Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin is presumed to be related to body mass index (BMI) and body fat stores and is involved together with neuropeptid Y (NPY) in the regulation of appetite. As pregnancy is accompanied both by changes of BMI and appetite, performance of studies presented in this paper were fully justified. In 43 healthy pregnant women and in 18 pregnant women with mild or moderate EPH-gestosis, concentrations of leptin and NPY were estimated in maternal venous blood, umbilical cord blood and in amniotic fluid. The control group consisted of 26 healthy nonpregnant women. Healthy nonpregnant women showed a BMI of 23.08+/-0.65 kg/m2 which was significantly lower than in healthy pregnant women (26.9+/-0.4 kg/m2, p < 0.001) and in women with EPH-gestosis (29.7+/-0.9, p < 0.0001). Also in healthy pregnant women the BMI was significantly lower than in EPH-gestosis subjects (p < 0.001). In healthy nonpregnant women plasma leptin levels were significantly lower than in healthy pregnant and EPH-gestosis women (10.9+/-1.68 vs 14.99+/-1.28 vs 21.89+/-2.58 ng/ml, respectively). In umbilical cord blood plasma leptin levels were significantly lower than in maternal blood only in healthy pregnant women (7.37+/-0.69 vs 14.99+/-1.28 ng/ml) but not in EPH-gestosis subjects (18.06+/-3.38 vs 21.89+/-2.58 ng/ml). Leptin levels in amniotic fluid were significantly lower than in umbilical cord blood both in healthy pregnant women (2.25+/-0.20 vs 7.37+/-0.69 ng/ml) and EPH-gestosis women (6.58+/-2.62 vs 18.06+/-3.38 ng/ml). In EPH-gestosis women leptin levels were significantly higher than in healthy pregnant women in maternal blood (21.89+/-2.58 vs 14.99+/-1.28 ng/ml), umbilical cord blood (18.06+/-3.38 vs 7.37+/-0.69 ng/ml) and amniotic fluid (6.58+/-2.62 vs 2.25+/-0.2 ng/ml). In both examined pregnant groups plasma NPY levels were nonsignificantly lower in healthy pregnant and EPH-gestosis women (42.28+/-4.09 and 43.68+/-8.45 pg/ml, respectively) than in nonpregnant women 50.65+/-6.13 pg/ml). In normal pregnancy a significantly higher NPY level was found in umbilical cord blood as compared with respective values in EPH-gestosis women (116.28+/-17.0 vs 49.65+/-7.01 pg/ml). Finally in both examined groups of pregnant women the amniotic fluid NPY level was of similar magnitude (13.85+/-1.52 and 13.89+/-2.46 pg/ml in healthy pregnant and EPH-gestosis women respectively). No significant correlation was found between fetal birth weight and cord-serum leptin and NPY levels respectively.
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PMID:Concentrations of leptin and neuropeptide Y in maternal plasma, umbilical cord blood and in amniotic fluid in pregnant women with EPH-gestosis. 983 71

The adipocyte-derived hormone leptin signals the status of body energy stores by activating the long form of the leptin receptor (LRb). Activation of LRb results in the activation of the associated Jak2 tyrosine kinase and the transmission of downstream phosphotyrosine-dependent signals. We have investigated the signaling function of mutant LRb intracellular domains under the control of the extracellular erythropoietin (Epo) receptor. By using this system, we confirm that two tyrosine residues in the intracellular domain of murine LRb become phosphorylated to mediate LRb signaling; Tyr(985) controls the tyrosine phosphorylation of SHP-2, and Tyr(1138) controls STAT3 activation. We furthermore investigated the mechanisms by which LRb controls downstream ERK activation and c-fos and SOCS3 message accumulation. Tyr(985)-mediated recruitment of SHP-2 does not alter tyrosine phosphorylation of Jak2 or STAT3 but results in GRB-2 binding to tyrosine-phosphorylated SHP-2 and is required for the majority of ERK activation during LRb signaling. Tyr(985) and ERK activation similarly mediate c-fos mRNA accumulation. In contrast, SOCS3 mRNA accumulation requires Tyr(1138)-mediated STAT3 activation. Thus, the two LRb tyrosine residues that are phosphorylated during receptor activation mediate distinct signaling pathways as follows: SHP-2 binding to Tyr(985) positively regulates the ERK --> c-fos pathway, and STAT3 binding to Tyr(1138) mediates the inhibitory SOCS3 pathway.
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PMID:Activation of downstream signals by the long form of the leptin receptor. 1079 42

