hand, two recently identified and highly homologous Stat5a and Stat5b proteins lack this putative mitogen-activated protein kinase phosphorylation site. The present study set out to establish whether Stat5a and Stat5b are under the control of an interleukin-2 (IL2)-activated Stat5 serine kinase. We now report that IL2 stimulated marked phosphorylation of serine and tyrosine residues of both Stat5a and Stat5b in human T lymphocytes and in several IL2-responsive lymphocytic cell lines. No Stat5a/b phosphothreonine was detected. Phosphoamino acid analysis also revealed that Stat5a/b phosphotyrosine levels were maximized within 1-5 min of IL2 stimulation, whereas serine phosphorylation kinetics were slower. Interestingly, IL2-induced serine phosphorylation of Stat5a differed quantitatively and temporally from that of Stat5b with Stat5a serine phosphorylation leveling off after 10 min and the more pronounced Stat5b response continuing to rise for at least 60 min of IL2 stimulation. Furthermore, we identified two discrete domains of IL2 receptor beta (IL2Rbeta) that could independently restore the ability of a truncated IL2Rbeta mutant to mediate Stat5a/b phosphorylation and DNA binding to the gamma-activated site of the beta-casein gene promoter. These observations demonstrated that there is no strict requirement for one particular IL2Rbeta region for Stat5 phosphorylation. Finally, we established that the IL2-activated Stat5a/b serine kinase is insensitive to several selective inhibitors of known IL2-stimulated kinases including MEK1/MEK2 (PD98059), mTOR (rapamycin), and phosphatidylinositol 3-kinase (wortmannin) as determined by phosphoamino acid and DNA binding analysis, thus suggesting that a yet-to-be-identified serine kinase mediates Stat5a/b activation.
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PMID:Two discrete regions of interleukin-2 (IL2) receptor beta independently mediate IL2 activation of a PD98059/rapamycin/wortmannin-insensitive Stat5a/b serine kinase. 918 78

The signal transduction pathways of a cloned human gastric inhibitory polypeptide (GIP) receptor have been investigated in CHO cells stably expressing this receptor. Exposure of GIP receptor expressing cells to GIP significantly increased MAP kinase activity. Time course analysis showed that a rapid and marked increase in MAP kinase activation was detected and that this activation reached maximal levels 10 min after the addition of GIP. Dose-response analysis showed that GIP activated MAP kinase activity in a dose-dependent manner with an ED50 value of 5.9 x 10(-10) M of GIP. Wortmannin, a potent inhibitor of phosphatidylinositol 3-kinase (PI3-kinase), partially inhibited GIP-induced MAP kinase activation, suggesting that GIP activates MAP kinase through two different, wortmannin-sensitive and -insensitive pathways. It has been demonstrated that in CHO cells cAMP attenuates MAP kinase activity by inhibiting Raf-1. Since GIP elevates intracellular cAMP, we examined the effects of cAMP on MAP kinase activation. Interestingly, forskolin, which increased intracellular cAMP levels, significantly inhibited MAP kinase activation by GIP, but did not affect MAP kinase activation by GIP in the presence of wortmannin, suggesting that the wortmannin-sensitive pathway activates an MAP kinase cascade at or above the level of Raf-1 and that the wortmannin-insensitive pathway activates an MAP kinase cascade below the level of Raf-1. These findings demonstrate that the GIP receptor is linked to the MAP kinase cascade via at least two different pathways.
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PMID:Gastric inhibitory polypeptide activates MAP kinase through the wortmannin-sensitive and -insensitive pathways. 919 57

Activation of protein kinase B (PKB) by growth factors has been demonstrated to proceed via phosphatidylinositol 3-kinase (PI3-kinase). Here, we show that agents which raise intracellular cAMP can also stimulate PKB. However, this effect is not sensitive to wortmannin, indicating that it is PI3-kinase independent. This activation does not appear to result from direct phosphorylation by protein kinase A (PKA) since GST-PKB is not an effective PKA substrate. In addition, the activation pathway of PKB by cAMP seems to be linked to that of growth factors, albeit downstream of PI3-kinase. Evidence for this is that a constitutive active PKB, T308D, S473D, containing activating mutations in the serine and threonine residues which are phosphorylated subsequent to PI3-kinase activation, cannot be further stimulated by cAMP elevations. Hence, these data suggest that, in addition to growth factors, cAMP can also lead to activation of PKB. This cAMP stimulatory action appears to require phosphorylation of T308 and S473, and hence would indicate that cAMP modulates the phosphorylation event of these PKB regulatory sites.
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PMID:cAMP stimulates protein kinase B in a Wortmannin-insensitive manner. 920 56

