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)

Microsomal triglyceride transfer protein (MTP) is necessary for hepatocyte assembly and secretion of apolipoprotein (apo)B100-containing lipoproteins. The citrus flavonoid naringenin, like insulin, decreased MTP expression in HepG2 cells, resulting in inhibition of apoB100 secretion; however, the mechanism for naringenin is independent of insulin receptor substrate-1/2. Recently, it was reported that insulin decreased MTP expression in HepG2 cells via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) (MAPK(erk)) pathway. We hypothesized that naringenin acts via a similar mechanism. Inhibition of MAPK kinase (MEK) 1/2 in HepG2 cells significantly attenuated the naringenin- and insulin-induced reduction in MTP expression. Both naringenin and insulin increased ERK1/2 phosphorylation, which was completely inhibited by MEK1/2 inhibition and enhanced by inhibition of MAPK(p38), a negative regulator of MAPK(erk) activity. Inhibition of MEK1/2 significantly attenuated both the naringenin- and insulin-induced decrease in apoB100 secretion demonstrating a direct link between MAPK(erk) activation and apoB100 secretion. Furthermore, both compounds increased MAPK(p38) activation, and therefore inhibition of MAPK(p38) amplified thenaringenin- and insulin-induced decrease in apoB100 secretion. We conclude that MAPK(erk) signaling in hepatocytes is critical for inhibition of apoB100 secretion by naringenin and insulin. Therefore, naringenin may prove useful for activating insulin-signaling pathways important for regulation of hepatocyte lipid homeostasis.
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PMID:Inhibition of microsomal triglyceride transfer protein expression and apolipoprotein B100 secretion by the citrus flavonoid naringenin and by insulin involves activation of the mitogen-activated protein kinase pathway in hepatocytes. 1591 88

Clinical evidence suggests a relationship between hypertension and insulin resistance, and cross-talk between angiotensin II (Ang II) and insulin signaling pathways may take place. We now report the effect of Ang II on insulin-induced glucose uptake and its intracellular mechanisms in vascular smooth muscle cells (VSMC). We examined the translocation of glucose transporter-4 (GLUT-4) and glucose uptake in rat aortic smooth muscle cells (RASMC). Mitogen-activated protein (MAP) kinases and Akt activities, and phosphorylation of insulin receptor substrate-1 (IRS-1) at the serine and tyrosine residues were measured by immunoprecipitation and immunoblotting. As a result, Ang II inhibited insulin-induced GLUT-4 translocation from cytoplasm to the plasma membrane in RASMC. Ang II induced extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) activation and IRS-1 phosphorylation at Ser307 and Ser616. Ang II-induced Ser307 and Ser616 phophorylation of IRS-1 was inhibited by a MEK inhibitor, PD98059, and a JNK inhibitor, SP600125. Ang II inhibition of insulin-stimulated IRS-1 tyrosyl phophorylation and Akt activation were reversed by PD98059 but not by SP600125. Ang II inhibited insulin-induced glucose uptake, which was also reversed by PD98059 but not by SP600125. It is shown that Ang II-induced ERK1/2 activation inhibits insulin-dependent glucose uptake through serine phophorylation of IRS-1 in RASMC.
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PMID:ERK1/2 activation by angiotensin II inhibits insulin-induced glucose uptake in vascular smooth muscle cells. 1592 82

