Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance is a defining feature of type 2 diabetes and the metabolic syndrome. While the molecular mechanisms of insulin resistance are multiple, recent evidence suggests that attenuation of insulin signaling by c-Jun N-terminal kinase (JNK) may be a central part of the pathobiology of insulin resistance. Here we demonstrate that the p85alpha regulatory subunit of phosphoinositide 3-kinase (PI3K), a key mediator of insulin's metabolic actions, is also required for the activation of JNK in states of insulin resistance, including high-fat diet-induced obesity and JNK1 overexpression. The requirement of the p85alpha regulatory subunit for JNK occurs independently of its role as a component of the PI3K heterodimer and occurs only in response to specific stimuli, namely, insulin and tunicamycin, a chemical that induces endoplasmic reticulum stress. We further show that insulin and p85 activate JNK by via cdc42 and MKK4. The activation of this cdc42/JNK pathway requires both an intact N terminus and functional SH2 domains within the C terminus of the p85alpha regulatory subunit. Thus, p85alpha plays a dual role in regulating insulin sensitivity and may mediate cross talk between the PI3K and stress kinase pathways.
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PMID:The p85alpha regulatory subunit of phosphoinositide 3-kinase potentiates c-Jun N-terminal kinase-mediated insulin resistance. 1728 57

The present article shows that a short-term exposure of purified human neutrophils to recombinant insulin conferred on these cells both the ability to migrate and the capacity to mobilize [Ca2+]i in response to CCL3, a chemokine per se ineffective with native neutrophils. Furthermore, the effects of recombinant insulin were reproduced by short-term incubation with sera from adult patients with metabolic syndrome, known to be characterized by a hyperinsulinemic state. A strict linear correlation (P<0.01) between sera insulin levels and sera's ability to induce neutrophil locomotion was indeed found. Our data also suggest that (i) insulin primed neutrophils for migration to CCL3 via the selective activation of JNK 1/2, as shown by the use of inhibitors and kinase activation assay; (ii) the activation of Src kinases was necessary but not sufficient for CCL3-induced locomotory activity; (iii) PI3K-Akt, ERK 1/2, and p38 MAPK were not involved in insulin-induced migratory competence. In summary, we provided evidence that the exposition of neutrophils to insulin, as it occurs in hyperinsulinemic conditions, confers the competence of the cells to migrate in response to CCL3, known to be generated near atherosclerotic plaques. As neutrophils have been recently suggested to be involved in breaking unstable atherosclerotic plaques, the present findings contribute to the understanding of the pathophysiology of plaque instability. Finally, biochemical analysis herein carried out raises the hypothesis of JNK 1/2 as an attractive therapeutic target.
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PMID:Insulin primes human neutrophils for CCL3-induced migration: crucial role for JNK 1/2. 1738 84

Uric acid is considered a major antioxidant in human blood that may protect against aging and oxidative stress. Despite its proposed protective properties, elevated levels of uric acid are commonly associated with increased risk for cardiovascular disease and mortality. Furthermore, recent experimental studies suggest that uric acid may have a causal role in hypertension and metabolic syndrome. All these conditions are thought to be mediated by oxidative stress. In this study we demonstrate that differentiation of cultured mouse adipocytes is associated with increased production of reactive oxygen species (ROS) and uptake of uric acid. Soluble uric acid stimulated an increase in NADPH oxidase activity and ROS production in mature adipocytes but not in preadipocytes. The stimulation of NADPH oxidase-dependent ROS by uric acid resulted in activation of MAP kinases p38 and ERK1/2, a decrease in nitric oxide bioavailability, and an increase in protein nitrosylation and lipid oxidation. Collectively, our results suggest that hyperuricemia induces redox-dependent signaling and oxidative stress in adipocytes. Since oxidative stress in the adipose tissue has recently been recognized as a major cause of insulin resistance and cardiovascular disease, hyperuricemia-induced alterations in oxidative homeostasis in the adipose tissue might play an important role in these derangements.
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PMID:Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. 1742 37

