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)

The alpha(1)-adrenergic agonist phenylephrine (PE) and insulin each stimulate protein synthesis in cardiomyocytes. Activation of protein synthesis by PE is involved in the development of cardiac hypertrophy. One component involved here is p70 S6 kinase 1 (S6K1), which lies downstream of mammalian target of rapamycin, whose regulation is thought to involve phosphatidylinositol 3-kinase and protein kinase B (PKB). S6K2 is a recently identified homolog of S6K1 whose regulation is poorly understood. Here we demonstrate that in adult rat ventricular cardiomyocytes, PE and insulin each activate S6K2, activation being 3.5- and 5-fold above basal, respectively. Rapamycin completely blocked S6K2 activation by either PE or insulin. Three different inhibitors of MEK1/2 abolished PE-induced activation of S6K2 whereas expression of constitutively active MEK1 activated S6K2, without affecting the p38 mitogen-activated protein kinase and JNK pathways, indicating that MEK/ERK signaling plays a key role in regulation of S6K2 by PE. PE did not activate PKB, and expression of dominant negative PKB failed to block activation of S6K2 by PE, indicating PE-induced S6K2 activation is independent of PKB. However, this PKB mutant did partially block S6K2 activation by insulin, indicating PKB is required here. Another hypertrophic agent, endothelin 1, also activated S6K2 in a MEK-dependent manner. Our findings provide strong evidence for novel signaling connections between MEK/ERK and S6K2.
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PMID:Cross-talk between the ERK and p70 S6 kinase (S6K) signaling pathways. MEK-dependent activation of S6K2 in cardiomyocytes. 1143 69

We recently reported that matrix metalloproteinase 2 (MMP-2, gelatinase A) cleaves big endothelin 1 (ET-1), yielding the vasoactive peptide ET-1[1-32]. We tested whether ET-1[1-32] could affect the adhesion of human neutrophils to coronary artery endothelial cells (HCAEC). ET-1[1-32] rapidly down-regulated the expression of L-selectin and up-regulated expression of CD11b/CD18 on the neutrophil surface, with EC50 values of 1-3 nM. These actions of ET-1[1-32] were mediated via ETA receptors and did not require conversion of ET-1[1-32] into ET-1 by neutrophil proteases, as revealed by liquid chromatography and mass spectroscopy. Moreover, ET-1[1-32] evoked release of neutrophil gelatinase B, which cleaved big ET-1 to yield ET-1[1-32], thus revealing a positive feedback loop for ET-1[1-32] generation. Up-regulation of CD11b/CD18 expression and gelatinase release was tightly associated with activation of extracellular signal-regulated kinase (Erk). Stimulation of Erk activity was due to activation of Ras, Raf-1, and MEK (MAPK kinase). ET-1[1-32] also produced slight increases in the expression of ICAM-1 and E-selectin on HCAEC, and markedly enhanced beta2 integrin-dependent adhesion of neutrophils to activated HCAEC. These results are the first indication that gelatinolytic MMPs via cleavage of big ET-1 to yield ET-1[1-32] activate neutrophils and promote leukocyte-endothelial cell adhesion and, consequently, neutrophil trafficking into inflamed tissues.
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PMID:Matrix metalloproteinases regulate neutrophil-endothelial cell adhesion through generation of endothelin-1[1-32]. 1164 Dec 50

Our previous study demonstrated that endothelin-1 induced a phosphorylation of GATA-4 transcription factor, which plays important roles in cardiac hypertrophy and failure. The goal of the present study was to determine whether protein kinase C (PKC) is involved in the signaling pathway, and, if so, whether alpha-tocopherol inhibits the GATA-4 phosphorylation. Treatment of HL-1 adult mouse cardiac muscle cells with PMA, a known activator of PKC, induced a transient phosphorylation of GATA-4. PMA also phosphorylated MEK and ERK, and PMA-induced GATA-4 phosphorylation was blocked by an MEK inhibitor, PD98059, suggesting that PMA phosphorylates GATA-4 via the MEK-ERK pathway. Treatment of HL-1 cells with 1 microM PMA for 24 h resulted in a downregulation of PKC. In PKC-downregulated cells, PMA- or ET-1-induced GATA-4 phosphorylation was suppressed, suggesting the role of PKC in GATA-4 phosphorylation. However, alpha-tocopherol (5--100 microM) did not inhibit the phosphorylation of GATA-4 or ERK in HL-1 cells. In contrast, alpha-tocopherol potently inhibited the PMA-induced ERK activation in smooth muscle cells. Our studies in HL-1 cells showed that PKC inhibitors, such as calphostin C and chelerythrin, failed to inhibit the PMA signaling. Furthermore, HL-1 cells appear to possess a unique PKC-signaling mechanism as PKC is constitutively phosphorylated and PMA did not cause further phosphorylation. Thus, in HL-1 cardiac muscle cells, PMA activates the MEK-ERK-GATA-4 pathway, apparently via a PKC-independent mechanism.
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PMID:Roles of protein kinase C and alpha-tocopherol in regulation of signal transduction for GATA-4 phosphorylation in HL-1 cardiac muscle cells. 1184 24

