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)

Platelet factor 4 (PF-4) is a member of the chemokine family with powerful antiangiogenic properties. The mechanism by which PF-4 inhibits endothelial cell proliferation is unclear. We investigated the effects of PF-4 on the intracellular signal transduction induced by basic fibroblast growth factor (FGF2). We found that PF-4 (10 microg/mL) inhibited the FGF2-induced proliferation of adrenal cortex capillary endothelial (ACE) cells. The inhibition of MEK1/2 (mitogen-activated protein kinase kinase) by PD98059 or of PI3K (phosphatidylinositol 3-kinase) by Ly294002 abolished the proliferation induced by FGF2, suggesting that ACE cell proliferation required dual signaling through both the extracellular signal-regulated kinase (ERK) and PI3K pathways. Ly294002 had no significant effect on ERK phosphorylation, whereas PD98059 had a weak effect on the phosphorylation of Akt, suggesting that 2 separate cascades are required for ACE cell proliferation. The addition of PF-4 (10 microg/mL) significantly inhibited ERK phosphorylation (95%), showing that PF-4 acted directly on or upstream from this kinase. Surprisingly, PF-4 did not affect FGF2-induced Akt phosphorylation. This suggests that PF-4 disrupts FGF2 signaling via an intracellular mechanism of inhibition. To exclude the possibility that PF-4 inhibited the binding of FGF2 to only one FGF receptor, preferentially activating the ERK pathway, we investigated the effect of PF-4 on FGF2-induced ERK and Akt phosphorylation, using mutant heparan sulfate-deficient Chinese hamster ovary cells transfected with the FGF-R1 cDNA. The addition of PF-4 (1 microg/mL) significantly inhibited ERK phosphorylation (90%), with no effect on Akt phosphorylation, suggesting that PF-4 acts downstream from the FGF-R1 receptor. In conclusion, this is the first report showing that PF-4 inhibits FGF2 activity downstream from its receptor.
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PMID:Platelet factor 4 inhibits FGF2-induced endothelial cell proliferation via the extracellular signal-regulated kinase pathway but not by the phosphatidylinositol 3-kinase pathway. 1238 3

Cell-cell contact between human retinal pigment epithelium (hRPE) cells and monocytes occurs in many retinal diseases involving blood-retinal barrier breakdown. This study investigates chemokine secretion induced by co-culture of hRPE cells and monocytes and illustrates the roles of p38 kinase, ERK, JNK/SAPK and NF-kappaB-inducing kinase signaling pathways for hRPE IL-8 and MCP-1 secretion induced in hRPE by co-culture with monocytes. Co-culture of hRPE cells with monocytes increased steady-state IL-8 and MCP-1 mRNA and protein secretion. Stimulation of hRPE cells by monocytes resulted in prominent increases in p38, ERK1/2 and JNK/SAPK phosphorolation, IkappaBalpha degradation, and NF-kappaB nuclear translocation. The induced IL-8 and MCP-1 proteins were almost completely supporessed by U0126, a specific mitogen-activated protein kinase kinase (MEK) inhibitor, or by SB203580, a selective p38 inhibitor. Chemokine secretion was completely blocked by simultaneous administration of U0126 and SB203580. Induction of IL-8 and MCP-1 was abrogated by Ro318220, an inhibitor of PKC, as well as by genistein or herbimycin A, inhibitors of PTK. In addition, anti-inflammatory drugs dexamethasone (DEX) and cyclosporin A (CSA) both blocked activation of JNKS/SAPK and the cell-cell contact induced production of hRPE IL-8 and MCP-1, while activation of p38 and ERK was only inhibited by DEX, but not by CSA. These results suggest that activation of DEX-sensitive, CSA-resistant MEK/ERK and p38 pathways, and activation of NF-kappaB, PKC, and PTK are essential for IL-8 and MCP-1 expression by hRPE cells.
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PMID:Human RPE-monocyte co-culture induces chemokine gene expression through activation of MAPK and NIK cascade. 1269 21