Fructose is a unique nutrient, due in part to its selective metabolism in the liver. Diets enriched in fructose or sucrose induce a hepatic stress response characterized by activation of c-jun N-terminal kinase. The aim of this study was to examine the regulation of c-jun N-terminal kinase by fructose in rat primary hepatocytes. Fructose was provided to rat primary hepatocytes using a fructose regenerating system, consisting of inulin and inulinase. This system provides a more physiologic delivery of fructose and avoids large disturbances in hepatocyte ATP concentrations. Fructose delivery increased c-jun N-terminal kinase activity and serine 307 phosphorylation of insulin receptor substrate-1 and reduced tyrosine phosphorylation of insulin receptor substrate-1. Activation of c-jun N-terminal kinase was maximal at a fructose concentration of 0.6 mmol/L. Fructose delivery did not increase the phosphorylation of p38 mitogen-activated protein kinase, extracellular signal regulated kinase, c-jun, or activating transcription factor-2, the latter 2 downstream nuclear targets of c-jun N-terminal kinase. However, fructose delivery increased the phosphorylation of mitogen-activated protein kinase kinase-7 (MKK7), an upstream activator of c-jun N-terminal kinase, and the association of c-jun N-terminal kinase with c-jun N-terminal kinase-interacting protein-1, a scaffold protein that can sequester protein signaling complexes in the cytosol. These data suggest that fructose may selectively activate c-jun N-terminal kinase via regulation of MKK7 and scaffold proteins.
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PMID:Fructose selectively modulates c-jun N-terminal kinase activity and insulin signaling in rat primary hepatocytes. 1598 43

Insulin resistance in polycystic ovary syndrome (PCOS) results from a postbinding defect in signaling. Insulin receptor and insulin receptor substrate (IRS)-1 serine hyperphosphorylation by an unidentified kinase(s) contributes to this defect. We investigated whether insulin resistance is selective, affecting metabolic but not mitogenic pathways, in skeletal muscle as it is in cultured skin fibroblasts in PCOS. Extracellular signal-regulated kinase (ERK)1/2 activation was increased in skeletal muscle tissue and in cultured myotubes basally and in response to insulin in women with PCOS compared with control women. Mitogen-activated/extracellular signal-regulated kinase kinase (MEK)1/2 was also activated in PCOS, whereas p38 mitogen-activated protein kinase phosphorylation and signaling from the insulin receptor to Grb2 was similar in both groups. The activity of p21Ras was decreased and Raf-1 abundance increased in PCOS, suggesting that altered mitogenic signaling began at this level. MEK1/2 inhibition reduced IRS-1 Ser312 phosphorylation and increased IRS-1 association with the p85 subunit of phosphatidylinositol 3-kinase in both groups. We conclude that in PCOS skeletal muscle, 1) mitogenic signaling is enhanced in vivo and in culture, 2) ERK1/2 activation inhibits association of IRS-1 with p85 via IRS-1 Ser312 phosphorylation, and 3) ERK1/2 activation may play a role in normal feedback of insulin signaling and contribute to resistance to insulin's metabolic actions in PCOS.
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PMID:Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome. 1650 39

To investigate the association between hyperinsulinemia and cardiac hypertrophy, we treated rats with insulin for 7 wk and assessed effects on myocardial growth, vascularization, and fibrosis in relation to the expression of angiotensin II receptors (AT-R). We also characterized insulin signaling pathways believed to promote myocyte growth and interact with proliferative responses mediated by G protein-coupled receptors, and we assessed myocardial insulin receptor substrate-1 (IRS-1) and p110 alpha catalytic and p85 regulatory subunits of phospatidylinositol 3 kinase (PI3K), Akt, MEK, ERK1/2, and S6 kinase-1 (S6K1). Left ventricular (LV) geometry and performance were evaluated echocardiographically. Insulin decreased AT1a-R mRNA expression but increased protein levels and increased AT2-R mRNA and protein levels and phosphorylation of IRS-1 (Ser374/Tyr989), MEK1/2 (Ser218/Ser222), ERK1/2 (Thr202/Tyr204), S6K1 (Thr421/Ser424/Thr389), Akt (Thr308/Thr308), and PI3K p110 alpha but not of p85 (Tyr508). Insulin increased LV mass and relative wall thickness and reduced stroke volume and cardiac output. Histochemical examination demonstrated myocyte hypertrophy and increases in interstitial fibrosis. Metoprolol plus insulin prevented the increase in relative wall thickness, decreased fibrosis, increased LV mass, and improved function seen with insulin alone. Thus our data demonstrate that chronic hyperinsulinemia decreases AT1a-to-AT2 ratio and increases MEK-ERK1/2 and S6K1 pathway activity related to hypertrophy. These changes might be crucial for increased cardiovascular growth and fibrosis and signs of impaired LV function.
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PMID:Hyperinsulinemia: effect on cardiac mass/function, angiotensin II receptor expression, and insulin signaling pathways. 1656 9