We have previously shown that cultured porcine inner medullary collecting duct cells produce endothelin (ET) which suppressed arginine vasopressin (AVP)-induced cyclic adenosine monophosphate (cAMP) generation in an autocrine/paracrine feedback-like fashion. Moreover, hyperosmolality, e.g. induced by sodium chloride and urea, stimulated ET synthesis. Since others showed that hyperosmolality also activates mitogen-activated protein (MAP) kinases and that p38 MAP kinase facilitates cellular influx of betaine to protect the cell from high extracellular solute (urea) concentrations, we were tempted to investigate a potential interaction of MAP kinases with ET production in cultured MDCK cells in response to extracellular hyperosmolality induced by betaine and urea, respectively. Increased extracellular tonicity (602 +/- 8 vs. control of 323 +/- 3 mosmol/kg H(2)O) induced by betaine stimulated ERK and, more strongly, p38 kinase activity at 0.5-2 h of incubation with a rise in ET-1 synthesis to 1,713 +/- 68 vs. 378 +/- 51 fmol/mg protein/24 h under control conditions (p < 0.01). The p38 MAP kinase inhibitor SB203580 suppressed the rise in betaine-induced ET-1 synthesis by 91% to 494 +/- 38 fmol/mg protein/24 h, whereas the MEK/ERK inhibitor U0126 suppressed it moderately by 34%. Hypertonicity induced by urea moderately stimulated ERK but not p38 MAP kinase activity at 0.5-2 h and at 24-48 h and resulted in a modest rise in ET-1 synthesis to 681 +/- 61 fmol/mg protein/24 h (p < 0.05) which was significantly suppressed by U0126 to 484 +/- 16 fmol/mg protein/24 h. These results suggest that a functional interaction between the MAP kinases ERK and p38 MAP kinase and ET-1 synthesis is involved in betaine's protection of MDCK cells in vitro which may represent an in vivo mechanism of protection from hyperosmotic stress induced by high extracellular solute concentrations.
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PMID:Hyperosmolality induced by betaine or urea stimulates endothelin synthesis by differential activation of ERK and p38 MAP kinase in MDCK cells. 1207 86

Endothelins (ET-1, ET-2 and ET-3) are 21-amino acid vasoactive peptides that bind to G-protein-linked transmembrane receptors, ET-RA and ET-RB. As well as modulating vasoconstriction, endothelins regulate growth in several cell types and may also affect differentiation, inflammation and angiogenesis. Both macrophages and endothelins are found in areas of hypoxia in solid tumors and ET-2 expression may be modulated by hypoxia in some tumors. As the peptide structure of mature endothelins is similar to that of CXC chemokines, we asked if endothelins contribute to control of macrophage distribution in tumors. We found that ET-2 is a chemoattractant for macrophages and THP-1 monocytic cells, but not for freshly isolated monocytes. The chemotactic response to ET-2 shows a typical bell-shaped response curve. Experiments with endothelin receptor antagonists showed that migration to ET-2 is mediated via the ET-RB receptor. Moreover, monocytes do not express ET-RB. Chemotaxis towards ET-2 is via the MAPK pathway: p44 and p42 are phosphorylated when THP-1 cells are stimulated with ET-2, and the MAPKK inhibitor PD98059 stops chemotaxis. As with 'classical' chemokines, migration toET-2 is also inhibited by hypoxia and by pertussis toxin. As well as its chemotactic properties, ET-2 leads to activation of macrophages. In human breast tumors that express ET-2, endothelins and ET-RB expressing macrophages often co-localized. While shorter than 'classical' chemokines, ET-2 shares a similar peptide sequence with chemokines and may signal via a similar receptor and MAPK-mediated pathway. Furthermore, ET-2 expression by tumors may modulate the behavior of macrophages such that activated cells accumulate in areas of hypoxia.
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PMID:Endothelin-2 is a macrophage chemoattractant: implications for macrophage distribution in tumors. 1220 23