The fetal environment is now recognized as a key determinant of the adult phenotype, being linked to development of diseases, including hypertension, as well as the timing of puberty. Such links may be related, in part, to the level of fetal exposure to maternal glucocorticoids in utero, which is normally regulated by placental expression of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD). The present study examined whether manipulation of fetal glucocorticoid exposure, either directly or indirectly via 11beta-HSD inhibition, influences the subsequent timing of puberty. Administration of dexamethasone acetate at low (LDEX, 0.25 microg/ml drinking water) or high doses (HDEX, 1 microg/ml) or carbenoxolone (CBX, 2 x 10 mg/day, sc; an inhibitor of 11beta-HSD) to pregnant rats from day 13 to term (day 23) reduced offspring birthweight (LDEX: 9%; HDEX: 27%; CBX: 8%) and resulted in a subsequent delay in the onset of puberty in females (control: 41.4 +/- 0.5; LDEX: 44.8 +/- 0.7; HDEX: 48.5 +/- 0.4; CBX: 43.6 +/- 0.5 days). Importantly, the effects of CBX were not observed in the absence of maternal adrenals, indicating that they were mediated by increased fetal exposure to endogenous maternal glucocorticoids. In contrast, maternal treatment with metyrapone (MET; an inhibitor of glucocorticoid synthesis; 500 microg/ml drinking water from day 13) increased birthweight by 5% and advanced puberty onset in male offspring (control: 48.8 +/- 1.0; MET: 45.7 +/- 0.8 days). Changes in the timing of puberty onset were not attributable to changes in either bodyweight at puberty or peripubertal plasma leptin concentrations. Peripubertal plasma LH was also unaffected in animals with delayed puberty but was elevated in male offspring of MET-treated mothers. Collectively, these results demonstrate that fetal glucocorticoid exposure is an important determinant of the timing of puberty onset in postnatal life, and that this effect is operable within the normal physiological range of glucocorticoid concentrations.
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PMID:Increased fetal glucocorticoid exposure delays puberty onset in postnatal life. 1087 42

During leptin signaling, each of the phosphorylated tyrosine residues on the long form of the leptin receptor (LRb) mediates distinct signals. Phosphorylated Tyr(1138) binds STAT3 to mediate its tyrosine phosphorylation and transcriptional activation, while phosphorylated Tyr(985) binds the tyrosine phosphatase SHP-2 and reportedly mediates both activation of ERK kinases and inhibition of LRb-mediated STAT3 activation. We show here that although mutation of Tyr(985) does not alter STAT3 signaling by erythropoietin receptor-LRb (ELR) chimeras in transfected 293 cells at short times of stimulation, this mutation enhances STAT3 signaling at longer times of stimulation (>6 h). These data suggest that Tyr(985) may mediate feedback inhibition of LRb signaling by an LRb-induced LRb inhibitor, such as SOCS3. Indeed, SOCS3 binds specifically to phosphorylated Tyr(985) of LRb, and SOCS3 fails to inhibit transcription by ELR following mutation of Tyr(985), suggesting that SOCS3 inhibits LRb signaling by binding to phosphorylated Tyr(985). Additionally, overexpression of SOCS3, but not SHP-2, impairs ELR signaling, and the overexpression of SHP-2 blunts SOCS3-mediated inhibition of ELR signaling. Thus, our data suggest that in addition to mediating SHP-2 binding and ERK activation during acute stimulation, Tyr(985) of LRb mediates feedback inhibition of LRb signaling by binding to LRb-induced SOCS3.
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PMID:SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. 1101 44

