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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many of the effects of growth factors or hormones are mediated through the activation of protein kinase cascades. In this regard, it is well established that the activity of several protein kinases can be dramatically increased when cells are treated with a variety of stimuli. Since 1987, there have been several reports demonstrating that the activity of casein kinase II (CKII) can be acutely increased by hormones or growth factors. However, these are a number of discrepancies regarding the activation of CKII. In this study, we have examined CKII activities in extracts prepared from cells following treatment with stimuli that had been previously shown to elicit dramatic increases in CKII activity. Human WI.38 diploid lung fibroblasts were stimulated with serum or a variety of other stimuli including insulin, platelet-derived growth factor, fibroblast growth factor, epidermal growth factor, or phorbol myristate acetate. Human A431 epidermal carcinoma cells were similarly treated with epidermal growth factor. No reproducible increases in CKII activity were observed in response to any of these treatments. By comparison, a dramatic increase in kinase activity towards a synthetic peptide based on phosphorylation sites within the ribosomal S6 protein was consistently measured. Our observations indicate that CKII is not regulated in a similar manner by growth factors as are the protein kinases of the MAP kinase cascade, e.g., MAP kinase itself or ribosomal protein S6 kinase.
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PMID:Regulation of casein kinase II by growth factors: a reevaluation. 773 11

Insulin stimulation of differentiated 3T3-L1 adipocytes or Chinese hamster ovary cells expressing high levels of the insulin receptor resulted in a time-dependent decrease in the electrophoretic mobility of SOS on sodium dodecyl sulfate-polyacrylamide gels. The reduction in SOS mobility was completely reversed by alkaline phosphatase treatment, and the in vitro phosphorylation of SOS by mitogen-activated protein kinase resulted in a decrease of electrophoretic mobility identical to that following in vivo insulin stimulation. Immunoprecipitation of Grb2 followed by SOS immunoblotting demonstrated a disassociation of the SOS-Grb2 complex that paralleled the decrease in SOS electrophoretic mobility. Similarly, SOS immunoprecipitation followed by Grb2 immunoblotting also indicated an uncoupling of the SOS-Grb2 complex. Further, incubation of whole-cell extracts with glutathione-S-transferase-Grb2 fusion proteins demonstrated that insulin stimulation resulted in a decreased affinity of SOS for Grb2. In contrast, the dissociation of SOS from Grb2 did not affect the interactions between Grb2 and tyrosine-phosphorylated Shc. In addition to insulin, several other agents which activate the mitogen-activated protein kinase pathway (platelet-derived growth factor, serum, and phorbol ester) also resulted in the uncoupling of the SOS-Grb2 complex. Consistent with these results, expression of v-ras and v-raf resulted in a constitutive decrease in the association between SOS and Grb2. Together, these data suggest a molecular mechanism accounting for the transient activation of ras due to the uncoupling of the SOS-Grb2 complex following SOS phosphorylation.
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PMID:Insulin-stimulated disassociation of the SOS-Grb2 complex. 773 60

Activation of glycogen synthase is one of the major metabolic events triggered by exposure of cells to insulin. The molecular mechanism by which insulin activates glycogen synthase was investigated. The possible role of Ras and mitogen-activated protein kinase cascade was investigated with a stable cell line, CHO-IR-C/S 46, that overexpresses insulin receptors and a catalytically inactive SH-PTP 2 protein phosphatase and in which insulin does not induce the formation of the Ras-GTP complex or the subsequently activation of the mitogen-activated protein kinase cascade. Insulin activated glycogen synthase in this cell line to a similar extent as in parental CHO-IR cells. The importance of heteromeric phosphoinositide (PI) 3-kinase in insulin activation of glycogen synthase was examined in a stable cell line, CHO-IR/delta p85, that overexpresses insulin receptors and a dominant negative mutant (delta p85) of the 85-kDa subunit of PI 3-kinase that lacks the binding site for the catalytic 110-kDa subunit. Insulin-dependent activation of PI-3 kinase and glucose transport, but not the formation of the Ras-GTP complex, are markedly attenuated in this cell line. In CHO-IR/delta p85 cells, insulin activated glycogen synthase to a similar extent as in parental CHO-IR cells. The failure of overproduction of the mutant (delta p85) protein to inhibit insulin activation of glycogen synthase was also confirmed by transient expression in Rat 1 cells with the use of a recombinant vaccinia virus. However, wortmannin abolished insulin activation of glycogen synthase in all cell lines. These data suggest that existence of a Ras-independent and wortmannin-sensitive pathway for activation of glycogen synthase by insulin.
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PMID:Ras-independent and wortmannin-sensitive activation of glycogen synthase by insulin in Chinese hamster ovary cells. 774 67

Wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase), inhibited adipocyte differentiation of 3T3-L1 fibroblasts induced by insulin/dexamethasone/IBMX (hormones/IBMX). Insulin as a key factor in the process of the adipocyte differentiation activated PI 3-kinase, Ras protein, and mitogen-activated protein kinase (MAP kinase, ERK) in 3T3-L1 fibroblasts. Pretreatment with wortmannin almost completely suppressed all these activations. These findings suggest that the sequential activation of PI 3-kinase, Ras protein, and MAP kinase is involved in the insulin signaling pathway(s) during differentiation by hormones/IBMX and in consequence of the inhibition of PI 3-kinase by wortmannin, the activation of Ras protein and MAP kinase which acts downstream of PI 3-kinase is suppressed and results in the inhibition of adipocyte differentiation.
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PMID:Wortmannin inhibits insulin-induced Ras and mitogen-activated protein kinase activation related to adipocyte differentiation in 3T3-L1 fibroblasts. 775 36

To elucidate the role of hyperinsulinemia in the development of atherosclerosis, we evaluated insulin-specific signaling in cultured vascular smooth muscle cells (SMCs) and its desensitization by continuous exposure to insulin. The concentration of unlabeled insulin that inhibited specific [A14-125I]-insulin binding by 50% (IC50) was 0.33 +/- 0.02 nM, which was 100 times less than the IC50 of unlabeled IGF-I. For [125I]-IGF-I binding, the IC50 of unlabeled IGF-I was found to be 6.6 +/- 0.88 nM, which was 100 times less than the IC50 of unlabeled insulin. The binding capacities for insulin and IGF-I were found to be 1.28 +/- 0.86 and 1200 +/- 170 fmol/0.5 mg protein, respectively. Autophosphorylation of the beta-subunit of the insulin receptor was stimulated at above 0.17 nM (24 microU/ml) insulin. Insulin concentrations exceeding 1 nM significantly activated the S6 kinase in a dose-dependent manner. In contrast, 10 nM insulin did not activate MAP kinase nor [3H]thymidine incorporation into DNA, while both were activated by 38% and 44% with 1 microM insulin and by 52% and 67% with 10 nM IGF-I, respectively. By pre-exposing cells to 10 nM insulin for 12 h, the binding capacity for insulin decreased by 34% (P < 0.05), and activation of S6 kinase by insulin almost disappeared, while both IGF-I binding and the activation of S6 kinase by IGF-I were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin-specific activation of S6 kinase and its desensitization in cultured rat vascular smooth muscle cells. 775 52

