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)

Ethanol inhibits insulin (IN) and epidermal growth factor (EGF)-induced hepatocyte DNA synthesis. Growth factor receptor kinases, such as IN and EGF, phosphorylate insulin receptor substrate (IRS-1) and p36 protein kinase substrate, respectively, on tyrosine residues. IRS-1 and p36 are thought to be important intracellular signal transduction molecules involved in the regulation of cell growth. These investigations explored the effect of ethanol additions on the expression and tyrosyl phosphorylation (TP) of p36 and IRS-1 in a human hepatocellular carcinoma cell line (FOCUS) in relationship to cell proliferation induced by IN and serum growth factor stimulation. It was found that p36 was constitutively and highly expressed in serum-starved cells and protein, and mRNA levels did not change with cell proliferation induced by growth factors. However, exposure of FOCUS cells to ethanol additions substantially inhibited TP of p36. The early TP of IRS-1 induced by IN stimulation was also reduced by ethanol additions. Finally, there was a parallel decrease of FOCUS cell proliferation in ethanol-exposed cultures. These studies suggest that one possible mechanism of ethanol inhibitory effect on cell proliferation is through reduced TP of putative intracellular signal transduction molecules, such as p36 and IRS-1.
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PMID:Effect of ethanol on p36 protein kinase substrate and insulin receptor substrate 1 expression and tyrosyl phosphorylation in human hepatocellular carcinoma cells. 754 50

Activation of the mitogen-activated protein kinase (MAP kinase) isoforms ERK1 and ERK2 was investigated in rat adipocytes. Kinase activities were measured by using myelin basic protein as substrate after the isoforms were resolved by Mono Q chromatography or by immunoprecipitation with specific antibodies. Insulin increased the activity of both isoforms by 3- to 4-fold. The beta-adrenergic agonist isoproterenol was without effect in the absence of insulin but markedly reduced the increases in ERK1 and ERK2 activities produced by the hormone. MAP kinase activation was also attenuated by forskolin and glucagon, which increase intracellular cAMP, and by dibutyryl-cAMP, 8-bromo-cAMP, and 8-(4-chlorophenylthio)-cAMP. Thus, increasing cAMP is associated with decreased activation of MAP kinase by insulin. Forskolin also inhibited activation of MAP kinase by several agents (epidermal growth factor, phorbol 12-myristate 13-acetate, and okadaic acid) that act independently of insulin receptors. Moreover, forskolin did not inhibit insulin-stimulated tyrosine phosphorylation of the insulin receptor substrate IRS-1. Therefore, the inhibitory effect on MAP kinase did not result from compromised functioning of the insulin receptor. The inhibitory effect was not confined to adipocytes, as forskolin and dibutyryl-cAMP inhibited the increase in MAP kinase activity by phorbol 12-myristate 13-acetate in wild-type CHO cells. In contrast, these agents did not inhibit MAP kinase activity in mutant CHO cells (line 10248) that express a cAMP-dependent protein kinase resistant to activation by cAMP. Our results suggest that activation of cAMP-dependent protein kinase represents a general counter-regulatory mechanism for opposing MAP kinase activation.
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PMID:Increasing cAMP attenuates activation of mitogen-activated protein kinase. 769 90

Chronic treatment of mice with insulin results in hypertrophy and hyperplasia of the parotid and submandibular glands (Wang et al.: 1994, Proc Soc Exp Biol Med 205:353-361). Hyperplasia of the parotid gland is mediated by the elevation of tyrosine phosphorylation of phospholipase C gamma, p21ras-GTPase activating protein (p21ras-GAP) and phosphatidylinositol 3-kinase. These proteins were found to be associated with the insulin receptor substrate-1 most likely through src homology (SH2) domains of these proteins. There was also a transient increase in intracellular cAMP and protein kinase A during the first day of treatment which declined by Day 3 to near control values. Protein kinase C activity, on the other hand, remained elevated for the 3-day injection regimen. Thus, acinar cell proliferation induced by insulin requires activation of many of the same signaling components as other tyrosine kinase possessing growth factor receptors.
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PMID:Activation of SH2-containing proteins by insulin in proliferating mouse parotid gland acinar cells. 780 Jun 88