Genetic factors, Helicobacter pylori infection, salt over-uptake, decreased vegetable/fruit consumption, smoking, and metabolic syndrome are risk factors of human gastric cancer. Germline mutations of CDH1 gene, and SNPs of PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 and RUNX3 genes are associated with gastric cancer. Helicobacter pylori activates CagA-SHP2-ERK and peptidoglycan-NOD1-NFkappaB signaling cascades in gastric epithelial cells using type IV secretion system, and also TRAF6-MAP3K7-NFkappaB and TRAF6-MAP3K7-AP-1 signaling cascades in epithelial and immune cells through lipopolysaccharide recognition by TLR2 or TLR4. IL-1beta, IL-6, IL-8, TNFalpha and IFNgamma are elevated in gastric mucosa with Helicobacter pylori infection. IL-6 and TNFalpha induce upregulation of WNT5A and WNT10B, respectively. WNT signals are transduced to beta-catenin-TCF/LEF, RhoA, JNK, PKC, NFAT, and NLK signaling cascades. WNT-beta-catenin-TCF/LEF signaling induces upregulation of MYC, CCND1, WISP1, FGF20, JAG1 and DKK1 genes. Notch signals are transduced to CSL-NICD-MAML and NFkappaB signaling cascades. FGF signals are transduced to ERK, PI3K-AKT, PKC, and NFAT signaling cascades. Helicobacter pylori infection induces SHH upregulation in parietal cell lineage, while BMP signals induce IHH upregulation in pit cell lineage. Hedgehog signals induce upregulation of GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1 genes. JAG1 and JAG2 activate Notch signaling, while DKK1 and SFRP1 inhibit WNT signaling. Stem cell signaling network, consisting of WNT, Notch, FGF, Hedgehog and BMP signaling pathways, is activated during chronic Helicobacter pylori infection. Epigenetic silencing of SFRP1 gene occurs in the earlier stage of carcinogenesis in the stomach, while amplification and overexpression of FGFR2 gene in the later stage. Dysregulation of the stem cell signaling network due to the accumulation of germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration gives rise to gastric cancer. SNP typing and custom-made microarray analyses on genes encoding stem cell signaling molecules could be utilized for the personalized medicine.
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PMID:Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. 1756 83

Saturated free fatty acid (FFA) is a major source of metabolic stress that activates the c-Jun NH(2)-terminal kinase (JNK). This FFA-stimulated JNK pathway is relevant to hallmarks of metabolic syndrome, including insulin resistance. Here we used gene ablation studies in mice to demonstrate a central role for mixed-lineage protein kinases (MLK) in this signaling pathway. Saturated FFA causes protein kinase C (PKC)-dependent activation of MLK3 that subsequently causes increased JNK activity by a mechanism that requires the MAP kinase kinases MKK4 and MKK7. Loss of PKC, MLK3, MKK4, or MKK7 expression prevents FFA-stimulated JNK activation. Together, these data establish a signaling pathway that mediates effects of metabolic stress on insulin resistance.
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PMID:Metabolic stress signaling mediated by mixed-lineage kinases. 1767 97

Aldosterone concentrations are inappropriately high in many patients with hypertension, as well as in an increasing number of individuals with metabolic syndrome and sleep apnoea. A growing body of evidence suggests that aldosterone and/or activation of the MR (mineralocorticoid receptor) contributes to cardiovascular remodelling and renal injury in these conditions. In addition to causing sodium retention and increased blood pressure, MR activation induces oxidative stress, endothelial dysfunction, inflammation and subsequent fibrosis. The MR may be activated by aldosterone and cortisol or via transactivation by the AT(1) (angiotenin II type 1) receptor through a mechanism involving the EGFR (epidermal growth factor receptor) and MAPK (mitogen-activated protein kinase) pathway. In addition, aldosterone can generate rapid non-genomic effects in the heart and vasculature. MR antagonism reduces mortality in patients with CHF (congestive heart failure) and following myocardial infarction. MR antagonism improves endothelial function in patients with CHF, reduces circulating biomarkers of cardiac fibrosis in CHF or following myocardial infarction, reduces blood pressure in resistant hypertension and decreases albuminuria in hypertensive and diabetic patients. In contrast, whereas adrenalectomy improves glucose homoeostasis in hyperaldosteronism, MR antagonism may worsen glucose homoeostasis and impairs endothelial function in diabetes, suggesting a possible detrimental effect of aldosterone via non-genomic pathways.
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PMID:Aldosterone and end-organ damage. 1768 82

Certain selective serotonin reuptake inhibitors (SSRIs) induce the clinical and biochemical manifestations of a metabolic syndrome by as yet unknown mechanism. Here we demonstrate that incubation (1 h) of rat hepatoma Fao cells with the SSRIs paroxetine and sertraline, but not with the atypical antipsychotic drug olanzapine, inhibited the insulin-stimulated Tyr phosphorylation of the insulin receptor substrate-1 (IRS-1) with half-maximal effects at approximately 10 microM. This inhibition correlated with a rapid phosphorylation and activation of a number of Ser/Thr IRS-1 kinases including JNK, S6K1, ERK and p38 MAPK, but not PKB (Akt). JNK appears as a key player activated by SSRIs because specific JNK inhibitors partially eliminated the effects of these drugs. The SSRIs induced the phosphorylation of IRS-1 on S307 and S408, which inhibits IRS-1 function and insulin signaling. These results implicate selected SSRIs as inhibitors of insulin signaling and as potential inducers of cellular insulin resistance.
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PMID:Antidepressants induce cellular insulin resistance by activation of IRS-1 kinases. 1772 40