We have investigated whether chemokine signaling to the extracellular-signal-regulated kinase (ERK) was regulated by beta 1-integrin-mediated adhesion in B- and T-cell lines. Activation of ERK by the chemokine SDF-1 can be regulated by adhesion to beta 1-integrin substrates in the T-cell lines MOLT-3, Jurkat, and H9 and in the Daudi B-cell line. In Jurkat T-cells, adhesion to the immobilized alpha 4 beta 1-integrin ligand VCAM-1 or to the alpha 5 beta 1-integrin ligand fibronectin regulated stromal-cell derived factor-1 (SDF-1) activation of ERK. Adhesion control of SDF-1 signaling was a rapid event, occurring as early as 10 min after adhesion, and loss of signaling occurred within 10 min of deadhesion. In contrast, SDF-1 activation of the ERK kinase MEK was independent of adhesion. Partial restoration of signaling to ERK in suspension was accomplished by pretreatment with pharmacological inhibitors of serine/threonine or protein-tyrosine phosphatases. In addition, we used a non-radioactive phosphatase assay using phosphorylated ERK as the substrate to determine relative ERK dephosphorylation in whole cell extracts. These results showed greater relative ERK dephosphorylation in extracts from Jurkat cells treated in suspension, as compared with adherent cells. Therefore, these data suggest that adhesion influences SDF-1 activation of ERK by regulating the activity of ERK phosphatases. This identifies a novel locus of adhesion regulation of the ERK cascade.
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PMID:Adhesion regulation of stromal cell-derived factor-1 activation of ERK in lymphocytes by phosphatases. 1278 69

Eosinophilic leukocytes are the cellular hallmark of allergic inflammation. Apart from being potent eosinophils chemoattractants, the eotaxins CCL11, CCL24 and CCL26 are capable of activating eosinophils to generate reactive oxygen species, lipid mediators of inflammation and degranulation of toxic granule proteins. Due to their central role in eosinophil trafficking and activation, understanding the signal transduction mechanism of the eotaxin-induced eosinophil effector functions may provide an innovative therapeutic strategy for eosinophil-associated diseases. Thus, these investigations were conducted to delineate signal transduction mechanisms of CCL11, CCL24 and CCL26-induced eosinophil peroxidase (EPO) degranulation following pretreatment of cells with or without a specific inhibitor of MEK1/MEK2 (U0126), inhibitor of p38 MAP kinase (SB203580) or a specific inhibitor of PI 3-kinase (LY294002). Results have shown that CCR3-mediated eotaxin-induced eosinophilic degranulation was concentration-dependently reduced by specific inhibitors of ERK1/ERK2, p38 MAP kinase and PI 3-kinase. However, the rank order of U0126 with respect to inhibition of chemokine-induced degranulation was CCL11 = CCL24 > CCL26. Potentiation of eotaxin-induced EPO degranulation by IL-5 was also seen. These investigations have not only confirmed the reported co-operativity between IL-5 and the eotaxins but also showed that the eosinophil-degranulating capabilities of the eotaxin CCL11, CCL24 and CCL26 is a consequence of activation of ERK1/ERK2, p38 MAP kinase and PI 3-kinase. Thus, these signaling molecules may provide the biochemical basis for mechanism-based therapy of allergic inflammatory diseases.
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PMID:Inhibition of CCL11, CCL24, and CCL26-induced degranulation in HL-60 eosinophilic cells by specific inhibitors of MEK1/MEK2, p38 MAP kinase, and PI 3-kinase. 1278 9