We have previously demonstrated that endothelin (ET)-1 and its subtype A receptor (ET-AR) expression are increased in lung under hypoxic conditions and that activation of ET-AR by ET-1 is a major mediator of hypoxia-induced pulmonary hypertension in the rat. The present study tested the hypothesis that the hypoxia-responsive tyrosine kinase receptor-activating growth factors fibroblast growth factor (FGF)-1, FGF-2, and platelet-derived growth factor (PDGF)-BB stimulate expression of the ET-AR in pulmonary arterial smooth muscle cells (PASMCs). Quiescent rat PASMCs were incubated under hypoxia (1% O2), or with FGF-1, FGF-2, PDGF-BB, vascular endothelial growth factor, ET-1, angiotensin II, or atrial natriuretic peptide under normoxic conditions for 24 h. FGF-1 and -2 and PDGF-BB, but not hypoxia, vascular endothelial growth factor, ET-1, angiotensin II, or atrial natriuretic peptide, significantly increased ET-AR mRNA levels. FGF-1-induced ET-AR expression was inhibited by FGF-receptor inhibitor PD-166866, MEK inhibitor U-0126, transcription inhibitor actinomycin D, and translation inhibitor cycloheximide. In contrast, the stimulatory effect of FGF-1 on ET-AR mRNA expression was not altered by PI3 kinase, PKA, PKC, or adenylate cyclase inhibitors. PASMC ET-AR gene transcription, assessed by nuclear-runoff analysis, was increased by FGF-1. These results provide novel finding that ET-AR in PASMCs in vitro is unresponsive to hypoxia per se but is robustly simulated by tyrosine kinase receptor-associated growth factors (FGF-1, FGF-2, PDGF-BB) that themselves are stimulated by hypoxia in lung. This observation suggests a novel signaling mechanism that may be responsible for overexpression of ET-AR in lung, and may contribute to the hypoxia-induced pulmonary vasoconstriction, hypertension, and vascular remodeling in hypoxia-adapted animal.
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PMID:Fibroblast growth factor mediates hypoxia-induced endothelin-- a receptor expression in lung artery smooth muscle cells. 1285 19

We have studied the role of endothelins (ET-1, ET-2 and ET-3) and ET receptors (ET-RA and ET-RB) in the invasive capacity of breast tumor cells, which express ET-1 and ET-2 as well as ET-RA and ET-RB. Of five human breast tumor cell lines tested, all expressed mRNAs for ET-1, ET-2, and ET-RB. ET-RA mRNA was expressed by four of five tumor cell lines. Breast tumor cells migrated toward ET-1 and ET-2 but not toward ET-3. Chemotaxis involved signaling via both receptors, and a pertussis toxin-sensitive p42/p44 mitogen-activated protein kinase (MAPK)-mediated pathway that could be inhibited by MAPK kinase (MEK)1/2 antagonists. Chemotaxis toward ETs did not involve p38 or stress-activated protein kinase (SAPK)/Jun N-terminal kinase (JNK) and was not inhibited by hypoxia. Incubation of tumor cells with ET-2 also increased chemotaxis toward the chemokines CXCL12 and CCL21. As well as inducing chemotaxis of tumor cells, ET-1 and ET-2 increased tumor cell invasion through Matrigel. Furthermore, stimulation of macrophage/tumor cell cocultures with ETs led to increased matrix metalloproteinase (MMP)-2 and -9 production by macrophages and a marked increase in invasion of tumor cells. Antagonism of either ET-RA or ET-RB decreased the invasion seen in ET-stimulated cocultures, as did a broad-spectrum MMP inhibitor. Immunohistochemical staining of human breast tumor sections showed increased ET and ET receptor protein expression by tumor cells in invasive ductal carcinoma compared with normal breast tissue or ductal carcinoma in situ. Furthermore, tumor cell ET and receptor expression was stronger at the invasive margin of invasive ductal carcinomas, in the lymphovascular space, and in lymph node metastases. ET expression often colocalized with ET-RB expression in all neoplastic tissue indicating a possible autocrine action of ETs. We suggest that expression of ETs and their receptors by human breast tumors, particularly in conjunction with a high macrophage infiltrate, may have a role in the progression of breast cancer and the invasion of tumor cells.
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PMID:A role for endothelin-2 and its receptors in breast tumor cell invasion. 1505 99

