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)

RAC protein kinase (RAC-PK), a serine/threonine protein kinase containing a pleckstrin homology (PH) domain, was activated by cellular stress such as heat shock and hyperosmolarity. Wortmannin, which is known as a potent inhibitor of phosphatidylinositol 3-kinase and normally inhibits growth factor-induced activation of RAC-PK, did not suppress heat-shock induced activation of RAC-PK, indicating that this stress-induced activation of the kinase is not mediated by phosphatidylinositol 3-kinase. The PH domain was indispensable for stress-induced activation of RAC PK. In heat-treated cells, PKC delta, a member of the protein kinase C family, was found to associate with the PH domain of RAC-PK. This PKC subspecies was phosphorylated in vitro by RAC-PK. The results suggest that RAC-PK may play a role in the cellular response to stress through its PH domain.
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PMID:Activation of RAC-protein kinase by heat shock and hyperosmolarity stress through a pathway independent of phosphatidylinositol 3-kinase. 875 28

This study was designed to evaluate the role of phosphatidylinositol (PI3) kinase, p70 S6 kinase (p70S6K), and mitogen-activated protein (MAP) kinase in the regulation of muscle protein metabolism by insulin and insulin-like growth factor I (IGF-I). Wortmannin and LY294002 (inhibitors of P13 kinase) both abolished the stimulation of protein synthesis by insulin or IGF-I in epitrochlearis muscle incubated in vitro. LY294002 also totally reversed the antiproteolytic action of these hormones. Although p70S6K activation by insulin and IGF-I may be mediated by PI3 kinase in epitrochlearis muscle, the specific inhibition of this kinase by rapamycin caused only partial (25%) inhibition of the stimulation of protein synthesis by these two hormones. Rapamycin had no effect on proteolysis. Finally, insulin or IGF-I did not stimulate MAP kinase activity at any of the times tested (2-25 min), suggesting that this protein kinase was not directly involved in the regulation of muscle protein metabolism. These observations provide evidence that PI3 kinase and p70S6K, but not MAP kinase, play a role in the regulation of muscle protein turnover by insulin or IGF-I.
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PMID:Phosphatidylinositol 3-kinase and p70 s6 kinase participate in the regulation of protein turnover in skeletal muscle by insulin and insulin-like growth factor I. 882 61

A key metabolic action of insulin is the stimulation of non-oxidative glucose utilization in skeletal muscle, by increasing both glucose uptake and glycogen synthesis. The molecular mechanism underlying this process has been investigated using a variety of experimental systems. We report here the use of cultured human myoblasts to study insulin control of glycogen synthesis in humans. In these cells insulin stimulates glycogen synthesis approx. 2.2-fold, associated with a similar activation of glycogen synthase (GS) which occurs within 5-10 min of the addition of insulin. Insulin also causes inactivation of glycogen synthase kinase-3 (GSK-3) and activation of protein kinase B, both processes being sufficiently rapid to account for the effects of insulin on GS. Activation by insulin of the protein kinases p70s6K, p90s6K and extracellular signal-regulated kinase 2 (ERK2) is observed, but is significantly slower than the activation of GS. Selective inhibitors of the p70s6K pathway (rapamycin), the ERK2/p90s6K pathway (PD98059) and phosphatidylinositol 3-kinase (wortmannin) have been used to probe the contribution of these components to insulin signalling in human muscle. Wortmannin blocks activation of both glycogen synthesis and GS and inactivation of GSK-3. PD98059 is without effect on these events, while rapamycin is without effect on inactivation of GSK-3 but partially blocks activation of glycogen synthesis and GS. Taken together, these findings suggest that protein kinase B is responsible for the inactivation of GSK-3, but that an additional rapamycin-sensitive mechanism may contribute to the activation of GS and stimulation of glycogen synthesis.
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PMID:Insulin action in cultured human myoblasts: contribution of different signalling pathways to regulation of glycogen synthesis. 900 74

The cellular response to 1-beta-D-arabinofuranosylcytosine (ara-C) includes activation of Jun/AP-1, induction of c-jun transcription, and programmed cell death. The stress-activated protein (SAP) kinases stimulate the transactivation function of c-jun by amino terminal phosphorylation. The present work demonstrates that ara-C activates p54 SAP kinase. The finding that SAP kinase is also activated by alkylating agents (mitomycin C and cisplatinum) and the topoisomerase I inhibitor 9-amino-camptothecin supports DNA damage as an initial signal in this cascade. The results demonstrate that ara-C also induces binding of SAP kinase to the SH2/SH3-containing adapter protein Grb2. SAP kinase binds to the SH3 domains of Grb2, while interaction of the p85 alpha-subunit of phosphatidylinositol 3-kinase complex. The results also demonstrate that ara-C treatment is associated with inhibition of lipid and serine kinase activities of PI 3-kinase. The potential significance of the ara-C-induced interaction between SAP kinase and PI 3-kinase is further supported by the demonstration that Wortmannin, an inhibitor of PI 3-kinase, stimulates SAP kinase activity. The finding that Wortmannin treatment is also associated with internucleosomal DNA fragmentation may support a potential link between PI 3-kinase and regulation of both SAP kinase and programmed cell death.
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PMID:Involvement of stress-activated protein kinase in the cellular response to 1-beta-D-arabinofuranosylcytosine and other DNA-damaging agents. 901 71