Insulin receptor tyrosine kinase activity accounts for tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), but the serine kinase(s) responsible for serine phosphorylation of IRS-1 is(are) unknown. In vitro kinase assays performed on PI3-kinase and IRS-1 immunoprecipitates demonstrated insulin-dependent serine phosphorylation of IRS-1. IRS-1 was associated with both insulin-dependent and independent serine kinases. Only the insulin-dependent serine kinase preferred Mn2+ over Mg2+ and was recovered from cell lysates containing dithiothreitol. In complexes of tyrosine phosphorylated recombinant IRS-1 and PI3-kinase, phosphorylation of IRS-1 was associated with decreased phosphorylation of the p85 subunit of PI3-kinase. These results are consistent with PI3-kinase being responsible for insulin-dependent serine phosphorylation of IRS-1 and suggest that this phosphorylation reaction may affect functions of both IRS-1 and the PI3-kinase.
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PMID:The PI3-kinase serine kinase phosphorylates its p85 subunit and IRS-1 in PI3-kinase/IRS-1 complexes. 781 31

Phosphatidylinositol 3-kinase (PI 3-kinase) is a heterodimer composed of an 85-kDa subunit that binds tyrosyl-phosphorylated proteins via its SH2 domains and a 110-kDa catalytic subunit. Expression and mutagenesis experiments have shown that the 110-kDa subunit is a dual specificity kinase that possesses both lipid and serine kinase activities. Except for the 85- and 110-kDa subunits of PI 3-kinase, however, no endogenous substrates for the serine kinase have been identified. The results of the present study show that another target of this kinase is the insulin receptor substrate, IRS-1. Serine phosphorylation of IRS-1 as well as the 85-kDa subunit of PI 3-kinase was demonstrated in immunoprecipitates of PI 3-kinase and IRS-1 isolated from rat adipocytes incubated with insulin. In adipocytes incubated in the absence of insulin, only the serine phosphorylation of p85 was observed in immunoprecipitates of PI 3-kinase. Both the serine and lipid kinase activities of PI 3-kinase were abolished by the fungal metabolite Wortmannin. Wortmannin also partially inhibited the ability of insulin to stimulate glucose transport and inhibit lipolysis in fat cells. These data raise the possibility that the serine kinase activity of PI 3-kinase is involved in insulin signaling. They also suggest that inhibition of the lipid or serine kinase activities of PI 3-kinase could explain the effect of Wortmannin to diminish insulin action.
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PMID:The phosphatidylinositol 3-kinase serine kinase phosphorylates IRS-1. Stimulation by insulin and inhibition by Wortmannin. 805 Nov 64

IRS-1, a principal substrate of the insulin receptor, is phosphorylated on serine, threonine, and tyrosine residues in a variety of tissues during insulin stimulation. Casein kinase II, an insulin-sensitive serine/threonine kinase, catalyzed the in vitro incorporation of 1 to 2 mol of phosphate/mol of recombinant rat IRS-1. Two-dimensional phosphopeptide mapping of IRS-1 phosphorylated by casein kinase II in vitro and IRS-1 immunoprecipitated from intact Chinese hamster ovary cells demonstrated multiple common phosphopeptides, suggesting that overexpressed IRS-1 is a substrate for casein kinase II in these cells. Moreover, the common phosphopeptides that appeared to be insulin-sensitive in intact cells comprised 22% of casein kinase II-catalyzed 32P incorporation into IRS-1 in vitro. These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. By using phosphoamino acid analysis, strong cation exchange analysis, manual Edman degradation, and automated amino acid sequencing, Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. Furthermore, Ser-99, an additional site labeled at low yield, appeared to be contained in an insulin-sensitive phosphopeptide. Thus, casein kinase II-catalyzed phosphorylation of IRS-1 may be a component of the intracellular insulin signalling cascade.
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PMID:Phosphorylation of the insulin receptor substrate IRS-1 by casein kinase II. 834 91