The protein tyrosine phosphatase SHP-2 has been proposed to serve as a regulator of leptin signaling, but its specific roles are not fully examined. To directly investigate the role of SHP-2, we employed dominant negative strategies in transfected cells. We show that a catalytically inactive mutant of SHP-2 blocks leptin-stimulated ERK phosphorylation by the long leptin receptor, ObRb. SHP-2, lacking two C-terminal tyrosine residues, partially inhibits ERK phosphorylation. We find similar effects of the SHP-2 mutants after examining stimulation of an ERK-dependent egr-1 promoter-construct by leptin. We also demonstrate ERK phosphorylation and egr-1 mRNA expression in the hypothalamus by leptin. Analysis of signaling by ObRb lacking intracellular tyrosine residues or by the short leptin receptor, ObRa, enabled us to conclude that two pathways are critical for ERK activation. One pathway does not require the intracellular domain of ObRb, whereas the other pathway requires tyrosine residue 985 of ObRb. The phosphatase activity of SHP-2 is required for both pathways, whereas activation of ERK via Tyr-985 of ObRb also requires tyrosine phosphorylation of SHP-2. SHP-2 is thus a positive regulator of ERK by leptin receptors, and both the adaptor function and the phosphatase activity of SHP-2 are critical for this regulation.
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PMID:Divergent roles of SHP-2 in ERK activation by leptin receptors. 1108 89

We have previously shown that murine recombinant leptin directly stimulates catecholamine synthesis through the long form of the leptin receptor (Ob-Rb) expressed in cultured porcine chromaffin cells. Additionally, we found that leptin activates IP3 production after PLC activation. It is well established that activation of PLC elicits IP3 production as well as an increase in diacylglycerol, a compound that stimulates PKC. Therefore, we investigated the involvement of PKC in leptin-induced catecholamine synthesis. Leptin was found to induce significant increases in PKC activity in a dose-dependent manner (1, 10, and 100 nM); chelation of extracellular Ca(2+) by EDTA abolished this PKC stimulatory activity. We also confirmed by Western blot analysis that leptin (at 100 nM) induced significant increases in Ca(2+)-dependent PKC alpha, -beta(I), and -gamma expression. The activity of the rate-limiting enzyme tyrosine hydroxylase (TH) in the biosynthesis of catecholamine is regulated at the transcriptional and posttranscriptional levels. TH enzyme activity and TH mRNA levels induced by 100 nM leptin were significantly inhibited by the PKC inhibitor Ro 32-0432 as well as by EDTA. In addition, increases in TH protein and intracellular catecholamine content stimulated by leptin were completely inhibited by Ro 32-0432. Leptin markedly activated ERKs and, to a lesser extent, JNK; these stimulatory effects on ERKs and JNK were completely inhibited by Ro 32-0432 as well as EDTA. In contrast, leptin did not activate P38 MAPK. Similar to leptin, PMA activated ERK and JNK. Nicardipine and omega-conotoxin GVIA, each at 1 microM, were effective at inhibiting leptin-induced TH enzyme activity, TH mRNA accumulation, PKC activity, and ERK activity. Leptin increased activating protein-1 DNA-binding activity, and this was diminished by Ro 32-0432 as well as EDTA, similar to the reduction of TH mRNA levels. In addition, using supershift analysis, we documented the involvement of c-Fos and, to a lesser extent, c-Jun in leptin-induced activating protein-1 activity. These results indicate that leptin stimulates Ca(2+)-dependent PKC isoform-dependent catecholamine synthesis in porcine chromaffin cells. Previously, we had shown that leptin stimulated cAMP. The present study also showed that H89 (a PKA inhibitor) moderately, but significantly, inhibited leptin-induced ERK and TH mRNA. Consistent with this finding, leptin is shown here to activate novel PKC epsilon, which is assumed to stimulate Raf, upstream of ERKs, via cAMP, supporting the suggestion that Ca(2+)-independent novel PKC may also play some physiological role in regulating catecholamine synthesis.
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PMID:Leptin stimulates catecholamine synthesis in a PKC-dependent manner in cultured porcine adrenal medullary chromaffin cells. 1160 54