In fetal brown adipocyte primary cultures, insulin rapidly (at 5 min) induced tyrosine phosphorylation of the insulin receptor beta-subunit; this effect was maximal at physiological concentrations (1 nM). Insulin also stimulated insulin receptor substrate-1 tyrosine phosphorylation and subsequently activated phosphatidylinositol 3-kinase. Moreover, a 3-fold increase in the Ras.GTP active form and a 6-fold increase in Raf-1 kinase activity were induced after insulin stimulation. An immortalized brown adipocyte cell line (by permanent simian virus 40 large T antigen and pMEXneo cotransfection) showed a reduced maximal responsiveness to insulin in the same range of insulin concentrations studied (1-100 nM). Transformed brown adipocyte cell line (by permanent simian virus 40 large T antigen and pMEXneo H-ras(lys12) cotransfection) developed insulin resistance upstream from Ras, showing an impairment in the insulin receptor autophosphorylation, and in insulin receptor substrate-1 tyrosine phosphorylation and its association with phosphatidylinositol 3-kinase upon treatment with 1 nM insulin, although insulin receptor number and affinity (Kd) remained unaltered. This lack of effect was ameliorated upon treatment with higher insulin concentrations, in a dose-dependent manner. However, downstream from Ras, events such as formation of the Ras.GTP active form, and Raf-1 kinase and 12-O-tetradecanoylphorbol-13-acetate response element-chloramphenicol transferase (transiently transfected) activities were overstimulated, compared with those in primary and immortalized cells, in an insulin-independent manner. Wheat-germ lectin-purified receptors from H-ras(lys12)-transformed brown adipocytes showed a marked phosphorylation in the basal state, which was suppressed by serine-threonine phosphatase pretreatment. Moreover, alkaline phosphatase pretreatment restored the tyrosine kinase activity of the receptor in response to insulin. We conclude that the decreased tyrosine autophosphorylation rate of the insulin receptor from H-ras(lys12)-transformed brown adipocytes is a consequence of its basal serine/threonine phosphorylation, resulting in severe insulin resistance.
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PMID:Alterations in the insulin signaling pathway induced by immortalization and H-ras transformation of brown adipocytes. 923 68

The stimulation of glucose transport is one of the early cellular responses to growth factors and is essential for cell proliferation, yet the molecular processes that underlie this response are poorly defined. The aim of this study was to characterize the role of the low-molecular-mass G-proteins, Ras and Rho, and their downstream targets, Raf protein kinase and phosphatidylinositol 3-kinase, in the regulation of glucose transport in Xenopus oocytes by two distinct growth-factor receptors: the insulin-like growth factor I (IGF-I) tyrosine kinase receptor and the heterotrimeric G-protein-coupled lysophosphatidic acid (LPA) receptor. Microinjection of a neutralizing anti-Ras antibody partially blocked IGF-I-stimulated deoxyglucose uptake but was without effect on LPA-stimulated deoxyglucose uptake. In contrast, microinjection of the C3 coenzyme of botulinum toxin, which selectively ADP-ribosylates and inactivates Rho, inhibited LPA-stimulated, but not IGF-I-stimulated, deoxyglucose uptake. Similarly, LPA- but not IGF-I-stimulated deoxyglucose uptake was attenuated in oocytes expressing a dominant negative rho construct. Cells expressing a dominant negative mutant of Raf protein kinase exhibited markedly reduced sensitivity to both LPA and IGF-I, consistent with a role for endogenous Raf in glucose uptake by both growth factors. Furthermore, expression of a constitutively activated form of raf-1 resulted in a growth-factor-independent increase in deoxyglucose uptake. Measurements of phosphatidylinositol 3-kinase activity in microinjected cells support the hypothesis that the IGF-I receptor stimulates glucose transport by a Ras-dependent activation of phosphatidylinositol 3-kinase, whereas the G-protein-coupled LPA receptor controls this response by a pathway that involves Rho-dependent activation of a distinct phosphatidylinositol 3-kinase. Thus we provide evidence for clear differences in the signalling pathways that control glucose transport by G-protein-coupled and tyrosine kinase growth-factor receptors. Furthermore this is the first demonstration that active Rho is involved in the signalling pathways that regulate glucose uptake in response to some growth factors.
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PMID:Characterization of the intracellular signalling pathways that underlie growth-factor-stimulated glucose transport in Xenopus oocytes: evidence for ras- and rho-dependent pathways of phosphatidylinositol 3-kinase activation. 927 Oct 83