Rats artificially selected as low capacity runners (LCR) exhibit features of the metabolic syndrome, and blunted exercise training-induced cardiac hypertrophy compared with high capacity runners (HCR). We tested the hypothesis that the divergent cardiac phenotypes may be due to diminished activation of signaling proteins in LCR vs HCR rats. LCR (n=18) and HCR (n=18) rats were randomly assigned to acute exercise or control groups. Ten minutes after a 10-min bout of high intensity treadmill exercise, rats were euthanized, and left ventricles (LV) were harvested. LV homogenates were immunoblotted for phosphorylated and total levels of extracellular regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38, Akt, S6, and the ribosomal S6 protein kinases S6K and p90RSK. Alterations in protein ubiquitination were examined as an index of protein turnover. In LCR and HCR rats, S6 was activated to a similar extent after exercise (5-fold vs control), as were JNK1/2, p38, and ERK1/2 (each 1.5-fold). Exercise significantly reduced ubiquitination of some proteins, suggesting diminished post-exercise protein degradation. That no significant LCR/HCR differences were observed 10-min post-exercise in the signaling pathways studied herein suggests that the source of the differing cardiac phenotypes in LCR/HCR rats may involve differing activation times and/or other signaling pathways.
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PMID:Initial signaling response to acute exercise bout is similar in hearts of rats bred for divergent exercise capacities. 1798 52

An inverse correlation between the pro-inflammatory cytokine interleukin-18 and the anti-atherogenic adipokine adiponectin has been reported in the chronic pathological conditions obesity, insulin resistance, coronary artery disease, and metabolic syndrome. We investigated whether this relationship is coincidental or has a causal basis. Here we show that interleukin-18 (IL-18) suppresses adiponectin transcription, mRNA expression, and secretion by 3T3-L1 adipocytes. IL-18 suppresses adiponectin promoter-reporter activity, an effect reversed by deletion or mutation of the NFATc4 core DNA-binding site. IL-18 induces NFATc4 phosphorylation (Ser(676)), nuclear translocation, and in vivo DNA binding. IL-18 induces ERK1/2 phosphorylation and enzyme activity, and pretreatment with the MEK inhibitor U0126, ERK1/2 inhibitor PD98059, or small interference RNA targeted to ERK1/2 attenuates ERK1/2 activation and NFATc4 phosphorylation. Finally, inhibition of ERK1/2 or NFATc4 knockdown reverses IL-18-mediated adiponectin suppression. In contrast to its inhibitory effects on adiponectin expression, IL-18 potently stimulates PAI-1 secretion. These data demonstrate for the first time that IL-18 selectively suppresses adiponectin expression via ERK1/2-dependent NFATc4 activation and suggest that the inverse relationship observed between IL-18 and adiponectin in various chronic pathological conditions is causally related. Thus, targeting IL-18 expression may enhance adiponectin expression and mitigate disease progression.
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PMID:Interleukin-18 suppresses adiponectin expression in 3T3-L1 adipocytes via a novel signal transduction pathway involving ERK1/2-dependent NFATc4 phosphorylation. 1808 72

Macrophage death in advanced atherosclerosis causes plaque necrosis, which promotes plaque rupture and acute atherothrombotic vascular events. Of interest, plaque necrosis and atherothrombotic disease are markedly increased in diabetes and metabolic syndrome. We discovered a novel 'multi-hit' macrophage apoptosis pathway that appears to be highly relevant to advanced atherosclerosis. The elements of the pathway include: (a) activation of the unfolded protein response (UPR) by cholesterol overloading of the endoplasmic reticulum or by other UPR activators known to exist in atheromata; and (b) pro-apoptotic signalling involving the type A scavenger receptor (SRA). The downstream apoptosis effectors include CHOP (GADD153) for the UPR and JNK for SRA signalling. Remarkably, components of this pathway are enhanced in macrophages with defective insulin signalling, including UPR activation and SRA expression. As a result, insulin-resistant macrophages show increased susceptibility to apoptosis when exposed to UPR activators and SRA ligands. Moreover, the advanced lesions of atherosclerosis-prone mice reconstituted with insulin-resistant macrophages show increased macrophage apoptosis and plaque necrosis. Based on these findings, we propose that one mechanism of increased plaque necrosis and atherothrombotic vascular disease in insulin resistant syndromes is up-regulation of a two-hit signal transduction pathway involved in advanced lesional macrophage death.
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PMID:The impact of insulin resistance on macrophage death pathways in advanced atherosclerosis. 1826 77


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