Many cytokines increase their receptor affinity for Janus kinases (JAKs). Activated JAK binds to signal transducers and activators of transcription, insulin receptor substrates (IRSs), and Shc. Intriguingly, insulin acting through its own receptor kinase also activates JAK2. However, the impact of such activation on insulin action remains unknown. To determine the contribution of JAK2 to insulin signaling, we transfected L6 myotubes with siRNA against JAK2 (siJAK2), reducing JAK2 protein expression by 75%. Insulin-dependent phosphorylation of IRS1/2 and Shc was not affected by siJAK2, but insulin-induced phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-related kinase, p38, and Jun NH2-terminal kinase and their respective upstream kinases MKK1/2, MKK3/6, and MKK4/7 was significantly lowered when JAK2 was depleted, correlating with a significant drop in insulin-mediated cell proliferation. These effects were reproduced by the JAK2 inhibitor AG490. Conversely, insulin-stimulated Akt phosphorylation, glucose uptake, and GLUT4 translocation were not affected by siJAK2. Interestingly, in two insulin-resistant states, siJAK2 led to partial restoration of Akt phosphorylation and glucose uptake stimulation but not of the MAPK pathway. These results suggest that JAK2 may depress the Akt to glucose uptake signaling axis selectively in insulin-resistant states. Inhibition of JAK2 may be a useful strategy to relieve insulin resistance of metabolic outcomes.
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PMID:Opposite effect of JAK2 on insulin-dependent activation of mitogen-activated protein kinases and Akt in muscle cells: possible target to ameliorate insulin resistance. 1656 15

There is a strong positive correlation between insulin resistance and cardiac diseases. We have already shown that chronic exposure to the ketone body beta-hydroxybutyrate (OHB) decreases insulin-mediated activation of protein kinase B (PKB) and glucose uptake in cardiomyocytes. To gain further insights into the mechanism underlying ketone body-induced insulin resistance, we examined whether OHB alters activation of the insulin-signaling cascade and whether the insulinomimetic agent vanadate could bypass insulin resistance and stimulate glucose uptake in these cells. Cardiomyocytes were incubated with 5 mM OHB, 50 microM vanadate or both for 16 h before the measurement of glucose uptake or the activation of insulin-signaling molecules. While chronic exposure to OHB did not alter insulin- or vanadate-mediated activation of the insulin receptor, it suppressed insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation in response to both agonists. Furthermore, this treatment decreased by 54 and 36% the phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-K) and PKB in response to insulin, whereas it did not alter vanadate-mediated activation of these enzymes. Although insulin did not significantly stimulate p38MAPK phosphorylation, vanadate increased it by 3.8-fold. Furthermore, chronic exposure to OHB potentiated vanadate's action, resulting in a 250% increase in enzyme activation compared to control cells. Though OHB induced a 2.1-fold increase of basal ERK1/2 phosphorylation, inhibition of this enzyme with the MEK inhibitor PD98059 demonstrated that ERK1/2 did not participate in OHB-induced insulin resistance. In conclusion, ketone bodies promote insulin resistance probably through decreased activation of the PI3-K/PKB signaling cascade. Furthermore, vanadate can bypass insulin resistance and stimulate glucose uptake in OHB-treated cardiomyocytes.
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PMID:Chronic exposure to ketone bodies impairs glucose uptake in adult cardiomyocytes in response to insulin but not vanadate: the role of PI3-K. 1696 Jun 57