Pleckstrin homology (PH) domains are difficult to find in protein sequence databases with widely used computer programs. A simple program developed to overcome this difficulty identified three proteins containing previously unrecognized PH domains; the beta-adrenergic receptor kinase (beta-ARK), the tecA protein kinase and the insulin receptor substrate protein IRS-1. The region of beta-ARK containing the novel PH domain coincides with that previously shown to bind the beta gamma subunits of trimeric G-proteins, suggesting a general hypothesis for PH domain function. PH domains were then found at the N-termini of the tecA homologues Btk and itk. In line with the hypothesis a point mutation in the PH domain of Btk is associated with defects in signal transduction.
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PMID:Identification of novel pleckstrin homology (PH) domains provides a hypothesis for PH domain function. 837 91

Tumor necrosis factor-alpha (TNF-alpha) is a proposed mediator of insulin resistance in obese/diabetic animals through its effects on tyrosine phosphorylation of the insulin receptor and its substrate, insulin receptor substrate-1. In this study, the acute effects of TNF-alpha on the mitogen-activated protein kinase (MAPK) signalling cascade were examined in cultured rat skeletal muscle cell line, L6. Insulin treatment of L6 cells resulted in a rapid increase in MAPK activity (> twofold in 5 min with 10 nM insulin). Prior treatment with TNF-alpha for 60 min blocked subsequent insulin-induced activation of MAPK in a dose- and time-dependent manner. Metabolic labelling studies with inorganic [32P]phosphate followed by immuno-precipitation of MAPK and its upstream activator, mitogen-activated protein kinase kinase, indicated decreased phosphorylation of MAPK and its kinase in response to insulin in cells exposed to TNF-alpha. This effect of TNF-alpha was not due to inhibition of insulin-stimulated p21ras-GTP loading or Raf-1 phosphorylation. Low concentrations (2 nM) of okadaic acid, a serine/threonine phosphatase inhibitor, prevented TNF-alpha-induced inhibition of MAPK and restored insulin's effect on MAPK activity, while orthovanadate (a tyrosine phosphatase inhibitor), inhibitor 2 (phosphatase-1 inhibitor) and FK506 (phosphatase-2B inhibitor) were ineffective. These results suggested an involvement of an okadaic-acid-sensitive serine/threonine phosphatase in TNF-alpha-induced blockade of insulin's effect on MAPK and/or its kinase. Therefore, we examined the effect of TNF-alpha on protein phosphatase-1 (PP-1) and protein phosphatase-2A (PP-2A) activities. As reported by us earlier, insulin rapidly stimulated PP-1 and concomitantly inhibited PP-2A activities in control cells. TNF-alpha treatment blocked insulin-induced activation of PP-1. In contrast to PP-1, TNF-alpha caused a 60% increase in PP-2A activity and insulin failed to prevent this TNF-alpha effect. The time course of PP-2A activation by TNF-alpha preceded the kinetics of inhibition of MAPK. Cell-permeable ceramide analogs mimicked the TNF-alpha effect on MAPK inhibition and PP-2A activation. We conclude that TNF-alpha abrogates the insulin effect on MAPK activation by increasing dephosphorylation of MAPK kinase via an activated phosphatase.
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PMID:Effect of tumor necrosis factor-alpha on insulin-stimulated mitogen-activated protein kinase cascade in cultured rat skeletal muscle cells. 866 40