This study examines the importance of mitogen-activated protein kinases (MAPKs) in upregulation of endothelin type B (ETB) receptors. Rat middle cerebral arteries (MCAs) were incubated for 24 h with or without kinase inhibitors. Vessel segments were mounted in myographs and the contractile responses to endothelin-1 (ET-1; ETA and ETB receptor agonist) and sarafotoxin 6c (S6c; ETB receptor agonist) were studied. We used real-time PCR to measure the receptor mRNA levels. An ELISA assay showed the activation of ERK1/2 kinases after 3 h. Immunohistochemistry revealed the presence of ETB receptors on the vessels. After organ culture, S6c induced vasoconstriction. Incubation with the MEK/ERK inhibitors U0126 and SB386023 diminished the contractile response to S6c. The p38 MAPK inhibitor SB239063 did not affect the S6c-induced contraction. The ET-1-induced vasoconstriction was increased after incubation with SB386023 or SB239063, while unaffected by U0126. The ETB receptor mRNA levels were diminished by SB386023 and U0126. The ETA receptor mRNA levels were unaffected. The levels of activated ERK1/2 kinases were significantly higher after 3 h of organ culture as compared to fresh vessels. The level of ETB receptor protein on the smooth muscle cells of the MCA, visualised by immunohistochemistry, was somewhat diminished by SB386023. Our results show that the ERK1/2 MAPK is important in the upregulation of contractile ETB receptors in MCA after organ culture. Since there is a similar upregulation in models of focal ischaemia and subarachnoid haemorrhage, this may be an important pathophysiological event.
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PMID:Importance of ERK1/2 in upregulation of endothelin type B receptors in cerebral arteries. 1523 95

Hepatic ischemia-reperfusion injury is an inevitable consequence during liver surgery. The outcome is particularly poor in cirrhotic livers, which are more prone to hepatic ischemia-reperfusion injury. We aim to study whether FTY720 could attenuate hepatic ischemia-reperfusion injury both in normal and in cirrhotic livers. We applied a 70% liver-ischemia (60 min) model in rats with normal or cirrhotic livers. FTY720 was given 20 min before ischemia and 10 min before reperfusion (1 mg/kg, i.v.). Liver tissues and blood were sampled at 20 min, 60 min, 90 min, 6 h and 24 h after reperfusion for detection of MAPK-Egr-1, Akt pathways and caspase cascade. Hepatic ultrastructure and apoptosis were also compared. FTY720 significantly improved liver function in the rats with normal and cirrhotic livers. Akt pathway was activated at 6 and 24 h after reperfusion. FTY720 significantly down-regulated Egr-1, ET-1, iNOS and MIP-2 accompanied with up-regulation of A20, IL-10, HO-1 and Hsp70. MAPK (Raf-MEK-Erk) pathway was down-regulated. Hepatic ultrastructure was well maintained and fewer apoptotic liver cells were found in the FTY720 groups. In conclusion, FTY720 attenuates ischemia-reperfusion injury in both normal and cirrhotic livers by activation of cell survival Akt signaling and down-regulation of Egr-1 via Raf-MEK-Erk pathway.
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PMID:FTY720 attenuates hepatic ischemia-reperfusion injury in normal and cirrhotic livers. 2824 Aug 25

Insulin stimulates production of NO in vascular endothelium via activation of phosphatidylinositol (PI) 3-kinase, Akt, and endothelial NO synthase. We hypothesized that insulin resistance may cause imbalance between endothelial vasodilators and vasoconstrictors (e.g., NO and ET-1), leading to hypertension. Twelve-week-old male spontaneously hypertensive rats (SHR) were hypertensive and insulin resistant compared with control Wistar-Kyoto (WKY) rats (systolic blood pressure 202 +/- 11 vs. 132 +/- 10 mmHg; fasting plasma insulin 5 +/- 1 vs. 0.9 +/- 0.1 ng/ml; P < 0.001). In WKY rats, insulin stimulated dose-dependent relaxation of mesenteric arteries precontracted with norepinephrine (NE) ex vivo. This depended on intact endothelium and was blocked by genistein, wortmannin, or N(omega)-nitro-l-arginine methyl ester (inhibitors of tyrosine kinase, PI3-kinase, and NO synthases, respectively). Vasodilation in response to insulin (but not ACh) was impaired by 20% in SHR (vs. WKY, P < 0.005). Preincubation of arteries with insulin significantly reduced the contractile effect of NE by 20% in WKY but not SHR rats. In SHR, the effect of insulin to reduce NE-mediated vasoconstriction became evident when insulin pretreatment was accompanied by ET-1 receptor blockade (BQ-123, BQ-788). Similar results were observed during treatment with the MEK inhibitor PD-98059. In addition, insulin-stimulated secretion of ET-1 from primary endothelial cells was significantly reduced by pretreatment of cells with PD-98059 (but not wortmannin). We conclude that insulin resistance in SHR is accompanied by endothelial dysfunction in mesenteric vessels with impaired PI3-kinase-dependent NO production and enhanced MAPK-dependent ET-1 secretion. These results may reflect pathophysiology in other vascular beds that directly contribute to elevated peripheral vascular resistance and hypertension.
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PMID:Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production. 1579 94


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