Transgenic mice which overexpress kinase-deficient human insulin receptors in muscle were used to study the relationship between insulin receptor tyrosine kinase and the in vivo activation of several downstream signaling pathways. Intravenous insulin stimulated insulin receptor tyrosine kinase activity by 7-fold in control muscle versus < or = 1.5-fold in muscle from transgenic mice. Similarly, insulin failed to stimulate tyrosyl phosphorylation of receptor beta-subunits or insulin receptor substrate 1 (IRS-1) in transgenic muscle. Insulin substantially stimulated IRS-1-associated phosphatidylinositol (PI) 3-kinase in control versus absent stimulation in transgenic muscles. In contrast, insulin-like growth factor 1 modestly stimulated PI 3-kinase in both control and transgenic muscle. The effects of insulin to stimulate p42 mitogen-activated protein kinase and c-fos mRNA expression were also markedly impaired in transgenic muscle. Specific immunoprecipitation of human receptors followed by measurement of residual insulin receptors suggested the presence of hybrid mouse-human heterodimers. In contrast, negligible hybrid formation involving insulin-like growth factor 1 receptors was evident. We conclude that (i) transgenic expression of kinase-defective insulin receptors exerts dominant-negative effects at the level of receptor auto-phosphorylation and kinase activation; (ii) insulin receptor tyrosine kinase activity is required for in vivo insulin-stimulated IRS-1 phosphorylation, IRS-1-associated PI 3-kinase activation, phosphorylation of mitogen-activated protein kinase, and c-fos gene induction in skeletal muscle; (iii) hybrid receptor formation is likely to contribute to the in vivo dominant-negative effects of kinase-defective receptor expression.
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PMID:Impaired insulin signaling in skeletal muscles from transgenic mice expressing kinase-deficient insulin receptors. 775 7

Bacterially expressed, dual specificity phosphatase VHR protein induced germinal vesicle breakdown (GVBD) when microinjected into Xenopus oocytes, albeit with slower kinetics than that observed in progesterone- or insulin-induced maturation. A mutant VHR protein missing an essential cysteine residue for its in vitro phosphatase activity completely lacked activity in injected oocytes. VHR injection done in conjunction with progesterone or insulin treatment resulted in highly synergized GVBD responses showing much faster kinetics than that produced by VHR or either hormone alone. The delayed kinetics of VHR-induced GVBD and the synergistic responses obtained in the presence of hormones suggested that this protein may be promoting G2/M transition by weakly mimicking the action of cdc25, the dual specificity phosphatase that physiologically activates the maturation promotion factor. Various experimental observations are consistent with such a role for the injected VHR in oocytes: 1) as opposed to hormone-treated oocytes, histone H1 kinase activation is not preceded by MAPK activation in the process of GVBD in VHR-injected oocytes; 2) incubation of purified VHR with highly concentrated cell-free extracts of untreated oocytes resulted in activation of histone H1 kinase activity in the lysates; 3) coinjection of VHR with activated Ras proteins resulted in synergized responses, faster than those produced by either protein alone; 4) coinjection of VHR with the purified amino-terminal SH2 domain of the p85 subunit of phosphatidylinositol 3-kinase (which blocks insulin-induced GVBD) does not affect VHR-induced maturation. The biological actions of VHR in oocytes clearly distinguish it from other dual specificity phosphatases, which have shown inhibitory effects when tested in oocytes. We speculate that VHR may represent a dual specificity phosphatase responsible for activation of cdk-cyclin complex(es) at a still undetermined stage of the cell cycle.
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PMID:Human dual specificity phosphatase VHR activates maturation promotion factor and triggers meiotic maturation in Xenopus oocytes. 777 84