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

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

Phosphoinositide (PI) 3-kinase and the mitogen-activated protein (MAP) kinase cascades are activated by many of the same ligands. Several groups have reported involvement of PI 3-kinase in the activation of Erk1 and Erk2, whereas many other groups have shown that activation of Erk1 and Erk2 is not sensitive to inhibitors of PI 3-kinase such as wortmannin. Here we show that wortmannin inhibition of the MAP kinase pathway is cell type- and ligand-specific. Wortmannin blocks platelet-derived growth factor (PDGF)-dependent activation of Raf-1 and the MAP kinase cascade in Chinese hamster ovary cells, which have few PDGF receptors, but has no significant effect on Erk activation in Swiss 3T3 cells, which have high levels of PDGF receptors. However, wortmannin blocks activation of Erk proteins if Swiss 3T3 cells are stimulated with lower, physiological levels of PDGF. These results suggest that PI 3-kinase is in an efficient pathway for activation of MAP kinase, but that MAP kinase can be stimulated by a redundant pathway when a large number of receptors are activated. We present evidence that a protein kinase C family member downstream of phospholipase Cgamma is involved in the redundant pathway.
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PMID:Conditional inhibition of the mitogen-activated protein kinase cascade by wortmannin. Dependence on signal strength. 934 6

Isolated skeletal muscle from healthy individuals was used to evaluate the role of phosphoinositide 3-kinase (PI 3-kinase) in insulin signalling pathways regulating mitogen activated protein kinase (MAP-kinase) and protein kinase-B and to investigate whether MAP-kinase was involved in signalling pathways regulating glucose metabolism. Insulin stimulated glycogen synthase activity (approximately 1.7 fold), increased 3-o-methylglucose transport into human skeletal muscle strips (approximately 2 fold) and stimulated phosphorylation of the p42 ERK-2 isoform of MAP-kinase. This phosphorylation of p42 ERK2 was not blocked by the PI 3-kinase inhibitors LY294002 and wortmannin although it was blocked by the MAP-kinase kinase (MEK) inhibitor PD 98059. However, PD98059 (up to 20 micromol/l) did not block insulin activation of glycogen synthase or stimulation of 3-o-methylglucose transport. Wortmannin and LY294002 did block insulin stimulation of protein kinase-B (PKB) phosphorylation and stimulation of 3-o-methylglucose transport was inhibited by wortmannin (IC50 approximately 100 nmol/l). These results indicate that MAP-kinase is activated by insulin in human skeletal muscle by a PI 3-kinase independent pathway. Furthermore this activation is not necessary for insulin stimulation of glucose transport or activation of glycogen synthase in this tissue.
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PMID:Involvement of phosphoinositide 3-kinase in insulin stimulation of MAP-kinase and phosphorylation of protein kinase-B in human skeletal muscle: implications for glucose metabolism. 934 98

Phosphatidylinositol 3-kinase (PI3K) is a heterodimer lipid kinase consisting of an 85-kD subunit bound to a 110-kD catalytic subunit that also possesses intrinsic, Mn(2+)-dependent protein serine kinase activity capable of phosphorylating the 85-kD subunit. Here, we examine the Mn(2+)-dependent protein kinase activity of PI3K alpha immunoprecipitated from normal resting or thrombin-stimulated platelets, and characterize p85/p110 phosphorylation, in vitro. Phosphoamino acid analysis of phosphorylated PI3K alpha showed p85 and p110 were phosphorylated on serine, but in contrast to previous results, were also phosphorylated on threonine and tyrosine. Wortmannin and LY294002 inhibited p85 phosphorylation; however, p110 phosphorylation was also inhibited suggesting p110 autophosphorylation on serine/threonine. The protein tyrosine kinase inhibitor, erbstatin analog, partially inhibited p85 and p110 phosphorylation but did not appear to affect PI3K lipid kinase activity. The in vitro phosphorylation of p85 alpha or p110 alpha derived from thrombin-stimulated platelets was no different than that of resting platelets, but we confirm that in thrombin receptor-stimulated platelets enhanced levels of p85 alpha and PI3K lipid kinase activity were recovered in antiphosphotyrosine antibody immunoprecipitates. These results suggest PI3K alpha can autophosphorylate on serine and threonine, and both p85 alpha and p110 alpha are substrates for a constitutively-associated protein tyrosine kinase in platelets.
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PMID:The p85 and p110 subunits of phosphatidylinositol 3-kinase-alpha are substrates, in vitro, for a constitutively associated protein tyrosine kinase in platelets. 944 54

The activation of phosphatidylinositol (PtdIns) 3-kinase is considered to be a key event occurring after stimulation of cells with growth factors. The proto-oncogenic protein kinase B (PKB; also known as RAC protein kinase or Akt) has recently been shown to be a downstream target of PtdIns 3-kinase and may be involved in cell survival. We therefore asked whether stimulation of neuronal cells with nerve growth factor (NGF), on which certain types of neurons are dependent for survival, causes activation of PKB. Stimulation of serum-starved PC12 rat pheochromocytoma cells with NGF caused an increase of up to 14-fold in PKB activity. This activation was detected within 1 min of stimulation and occurred at NGF concentrations that are consistent with TrkA-mediated signaling. PKB activation was accompanied by a decrease in electrophoretic mobility of the kinase, which is characteristic of phosphorylation. Both PKB activation and mobility changes were prevented by wortmannin, indicating the upstream involvement of PtdIns 3-kinase in these events. Analyses employing isoform-specific antibodies for immunoprecipitation suggested that all three isoforms of PKB (alpha, beta and gamma) are activated in response to NGF. G-protein-coupled-receptor agonists, lysophosphatidic acid (lyso-PtdH) and thrombin, which induce rapid neurite retraction, neither stimulated PKB activity, nor affected NGF-induced or insulin-induced kinase activation. Wortmannin treatment did not prevent neurite retraction induced by lyso-PtdH or thrombin. These data suggest that PtdIns 3-kinase and PKB are not involved in cytoskeletal changes mediated by the small GTPase Rho.
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PMID:Nerve growth factor promotes activation of the alpha, beta and gamma isoforms of protein kinase B in PC12 pheochromocytoma cells. 949 84


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