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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

The leptin receptor (LEPR) is a class I cytokine receptor signalling via both the janus kinase/signal transducer and activator of transcription (JAK/STAT) and the MAP kinase pathways. In addition, leptin has been shown previously to activate AMP-activated kinase (AMPK) in skeletal muscle. To enable a detailed analysis of leptin signalling in pancreatic beta cells, LEPR point mutants with single or combined exchanges of the three intracellular tyrosines were expressed in HIT-T15 insulinoma cells. Western blots with activation state-specific antibodies recognizing specific signalling molecules revealed that the wild-type receptor activated STAT1, STAT3, STAT5 and ERK1/2 but failed to alter the phosphorylation of AMPK. Each of the three intracellular tyrosine residues in LEPR exhibited different signalling capacities: Tyr985 was necessary and sufficient for leptin-induced activation of ERK1/2; Tyr1077 induced tyrosyl phosphorylation of STAT5; and Tyr1138 was capable of activating STAT1, STAT3 and STAT5. Consistent results were obtained in reporter gene assays with STAT3 or STAT5-responsive promoter constructs, respectively. Furthermore, the sequence motifs surrounding the three tyrosine residues are conserved in LEPR from mammals, birds and in a LEPR-like cytokine receptor from pufferfish. Mutational analysis of the box3 motif around Tyr1138 identified Met1139 and Gln1141 as important determinants that define specificity towards the different STAT factors. These data indicate that all three conserved tyrosines are involved in LEPR function and define the pleiotropy of signal transduction via STAT1/3, STAT5 or ERK kinases. Activation and inhibition of AMPK appears to require additional components of the signalling pathways that are not present in beta cells.
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PMID:Pleiotropy of leptin receptor signalling is defined by distinct roles of the intracellular tyrosines. 1563 36

Leptin is now recognized as a proinflammatory cytokine and thought to be a progressive factor for non-alcoholic steatohepatitis (NASH). Here we showed the effects of leptin on the production of TNF-alpha (tumor necrosis factor-alpha) by Kupffer cells (KCs) with signal transduction. Leptin enhanced TNF-alpha production accompanied by a dose-dependent increase of MAPK activity in lipopolysaccharide (LPS)-stimulated KCs. SB203580 and JNK inhibitor I, specific inhibitors of P38 and JNK, inhibited TNF-alpha production in KCs but PD98059, an inhibitor of the ERK pathway, did not affect TNF-alpha production by KCs. Recombinant constitutively active adenovirus (Ad)-MKK6 and-MKK7 increased TNF-alpha production in KCs with activation of P38 and JNK without any change by Ad-MEK1 delivery. On the other hand, KCs isolated from the Zucker rat (fa/fa), a leptin receptor-deficient rat, showed reduced production of TNF-alpha on stimulation with LPS. The delivery of Ad-MKK6 and-MKK7, but not Ad-MEK1, increased TNF-alpha production in KCs of Zucker rats with activation of P38 and JNK. Addition of leptin to normal rats increased LPS-induced hepatic TNF-alpha production in vivo and leptin receptor-deficient Zucker rats showed reduced hepatic TNF-alpha production on addition of LPS in vivo. These findings indicate that P38 and JNK pathways are involved in the signal transduction of leptin enhancement of LPS-induced TNF-alpha production.
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PMID:Leptin enhances TNF-alpha production via p38 and JNK MAPK in LPS-stimulated Kupffer cells. 1597 53

We found leptin to be strongly expressed in undifferentiated human myoblasts derived from biopsies of the thigh (Musculus vastus lateralis). Both mRNA expression and secretion of leptin were reduced during in vitro differentiation into primary myotubes. However, the expression of the leptin receptor (OB-Rb) mRNA, was unchanged during differentiation of the muscle cells. Administration of recombinant leptin had no effect on leptin, myogenin, myoD, or GLUT4 mRNA expressions during the period of cellular differentiation. A functional leptin receptor was demonstrated by an acute leptin-induced 1.5-fold increase in ERK activity (P = 0.029). Although mRNA expression of regulation of suppressor of cytokine signaling-3 (SOCS-3) mRNA expression was unaltered, leptin significantly stimulated fatty acid oxidation after 6 h measured as acid soluble metabolites (ASM). Palmitic acid (PA), oleic acid (OA), and eicosapentaenoic acid (EPA), known to modulate leptin expression in other tissues, had no effect on mRNA expression or secretion of leptin from human myotubes. In conclusion, we demonstrate that leptin is highly expressed in undifferentiated human myoblasts and the expression is reduced during differentiation to mature myotubes. The role of leptin in these cells needs to be further characterized.
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PMID:Leptin expression in human primary skeletal muscle cells is reduced during differentiation. 1605 73