We used a bacterially expressed fusion protein containing the entire cytoplasmic domain of the human leukemia inhibitory factor (LIF) receptor to study its phosphorylation in response to LIF stimulation. The dose- and time-dependent relationships for phosphorylation of this construct in extracts of LIF-stimulated 3T3-L1 cells were superimposable with those for the stimulation of mitogen-activated protein kinase (MAPK). Indeed, phosphorylation of the cytoplasmic domain of the low-affinity LIF receptor alpha-subunit (LIFR) in Mono Q-fractionated, LIF-stimulated 3T3-L1 extracts occurred only in those fractions containing activated MAPK; Ser-1044 served as the major phosphorylation site in the human LIFR for MAPK both in agonist-stimulated 3T3-L1 lysates and by recombinant extracellular signal-regulated kinase 2 in vitro. Expression in rat H-35 hepatoma cells of LIFR or chimeric granulocyte-colony-stimulating factor receptor (G-CSFR)-LIFR mutants lacking Ser-1044 failed to affect cytokine-stimulated expression of a reporter gene under the control of the beta-fibrinogen gene promoter but eliminated the insulin-induced attenuation of cytokine-stimulated gene expression. Thus, our results identify the human LIFR as a substrate for MAPK and suggest a mechanism of heterologous receptor regulation of LIFR signaling occurring at Ser-1044.
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PMID:Phosphorylation of the human leukemia inhibitory factor (LIF) receptor by mitogen-activated protein kinase and the regulation of LIF receptor function by heterologous receptor activation. 777 12

Polyunsaturated fatty acids enhance the proliferation of mouse mammary epithelial cells stimulated by epidermal growth factor (EGF) by modulating the post-receptor signaling pathways. The growth stimulatory effect of these fatty acids is completely inhibited by pertussis toxin, whereas the inhibition of EGF and insulin stimulated growth is only partial. The treatment of cell cultures with 12-O-tetradecanoyl-phorbol-13 acetate (TPA) reverses the growth inhibitory effect of pertussis toxin and fully restores the growth as was in the control cultures untreated with the toxin suggesting a role for PKC in this reversal. It appears that the functions of Gi-proteins are required in the mediation of fatty acid effect on growth. The predominant types of Gi alpha in mammary epithelial cells are Gi alpha 1, Gi alpha 2, and Gi alpha 3. Among these, the levels of Gi alpha 1 and 2 appears to be regulated by steroid hormones. Linoleic acid raises the level of GTP-bound Ras in the cells above the levels induced by EGF. Pertussis toxin reduces the level of Ras-GTP and inhibits phosphorylation of MAP kinase by EGF. It has been speculated that Gi-proteins interact with the receptor bound nucleotide exchange factor and the membrane anchored Raf kinase and constitute two sites for pertussis toxin action. The phosphorylation by PKC may uncouple Gi-protein interaction with these effectors and enable the agonist-induced signals to bypass the inhibitory action of PT on growth.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of GTP-binding proteins in the polyunsaturated fatty acid stimulated proliferation of mouse mammary epithelial cells. 778 51

Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the rate-limiting step in hepatic gluconeogenesis. Glucagon (via the second messenger cAMP) and glucocorticoids stimulate the transcription of the PEPCK gene, whereas insulin and phorbol esters inhibit, in a dominant fashion, these effects. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, prevents the stimulation of glycogen synthesis, glucose transport, mitogen-activated protein kinase, and p70/p85 ribosomal S6 protein kinase by insulin. We now show that wortmannin can also block the inhibition of glucocorticoid- and cAMP-stimulated PEPCK gene expression by insulin. PEPCK-chloramphenicol acetyltransferase fusion gene experiments demonstrate that wortmannin blocks an activity that is required for insulin signaling to elements within the PEPCK promoter. Phorbol esters mimic the action of insulin on the regulation of PEPCK gene expression, but wortmannin does not block the effect of these agents. Thus, phosphatidylinositol 3-kinase is required for the regulation of PEPCK gene expression by insulin, but not by phorbol esters. The immunosuppressant rapamycin, a potent inhibitor of insulin or phorbol ester stimulation of p70/p85 ribosomal S6 protein kinase, has no significant effect on the regulation of PEPCK gene expression by insulin or phorbol esters. Thus, p70/p85 ribosomal S6 protein kinase does not have a role in signaling to the PEPCK promoter by insulin or phorbol esters.
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PMID:Phosphatidylinositol 3-kinase, but not p70/p85 ribosomal S6 protein kinase, is required for the regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene expression by insulin. Dissociation of signaling pathways for insulin and phorbol ester regulation of PEPCK gene expression. 779 43


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