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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubating either Chinese hamster ovary (CHO) cells or 3T3-L1 adipocytes with insulin increased the phosphorylation of the eIF-4E-binding protein, PHAS-I. Insulin also activated p70S6K and the Erk-1 and Erk-2 isoforms of mitogen-activated protein kinase (MAP kinase). However, the concentrations of the hormone needed to activate MAP kinase were 10-100 times higher than those needed to increase PHAS-I phosphorylation and p70S6K activity. Incubating cells with the inhibitor of MAP kinase kinase (MEK) activation, PD 098059, blocked the effects of low concentrations of insulin on PHAS-I and p70S6K. The effects of the inhibitor were overcome by increasing concentrations of insulin. The results indicate that insulin activates a PD 098059-sensitive kinase that is involved in the regulation of both p70S6K and PHAS-I.
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PMID:Insulin activates a PD 098059-sensitive kinase that is involved in the regulation of p70S6K and PHAS-I. 920 40

Evidence has accumulated that suggests that insulin-like growth factors (IGFs) exert a positive influence on myoblast differentiation. We have undertaken to study the signalling events required for differentiation resulting from type-1 IGF receptor stimulation in C2 myoblasts, where autocrine production of IGF-II was abolished by means of antisense RNA. Exposure of the cells to IGFs leads to a rapid and sustained activation of phosphatidyl-inositol 3-kinase followed by the expression of Myod, myogenin and differentiation. The fungal metabolite, wortmannin, inhibits both PI 3-kinase and muscle differentiation with an IC 50 in the nanomolar range. IGFs are also known to cause a rapid activation of MAP kinase. However, the synthetic inhibitor of MEK, PD098059, which prevents MAP kinase activation, does not affect myoblast differentiation. These results provide evidence that PI 3-kinase, but not MAP kinase, is required for insulin-like growth factor receptor-dependent differentiation of muscle cells.
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PMID:Wortmannin inhibits IGF-dependent differentiation in the mouse myogenic cell line C2. 923 22

Xenopus postvitellogenic oocytes resume meiosis in vitro upon exposure to insulin or insulin-like growth factor 1 (IGF-1) via a ras-dependent pathway, whereas stage IV (600 micron < diameter < 1000 micron) oocytes cannot. The aim of the present study was to determine which event(s) of the transduction pathway from IGF-1 receptor to maturation-promoting factor (MPF) activation is deficient in the small, vitellogenic, oocytes to explain their inability to undergo germinal vesicle breakdown (GVB) after insulin treatment. We thus analyzed the effect of insulin on the Ras/Raf-dependent mitogen-activated protein kinase cascade because of its crucial role prior to MPF activation. The effect of insulin on pp39mos synthesis in stage IV oocytes was also studied since this protein kinase participates in the mitogen-activated protein kinase (MAPK) pathway as a MAPKK kinase like Raf. Contrary to what is observed in postvitellogenic oocytes, MAPK was not activated in insulin-treated stage IV oocytes even 20 hr after the stimulation. This was not caused by the absence of MAPK activators like MEK (MAPKK), Raf, or Ras, but rather by the inability of insulin to activate Ras. Interestingly, injection of constitutively active raf mRNA as well as oncogenic Ras protein, Ha-Ras lys12, in stage IV oocytes resulted in MAPK activation, whereas neither Mos accumulation nor GVB occurred, suggesting that the Ras --> Raf --> MAPKK --> MAPK cascade was functional but that MAPK activation alone was not sufficient for the mitogenic signal to proceed further down in the pathway leading to MPF activation. Treatment of stage IV oocytes with insulin did not stimulate Mos synthesis either, indicating a dysfunction in the "Mos synthesis machinery." The present results show that incompetence of Xenopus stage IV oocytes to activate MPF in response to insulin is primarily due to the inability of the peptide to activate Ras and to stimulate pp39mos synthesis and secondarily to a deficiency in the mitogenic pathway that connects MAPK to MPF activation.
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PMID:Comparative effects of insulin on the activation of the Raf/Mos-dependent MAP kinase cascade in vitellogenic versus postvitellogenic Xenopus oocytes. 924 17