An ovine-specific RIA, shown to be reliable for bovine leptin determination, was used to study the effects of breed, body fatness, feeding level, and meal intake on plasma leptin level in adult cattle. Eighteen fat Charolais, fat Holstein, and lean Holstein adult cows were either well-fed (130% of maintenance energy requirements [MER]) or underfed (60% of MER) for 3 wk. The breed tended to have a small effect on plasma leptin level, which was decreased by 70% (P < 0.05) in lean compared to fat Holstein cows. A strong curvilinear relationship was found between mean adipocyte volume and plasma leptin concentrations in well-fed (r = +0.95) and underfed (r = +0.91) cows. Underfeeding caused a significant decrease in plasma leptin levels from 8.0+/-3.1 to 6.1+/-2.3 ng/mL (P < 0.01). Nine adult Holstein cows initially fed at 130% of MER (control) were underfed to 21% of MER for 7 d, and five of them were refed to 237% of MER for 21 d. Plasma leptin measured 1 h before meal distribution was decreased from 5.9+/-0.4 to 3.8+/-0.2 ng/mL (P < 0.01) by underfeeding and increased to reach 8.8+/-1.0 ng/mL (P < 0.01) after refeeding. It was positively related to plasma glucose (r = +0.52, P < 0.01) and negatively related to plasma NEFA (r = -0.67, P < 0.001). Plasma leptin measured 4 h after meal distribution was positively related to feeding level and to plasma 3-OH-butyrate (r = +0.61, P < 0.005) and negatively related to plasma NEFA (r = -0.56, P < 0.01). Differences between pre- and postprandial leptin concentrations showed a decrease after meal intake in control and well-fed cows (-7 and -19%, P < 0.01, respectively) and an increase in underfed cows (+12%, P < 0.01). Leptin response to meal intake was positively related to glucose response (r = +0.66, P < 0.001) and negatively related to 3-OH-butyrate response (r = -0.78, P < 0.001). By using the "multispecies" commercial RIA, leptin concentrations were lower and we observed similar physiological responses, although less related to other hormones or metabolites. These data provide evidence, first, that a specific RIA for ruminant leptin determination is necessary to better understand leptin regulation, and second, that plasma leptin is strongly related to adipose cell size and positively related to feeding level in adult cattle, and that an effect of meal intake could be mediated by glucose and(or) ketone bodies.
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PMID:Plasma leptin concentration in adult cattle: effects of breed, adiposity, feeding level, and meal intake. 1201 21

Energy homeostasis is regulated by peripheral signals, such as leptin, and by several orexigenic and anorectic neuropeptides. Recently, we reported that the orexigenic neuropeptide melanin-concentrating hormone (MCH) stimulates leptin production by rat adipocytes and that the MCH receptor (MCH-R1) is present on these cells. Here, we show that MCH-R1 is present on murine 3T3-L1 adipocytes. Treatment of 3T3-L1 adipocytes with 1 micromolar MCH for up to 2 h acutely downregulated MCH-R1, indicating a mechanism of ligand-induced receptor downregulation. Potential signaling pathways mediating MCH-R1 action in adipocytes were investigated. Treatment of 3T3-L1 adipocytes with 1 micromolar MCH rapidly induced a threefold and a fivefold increase in p44/42 MAPK and pp70 S6 kinase activities, respectively. In addition, 3T3-L1 adipocytes transiently transfected with a murine leptin-luciferase promoter construct showed a fourfold and a sixfold increase in leptin promoter-reporter gene expression at 1 h and 4 h, respectively, in response to MCH. Activity decreased to basal levels at 8 h. Furthermore, MCH-stimulated leptin promoter-driven luciferase activity was diminished in the presence of the MAP/ERK kinase inhibitor PD-98059 and in the presence of rapamycin, an inhibitor of pp70 S6 kinase activation. These results provide further evidence for a functional MCH signaling pathway in adipocytes.
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PMID:Melanin-concentrating hormone activates signaling pathways in 3T3-L1 adipocytes. 1216 53