The metabolic effects of insulin are initiated by the binding of insulin to the extracellular domain of the insulin receptor within the plasma membrane of muscle and adipose and liver cells. The subsequent activation of the intracellular tyrosine protein kinase activity of the receptor leads to autophosphorylation of the receptor as well as phosphorylation of a number of intracellular proteins. This gives rise to the activation of Ras and phosphatidylinositol 3-kinase and hence to the activation of a number of serine/threanine protein kinases. Many of these kinases appear to be arranged in cascades, including a cascade that results in the activation of mitogen-activated protein kinase and another that may result in the activation of protein kinase B, leading to the inhibition of glycogen synthase kinase-3 and the activation of the 70 kiloDalton ribosomal S6 protein kinase (p70 S6 kinase). We have explored the role of these early events in the the stimulation of glycogen, fatty acid, and protein synthesis by insulin in rat epididymal fat cells. Comparisons have been made between the metabolic effects of insulin and those of epidermal growth factor, since these 2 agents have contrasting effects on p70 S6 kinase and mitogen-activated protein kinase. The effects of wortmannin (which inhibits phosphatidylinositol 3-kinase), and rapamycin (which blocks the activation of p70 S6 kinase) have also been studied. These and other studies indicate that the mitogen-activated protein kinase cascade is probably not important in the acute metabolic effects of insulin, but may have a role in the regulation of gene transcription and hence the more long-term effects of insulin. The short-term metabolic effects of insulin appear to involve at least 3 distinct signaling pathways: (1) those leading to increases in glucose transport and the activation of glycogen synthase, acetyl-CoA carboxylase, eukaryotic initiation factor-2B, and phosphodiesterase, which may involve phosphatidylinositol 3-kinase and protein kinase B; (2) those leading to some of the effects of insulin on protein synthesis (formation of eukaryotic initiation factor-4F complex, S6 phosphorylation, and activation of eukaryotic elongation factor-2), which may involve phosphatidylinositol 3-kinase and p70 S6 kinase; and finally, (3) that leading to the activation of pyruvate dehydrogenase, which is unique in apparently not requiring activation of phosphatidylinositol 3-kinase.
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PMID:Multiple signaling pathways involved in the metabolic effects of insulin. 929 55

We investigated whether or not beta and alpha adrenergic agonists could affect proliferation of adult rat hepatocytes induced by hepatocyte growth factor (HGF) during the early and late phases of primary culture. Adult rat hepatocytes underwent significant DNA synthesis after culture with 5 ng/ml HGF for 3 h at a low cell density (3.3 x 10(4) cells/cm2). Under these culture conditions, the number of nuclei increased significantly during a subsequent 4-h culture period. Hepatocyte DNA synthesis and proliferation induced by 5 ng/ml HGF was reduced at high cell densities near confluence. A beta adrenergic agonist, metaproterenol (10(-7) M), and dibutyryl cAMP significantly potentiated hepatocyte DNA synthesis and proliferation at a concentration as low as 10(-7) M when cultured in combination with 5 ng/ml HGF. Similarly, an alpha-1 adrenergic agonist, phenylephrine (10(-6)-10(-4) M) markedly potentiated HGF-induced hepatocyte DNA synthesis and proliferation. The phenylephrine effect was mimicked by a phorbol ester (10(-6) M), but not by ionomycin (10(-6) M). The mitogenic effects of HGF were almost completely blocked by simultaneous treatment of hepatocytes with genistein (5 x 10(-6) M), U-73122 (10(-6) M), wortmannin (10(-7) M), sphingosine (3 x 10(-6) M) and rapamycin (10 ng/ml). These results demonstrate that HGF can rapidly induce proliferation of adult rat hepatocytes in primary culture. However, this effect is dependent on the initial plating density. The co-mitogenic effects of metaproterenol and phenylephrine may involve both protein kinase A and protein kinase C activation, respectively. The results also suggest that following stimulation with HGF, activation of tyrosine kinase, phosphatidylinositol 3-kinase, phospholipase C and p70 ribosomal protein S6 kinase is essential for hepatocyte proliferation.
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PMID:Proliferation of adult rat hepatocytes by hepatocyte growth factor is potentiated by both phenylephrine and metaproterenol. 931 20


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