p38 is a member of the mitogen-activated protein (MAP) kinase superfamily activated by stress signals and implicated in cellular processes involving inflammation and apoptosis. Unlike the extracellular signal-regulated kinases (p42 and p44 MAP kinases), which are stimulated by insulin in many cell types, p38 activity is inhibited by insulin in postmitotic fetal neurons for which insulin is a potent survival factor (Heidenreich, K. A., and Kummer, J. L. (1996) J. Biol. Chem. 271, 9891-9894). These data suggested that insulin's effects on neuronal survival are mediated by inhibition of a p38-mediated apoptotic pathway. To better understand the relationship between p38 activity and cell survival, we induced apoptosis in two cell lines and examined the ability of insulin or a specific p38 inhibitor (a pyridinyl imidazole compound PD169316) to block p38 activity and cell death. In Rat-1 fibroblasts grown in the presence of serum, p38 activity was undetectable by immune complex assays, and the number of apoptotic cells was very low (<0.5%). After the removal of serum for 16 h, p38 activity was markedly elevated, and apoptosis increased by 14-15-fold. Insulin (50 ng/ml) inhibited p38 activity by approximately 70% and blocked apoptosis by at least 80%. PD169316 also blocked p38 enzyme activity and apoptosis by approximately 80%. Similar results were obtained in differentiated PC12 cells that were deprived of nerve growth factor (NGF) for 16 h. In the presence of NGF, p38 activity and the number of apoptotic cells was very low (approximately 1.0%). After NGF withdrawal, p38 activity was selectively elevated and apoptosis increased to 15%. Both insulin and PD169316 markedly blocked the increase in p38 activity and apoptosis. The MAP kinase kinase inhibitor, PD98059, had no effect on apoptosis in Rat-1 fibroblasts and only partially blocked apoptosis in PC12 cells. PD98059 did not influence insulin's ability to block apoptosis, indicating that the extracellular signal-regulated kinase pathway does not mediate insulin's survival effects. These data further support the role of p38 in cellular apoptosis and support the hypothesis that insulin promotes cell survival, at least in part, by inhibiting the p38 pathway.
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PMID:Apoptosis induced by withdrawal of trophic factors is mediated by p38 mitogen-activated protein kinase. 925 60

Stimulation of the T cell antigen receptor (TCR) activates signaling pathways involving protein kinases, phospholipase Cgamma1, and Ras. How these second messengers interact to initiate distal activation events is an area of intense scrutiny. In this report, we confirm that TCR ligation results in phosphorylation of Sos, a guanine nucleotide exchange factor for Ras. This requires expression of both the CD45 tyrosine phosphatase and the Lck protein tyrosine kinase and depends upon signaling via protein kinase C. In contrast to previous studies examining requirements for Sos phosphorylation following insulin and epidermal growth factor receptor engagement, we show that TCR-induced phosphorylation of Sos does not require activation of the mitogen-activated protein kinase/extracellular-signal regulated kinase (MEK/ERK) pathway. However, the basal phosphorylation of Sos in T cells is affected by either MEK or MEK-dependent kinases. Although Sos phosphorylation results in its dissociation from Grb2 following insulin stimulation in Chinese hamster ovary cells, TCR engagement on the Jurkat T cell line fails to elicit a similar effect. These data demonstrate that the kinases responsible for Sos phosphorylation differ following ligation of various cell surface receptors and that the consequences of Sos phosphorylation relies, at least in part, on sites of its phosphorylation.
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PMID:T cell receptor-induced phosphorylation of Sos requires activity of CD45, Lck, and protein kinase C, but not ERK. 926 Nov 85

In 3T3-L1 fibroblasts, Ras proteins mediate both insulin-induced differentiation to adipocytes and its activation of cytosolic serine/threonine kinases, including Raf-1 kinase, mitogen-activated protein kinase (MAPK), and Rsk. Here, we report that insulin- and Ras-induced activation of MAPK is not required for the differentiation process and in fact antagonizes it. The treatment of 3T3-L1 preadipocytes with MEK-specific inhibitor PD98059 blocked insulin- and Ras-induced MAPK activation but had no effect on or slightly enhanced adipocytic differentiation. Tumor necrosis factor alpha (TNF-alpha), an inhibitor of insulin-stimulated adipogenesis, activated MAPK in 3T3-L1 cells. PD98059 treatment blocked MAPK activation by TNF-alpha and reversed the blockade of adipogenesis mediated by low (1 ng/ml) TNF-alpha concentrations. 3T3-L1 transfectants containing hyperactivated MEK1 or overexpressed MAPK displayed impaired adipocytic differentiation. PD98059 treatment also reversed the blockade of differentiation in MEK1 transfectants. These results indicate that MAPK does not promote but can contribute to inhibition of the process of adipocytic differentiation of 3T3-L1 cells.
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PMID:Mitogen-activated protein kinase activation is not necessary for, but antagonizes, 3T3-L1 adipocytic differentiation. 931 66

We recently reported that insulin stimulation results in the serine phosphorylation of STAT3 (signal transducer and activator of transcription-3). In the present study, we identified serine 727 as the site of insulin-stimulated STAT3 serine phosphorylation. This phosphorylation event occurs independent of tyrosine phosphorylation. Furthermore, interleukin-6-induced tyrosine phosphorylation can occur independent of serine phosphorylation, demonstrating that these two phosphorylation pathways are mechanistically unrelated. Selective activation of the JNK and p38 family of mitogen-activated protein (MAP) kinases by anisomycin treatment did not result in the phosphorylation of STAT3. In contrast, activation of the ERK MAP kinase pathway with both insulin and osmotic shock resulted in the serine phosphorylation of STAT3. In addition, expression of a dominant-interfering Ras mutant (N17Ras) or treatment with the specific MEK inhibitor (PD98059) prevented the insulin stimulation of STAT3 serine phosphorylation. Blockade of ERK activation by expression of the MAP kinase phosphatase (MKP-1) had no effect on insulin-stimulated STAT3 serine phosphorylation. Together, these data demonstrate that the insulin-stimulated serine phosphorylation of STAT3 occurs by a MEK-dependent pathway that is independent of ERK activation.
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PMID:Signal transducer and activator of transcription-3 serine phosphorylation by insulin is mediated by a Ras/Raf/MEK-dependent pathway. 932 21