Migration of endothelial cells (EC) is a key event in angiogenesis that contributes to neovascularization in diabetic vasculopathy. Leptin induces angiogenesis and is elevated in obesity and hyperinsulinemia. The antidiabetic thiazolidinediones (TZD) inhibit leptin gene expression and vascular smooth muscle cell migration through activation of the peroxisome proliferator-activated receptor-gamma (PPARgamma). This study investigates the role of leptin in EC migration, the chemotactic signaling pathways involved, and the effects of the TZD-PPARgamma ligands troglitazone (TRO) and ciglitazone (CIG) on EC migration. We demonstrate that leptin induces EC migration. Because activation of two signaling pathways, the phosphatidylinositol-3 kinase (PI3K)-->Akt-->eNOS and the ERK1/2 MAPK pathway, is known to be involved in cell migration, we used the pharmacological inhibitors wortmannin and PD98059 to determine if chemotactic signaling by leptin involves Akt or ERK1/2, respectively. Both wortmannin and PD98059 significantly inhibited leptin-induced migration. Treatment with the TZD-PPARgamma-ligands TRO and CIG significantly inhibited the chemotactic response toward leptin. Both PPARgamma-ligands inhibited leptin-stimulated Akt and eNOS phosphorylation, but neither attenuated ERK 1/2 activation in response to leptin. The inhibition of Akt-phosphorylation was accompanied by a PPARgamma-ligand-mediated upregulation of PTEN, a phosphatase that functions as a negative regulator of PI3K-->Akt signaling. These experiments provide the first evidence that activation of Akt and ERK 1/2 are crucial events in leptin-mediated signal transduction leading to EC migration. Moreover, inhibition of leptin-directed migration by the PPARgamma-ligands TRO and CIG through inhibition of Akt underscores their potential in the prevention of diabetes-associated complications.
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PMID:Leptin induces endothelial cell migration through Akt, which is inhibited by PPARgamma-ligands. 1241 72

We previously established that the trefoil peptides (TFFs) pS2, spasmolytic polypeptide, and intestinal trefoil factor are involved in cellular scattering and invasion in kidney and colonic cancer cells. Using the chorioallantoic membrane (CAM) assay and the formation of tube-like structures by human umbilical vein endothelial cells (HUVEC) plated on the Matrigel matrix substratum, we report here that TFFs are proangiogenic factors. Angiogenic activity of TFFs is comparable to that induced by vascular endothelial growth factor, leptin, and transforming growth factor-alpha. Stimulation of angiogenesis by pS2 in the CAM assay is blocked by pharmacological inhibitors of cyclooxygenase COX-2 (NS-398) and epidermal growth factor receptor (EGF-R) tyrosine kinase (ZD1839), but is independent of KDR/Flk-1 and thromboxane A2 receptors. In contrast, the morphogenic switch induced by pS2 in HUVEC cells could be inhibited by the specific KDR heptapeptide antagonist ATWLPPR and by inhibitors of COX-2 and EGF-R signaling. These results implicate TFFs in the formation of new blood vessels during normal and pathophysiological processes linked to wound healing, inflammation, and cancer progression in the digestive mucosa and other human solid tumors associated with aberrant expression of TFFs.
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PMID:Trefoil peptides as proangiogenic factors in vivo and in vitro: implication of cyclooxygenase-2 and EGF receptor signaling. 1252 7


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