Two H7721 human hepatocarcinoma cell lines showing moderate and high expression of alpha1,3-fucosyltransferase (FucT)-VII cDNA were established and designated FucTVII-M and FucTVII-H, respectively. In alpha1,3-FucT-VII-transfected cells, expression of insulin receptor (InR) alpha- and beta subunits and epidermal growth factor receptor (EGFR) on the cell surface and in cells, as well as the sialyl Lewis X (SLe(x), the product of alpha1,3-FucT-VII) content of the EGFR were unchanged. However the level of SLe(x) on the InR alpha subunit (InR-alpha) was increased dramatically. Tyrosine autophosphorylation of InR-beta , but not EGFR, was elevated. Concomitantly, tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), Ser/Thr phosphorylation of protein kinase B (PKB; Akt), p42/44 mitogen-activated protein kinase (MAPK), MAPK kinase (MEK), and the protein of some other signaling molecules, such as phosphoinositide-dependent kinase-1 (PDK-1), novel protein kinase (PKN), c-Raf-1 and beta-catenin were also upregulated. The activities of PKB and transcription factor TCF were concomitantly stimulated. Upregulation of InR signaling molecules and their phosphorylation was correlated with the level of SLe(x) on InR-alpha and alpha1,3-FucT-VII expression in cells. In addition, the phosphorylation intensity and difference in phosphorylation intensity between cells with different levels of alpha1,3-FucT-VII expression were attenuated significantly by the inhibitor of InR tyrosine kinase and by the mAb to SLe(x). Furthermore, insulin-induced signaling was facilitated in alpha1,3-FucT-VII-transfected cells, particularly FucTVII-H. These findings provide strong evidence that alpha1,3-FucT-VII may affect insulin signaling by upregulating the phosphorylation and expression of some signaling molecules involved in the InR-signaling pathway. These effects are likely mediated by its product, SLe(x), on the glycans of the InR. This is the first study to report that changes in the terminal structure of glycans on a surface receptor can modify cell signaling.
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PMID:Alpha 1,3-fucosyltransferase-VII regulates the signaling molecules of the insulin receptor pathway. 1722 54

Obesity and insulin resistance are independent risk factors for metabolic syndrome, diabetes, and cardiovascular disease. Adipose tissue samples from nonobese (NO), insulin-sensitive obese (ISO), and insulin-resistant obese (IRO) subjects from subcutaneous (SC) and omental (OM) adipose tissue (n = 28) were analyzed by microarray and confirmed by real-time PCR. Insulin signaling gene expression changes were greater in OM than in SC tissue and were related to insulin resistance rather than to obesity; few genes correlated with body mass index. Insulin receptor and insulin receptor substrate 1 (IRS-1) increased in the IRO versus pooled insulin-sensitive (NO+ISO) subjects. In glucose transport, PI3Kalpha and PDK2 decreased in IRO subjects, whereas PI3Kgamma, Akt2, GLUT4, and GLUT1 increased. IRS-1 regulators Jnk and IKK increased in IRO (P < 0.01 and P < 0.001 respectively). In protein synthesis, most genes examined were downregulated in IRO subjects, including mTor, Rheb, and 4EBP and eIF members (all P < 0.05). In proliferation, SHC, SOS, and Raf1 (P < 0.05) were increased, whereas Ras and MEK1/2 kinase 1 (P < 0.05) were decreased, in IRO subjects. Finally, in differentiation, PPARgamma, CEBPalpha, and CEBPbeta decreased, whereas PPARdelta, CEBPgamma, and CEBPepsilon increased, in IRO subjects (P < 0.05). Together, microarray and real-time PCR data demonstrate that insulin resistance rather than obesity is associated with altered gene expression of insulin signaling genes, especially in OM adipose tissue.
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PMID:Influence of obesity and insulin sensitivity on insulin signaling genes in human omental and subcutaneous adipose tissue. 1798 14

Recent genetic studies have documented a pivotal growth-regulatory role played by the Cullin 7 (CUL7) E3 ubiquitin ligase complex containing the Fbw8-substrate-targeting subunit, Skp1, and the ROC1 RING finger protein. In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities. Interestingly, while embryonic fibroblasts of Cul7-/- mice were found to accumulate IRS-1 and exhibit increased activation of IRS-1's downstream Akt and MEK/ERK pathways, these null cells grew poorly and displayed phenotypes reminiscent of those associated with oncogene-induced senescence. Taken together, our findings demonstrate a key role for the CUL7 E3 in targeting IRS-1 for degradation, a process that may contribute to the regulation of cellular senescence.
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PMID:The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation. 1849 45


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