hGrb10alpha (previously named Grb-IR) is a Src-homology 2 domain-containing protein that binds with high affinity to the tyrosine-phosphorylated insulin receptor and insulin-like growth factor-1 receptor. At least two isoforms of human Grb10, (hGrb10alpha and hGrb10beta), which differ in the pleckstrin homology (PH) domain and the N-terminal sequence, have previously been identified in insulin target tissues such as human skeletal muscle and fat cells. Here we report the cloning of the third isoform of the hGrb10 family (hGrb10gamma) from human skeletal muscle and its localization to human chromosome 7. We have also determined the human chromosome localization of Grb7 to 17q21-q22 and Grb14 to chromosome 2. hGrb10gamma contains an intact PH domain and an N-terminal sequence that is present in hGrb10alpha but absent in hGrb10beta. RNase protection assays and Western blot analysis showed that hGrb10alpha and hGrb10gamma are differentially expressed in insulin target cells including skeletal muscle, liver, and adipocyte cells. hGrb10gamma is also expressed in HeLa cells and various breast cancer cell lines. The protein bound with high affinity to the insulin receptor in cells, and the interaction was dependent on the tyrosine phosphorylation of the receptor. hGrb10gamma also underwent insulin-stimulated membrane translocation and serine phosphorylation. hGrb10gamma phosphorylation was inhibited by PD98059, a specific inhibitor of mitogen-activated protein kinase kinase, and wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase. Taken together, our data suggest that hGrb10 isoforms are potential downstream signaling components of the insulin receptor tyrosine kinase and that the PH domain may play an important role in the involvement of these isoforms in signal transduction pathways initiated by insulin and other growth factors.
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PMID:Cloning, chromosome localization, expression, and characterization of an Src homology 2 and pleckstrin homology domain-containing insulin receptor binding protein hGrb10gamma. 936 Sep 86

Glycogen synthesis was studied in rat hepatocytes isolated by EDTA perfusion. Insulin induced a one and a half to twofold increase in glucose incorporation into glycogen. Insulin stimulated glycogen synthesis was inhibited by the phosphatidylinositol 3-kinase inhibitors wortmannin (IC50 approximately 40 nM) and LY 294002 (IC50 approximately 20 microM) and the mitogen-activated protein kinase kinase inhibitor PD 98059 (IC50 approximately 40 microM). Wortmannin was without appreciable effect on non-insulin stimulated glycogen synthesis, while LY 294002 and PD 98059 also inhibited the non-insulin stimulated glycogen synthesis. Rapamycin, an inhibitor of p70 ribosomal protein-S6 kinase, was without effect on glycogen synthesis regardless of insulin stimulation.
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PMID:Insulin stimulated glycogen synthesis in isolated rat hepatocytes: effect of protein kinase inhibitors. 937 26

Adipose-tissue lipolysis (assessed from glycerol release) and glucose uptake were examined in parametrial and mesenteric adipocytes prepared from control or hyperthyroid rats in relation to changes in insulin sensitivity. Basal rates of lipolysis did not differ significantly between adipose-tissue depots. Lipolysis was maximally stimulated by noradrenaline at 1 microM, half-maximal anti-lipolytic effects of insulin were observed at approximately 11 microU/ ml insulin, and half-maximal stimulation of glucose uptake was observed at approximately 16 microU/ml insulin in adipocytes from both depots. Wortmannin caused a dose-dependent inhibition of the anti-lipolytic effect of insulin (150 microU/ml) on noradrenaline-stimulated lipolysis. Half-maximal effects of wortmannin were observed at 20-40 nM. The p70S6K inhibitor rapamycin and the mitogen-activated protein kinase kinase inhibitor PD098059 had no effects on noradrenaline-stimulated lipolysis. Hyperthyroidism increased basal rates of lipolysis and the maximal response of lipolysis to noradrenaline stimulation (3.1-fold, P < 0.001 and 2.1-fold, P < 0.05 respectively) in parametrial adipocytes. Hyperthyroidism markedly blunted the sensitivity of noradrenaline-stimulated lipolysis to half-maximal suppression by insulin in both parametrial and mesenteric adipocyte depots, and noradrenaline-stimulated lipolysis at a maximal insulin concentration remained significantly higher in adipocytes prepared from hyperthyroid rats compared with controls. Hyperthyroidism had no effect on basal and little effect on insulin-stimulated glucose uptake. Tri-iodothyronine administered at a low dose selectively influenced the anti-lipolytic action of insulin in parametrial adipocytes, and led to significantly less marked elevation in plasma non-esterified fatty acid concentrations in vivo. The results demonstrate a selective effect of hyperthyroidism to impair insulin's anti-lipolytic action, and are consistent with the operation of different downstream signalling mechanisms for the effects of insulin on adipocyte glucose transport and lipolysis.
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PMID:Selective modification of insulin action in adipose tissue by hyperthyroidism. 937 29


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