Various cardiovascular pathologies are associated with vascular smooth muscle cell (VSMC) hypertrophy and elevated plasma leptin levels. We used the rat portal vein (RPV) cultured for three days to investigate the effect of mechanical stretch on autocrine secretion of leptin and the effect of exogenous leptin (3.1 nM) on VSMC. Stretching the RPV significantly up-regulated leptin production by greater than 100-fold and leptin receptor expression by up to 10-fold. In addition, stretch increased tissue weight by 23 +/- 1.3 and 30 +/- 1% (P < 0.05), respectively, in the absence or presence of leptin, although this was significantly attenuated by an antileptin antibody (166 ng/ml). Unstretched RPV weight decreased by 7.5 +/- 1.8% in the absence of leptin, whereas in the presence of leptin, weight increased by 6.5 +/- 1.8% (P < 0.05). VSMC size and [3H]leucine incorporation rates were significantly increased by leptin in stretched and unstretched tissues. Leptin-induced hypertrophy was associated with significant extracellular signal-regulated kinase (ERK1/2) activation as well as increased expression of angiotensinogen, the angiotensin type 1 receptor as well as preproendothelin-1, and the endothelin type A receptor, whereas ERK inhibition or inhibition of either the angiotensin II or endothelin-1 systems at both the synthesis and receptor levels blocked the hypertrophic response. The effects of leptin were also completely blocked by the cholesterol-chelating agent methyl-beta-cyclodextrin. Therefore, our study demonstrates stretch-dependent leptin release and a direct hypertrophic effect of leptin on RPV, the latter likely dependent on intact cholesterol-rich membrane microdomains and locally produced paracrine factors.
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PMID:Leptin induces vascular smooth muscle cell hypertrophy through angiotensin II- and endothelin-1-dependent mechanisms and mediates stretch-induced hypertrophy. 1614 73

Obesity is considered a risk factor for many cancers, including breast cancer. Our laboratory has previously shown that leptin is mitogenic in many cancer cell lines, including breast. Information regarding the effects of high leptin levels on leptin receptor expression and signaling is lacking. The purpose of this study was to characterize leptin receptor expression in response to leptin in breast cancer cells. In addition, SOCS-3 expression (a leptin inducible inhibitor of leptin signaling), plus MAPK and PI3K signaling, were examined to determine their role in leptin-induced cell proliferation. Breast cancer cell lines, ZR75-1 and HTB-26, were treated with 0, 4, 40 or 80 ng/ml of leptin. Multiplex RT-PCR was performed to determine relative mRNA expression levels of the human short (huOB-Ra) or long (huOB-Rb) leptin receptor isoforms, or SOCS-3. MAPK and PI3K signaling was analyzed by phosphorylation of ERK and Akt, respectively, via Western blotting. Cell proliferation and inhibitor studies were analyzed by MTT assay. HTB-26 and ZR75-1 both expressed huOB-Ra, huOB-Rb and SOCS-3 mRNA; however, mRNA expression levels generally remained unchanged over time with leptin treatment. MAPK and PI3K pathways were activated in the presence of leptin over time. MAPK and PI3K inhibitors significantly blocked leptin-induced proliferation. Higher levels of circulating leptin contribute to breast cancer proliferation by activation of the MAPK and PI3K signaling pathways involved in cell growth and survival. The mitogenic effects of leptin are not a consequence of altered leptin receptor or SOCS-3 mRNA expression.
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PMID:Leptin receptor expression and cell signaling in breast cancer. 1652 50

Obesity and gastro-oesophageal reflux are the main predisposing factors for oesophageal adenocarcinoma. We have examined the effects of transient acid exposure and leptin on OE33 oesophageal adenocarcinoma cells. Leptin and acid individually stimulated proliferation and inhibited apoptosis and the combination was synergistic. Leptin receptor protein levels were unchanged by acid exposure. The COX-2 inhibitor NS 398 blocked the effects of acid and leptin but while both acid and leptin individually significantly increased PGE2 production and COX-2 mRNA levels, the combination was not more effective than either stimulant alone. Leptin synergistically enhanced acid-stimulated EGFR and ERK phosphorylation but did not further increase JNK or p38 MAP kinase phosphorylation. Specific EGFR and ERK inhibitors reduced the effects of leptin and acid alone and in combination. The combination of increased circulating leptin levels in obesity and transient reflux of gastric acid may promote oesophageal carcinogenesis by increasing proliferation and inhibiting apoptosis.
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PMID:Leptin synergistically enhances the anti-apoptotic and growth-promoting effects of acid in OE33 oesophageal adenocarcinoma cells in culture. 1761 45


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