In the present study we have examined the signaling cascades involved in insulin-like growth factor I (IGF-I)-induced mitogenesis in fetal rat brown adipocyte primary cultures, a model that constitutively expresses a high number of IGF-I receptors, where IGF-I is a complete mitogen at physiological concentrations. IGF-I rapidly stimulated beta-chain IGF-I receptor autophosphorylation, which peaked at a physiological/mitogenic concentration (1.4 nM) and also stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). Tyrosine-phosphorylated IRS-1 bound and subsequently activated phosphatidylinositol 3-kinase by 3.5-fold, whereas the tyrosine-phosphorylated IGF-I receptor was not directly associated with the p85 subunit of the phosphatidylinositol 3-kinase. Moreover, mitogenic concentrations of IGF-I enhanced glucose transport by 2.5-fold. In addition, tyrosine phosphorylation of the 46- and 52-kDa SHC proteins was high in the basal state and doubled after IGF-I treatment, whereas IGF-I enhanced by 4-fold tyrosine phosphorylation of the 66-kDa SHC band. Furthermore, a 2-fold increase in the Ras. GTP active form was induced upon IGF-I stimulation. Downstream from Ras, IGF-I increased both Raf kinase and protein kinase C (PKC) zeta activities by 3.5-fold. (Bu)2cAMP, an inhibitor of IGF-I-induced mitogenesis in fetal brown adipocyte primary cultures, did not block the very early steps of the IGF-I-induced mitogenic cascade, such as IGF-I receptor autophosphorylation, IRS-1 or SHC tyrosine phosphorylation, and Ras activation to its GTP active form. However, (Bu)2cAMP disrupted IGF-I-Raf and IGF-I-PKC zeta signaling pathways by preventing IGF-I-induced Raf-1 kinase and PKC zeta enzymatic activities, respectively. Our results show the first characterization in situ of an IGF-I mitogenic signaling cascade that downstream Ras diverges to the nucleus through two different serine/threonine kinases (Raf-1 kinase and PKC zeta) in mammalian fetal primary cells under physiological conditions. Both kinases represent a point of regulation primarily described for IGF-I-induced, cAMP-inhibited mitogenic pathways.
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PMID:Involvement of Raf-1 kinase and protein kinase C zeta in insulin-like growth factor I-induced brown adipocyte mitogenic signaling cascades: inhibition by cyclic adenosine 3',5'-monophosphate. 875 54

We have reported previously that substitution of the transmembrane domain of the insulin receptor with that of the erbB-2 oncogene (IRerbV-->E) results in constitutive activation of the insulin receptor kinase. Compared to NIH3T3 cells overexpressing wild-type insulin receptors (IRwt), cells overexpressing IRerbV-->E displayed a decrease in IRS-1 protein content by 55%, but basal tyrosine phosphorylation of IRS-1 was increased. This resulted in an increased association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, increased phosphatidylinositol 3-kinase activity in anti-IRS-1 immunoprecipitates, constitutive activation of p70 S6 protein kinase, and an increased association of Grb2 with Shc in the absence of ligand. However, Grb2 association with IRS-1 could not be detected in the basal or insulin-stimulated states, and mitogen-activated protein kinase (MAPK) activity could not be stimulated by insulin, epidermal growth factor, or platelet-derived growth factor. In contrast to IRerbV-->E, the insulin receptor content and its tyrosine phosphorylation were significantly decreased in IRwt cells chronically stimulated (>24 h) with insulin. With decreased IRS-1 content, tyrosine phosphorylation of IRS-1 was decreased by over 75%, leading to decreased IRS-1-associated PI 3-kinase and Grb2. In addition, Grb2 association with Shc and activation of MAPK and the p70 S6 kinase were insensitive to insulin stimulation. By contrast, association of Grb2 with Shc and activation of MAPK, but not the p70 S6 kinase, could be stimulated by epidermal growth factor or platelet-derived growth factor. These data suggest that there are multiple levels of postreceptor desensitization to insulin action. These are used somewhat differently in these two different models, probably due in part to the difference in receptor down-regulation.
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PMID:Different pathways of postreceptor desensitization following chronic insulin treatment and in cells overexpressing constitutively active insulin receptors. 891 Apr 37


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