CXCR6, the receptor for the membrane-anchored chemokine, CXCL16, is expressed on a subset of CCR5-bearing memory T cells, and may play a role in recruiting these cells to sites of inflammation. Here, we set out to determine the effect of T cell activation on CXCR6 expression. Highly purified human peripheral blood T cells were cultured for 7-8 days in presence of IL-2 (400 U/ml) to enhance CXCR6 expression. Overnight stimulation with anti-CD3 mAb+anti-CD28 mAb, which resulted in CD69 induction and cytokine (IL-2 and IFN-gamma) production, reduced cell surface expression of CXCR6 by 85% and that of CCR5 by 76%. The Ca(2+) ionophore, ionomycin (125-500 ng/ml), also markedly diminished CXCR6 expression (85%), but without inducing CD69 expression or cytokine production, and reduced CCR5 expression by only 40%. In contrast, the phorbol esters, PdBu or PMA had little effect on CXCR6 expression (23% reduction) but induced CD69 expression and caused a profound down-regulation (92%) of CCR5 expression. Moreover, CCR7, whose expression was low on CXCR6(+) T cells, was little affected by any of these modes of activation. The down-regulation of CXCR6 expression induced by CD3/CD28 activation was blocked by the broad kinase inhibitor, staurosporine, and by the src kinase inhibitor, PP2, but not by the MEK1 inhibitor, U0106. Most interestingly, the calcineurin inhibitor, FK506, consistently inhibited CD3/CD28-induced CXCR6 down-regulation. FK506 also blocked the decrease of CXCR6 expression caused by ionomycin, whereas staurosporine or PP2 had no effect on this decrease. Altogether, these data indicate that CXCR6 expression is down-regulated, independent of CCR5 or CD69 expression and of cytokine induction, by T cell activation signals that involve predominantly the Ca(2+)-dependent calcineurin pathway.
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PMID:Down-regulation of cell surface CXCR6 expression during T cell activation is predominantly mediated by calcineurin. 1291 53

Neutrophil recruitment into the airway typifies pulmonary inflammation and is regulated through chemokine network, in which two C-X-C chemokines play a critical role. Airway epithelial cells and vein endothelial cells are major cell sources of chemokines. ML-1 (interleukin-17F) is a recently discovered cytokine and its function still remains elusive. In this report, we investigated the functional effect of ML-1 in the expression of growth-related oncogene (GRO)alpha and epithelial cell-derived neutrophil activating protein (ENA)-78. The results showed first that ML-1 induces, in time- and dose-dependent manners, the gene and protein expressions for both chemokines in normal human bronchial epithelial cells and human umbilical vein endothelial cells. Furthermore, selective mitogen-activated protein kinase kinase (MEK) inhibitors 2'-amino-3'-methoxyflavone (PD98059), 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene (U0126), and Raf1 kinase inhibitor I partially inhibited Ml-1-induced GROalpha and ENA-78 production. In contrast, the combination of PD98059 and Raf1 kinase inhibitor I completely abrogated the chemokine production, whereas a protein kinase C inhibitor, 2-(1-(3-aminopropyl) indol-3-yl)-3-(1-methylindol-3-yl) maleimide, acetate (Ro-31-7549), and a phosphatidylinositol 3-kinase inhibitor, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), did not affect their production. Together, these data indicates a role for Raf1-MEK-extracellular signal-regulated kinase 1/2 pathway in ML-1 induced C-X-C chemokine expression, suggesting potential pharmacological targets for modulation.
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PMID:Induction of C-X-C chemokines, growth-related oncogene alpha expression, and epithelial cell-derived neutrophil-activating protein-78 by ML-1 (interleukin-17F) involves activation of Raf1-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase 1/2 pathway. 1455 79

Growth related oncogene protein-alpha (GRO-alpha) is a member of C-X-C chemokine and plays an important role in inflammatory responses. Expression of GRO gene family is regulated by a number of factors at both transcriptional and posttranscriptional levels. In the present study, we have addressed the possible regulation of GRO-alpha expression by ubiquitin-proteasome system. Cultures of human umbilical vein endothelial cells were treated with a proteasome inhibitor, MG132, and the levels of GRO-alpha mRNA were analyzed by reverse transcription-polymerase chain reaction or northern blotting. Levels of GRO-alpha protein in the cell-conditioned medium were determined by enzyme-linked immunosorbent assay. MG132 alone increased the levels of GRO-alpha mRNA and protein; however, it did not affect the GRO-alpha mRNA induced by lipopolysaccharide (LPS) and inhibited the LPS-induced decrease in IkappaB levels. Other proteasome inhibitors, MG115 and lactacystin, also induced the expression of GRO-alpha mRNA. MG132 induced the phosphorylation of p38 MAPK, MEK and JNK. Pretreatment of the cells with SB203580, an inhibitor of p38 MAPK, suppressed the MG132-induced GRO-alpha expression, but pretreatment of the cells with U0126, PD98059 or SP600125, inhibitors of MEK1/2 or JNK, did not influence the effect of MG132. We conclude that MG132 upregulates GRO-alpha expression in vascular endothelial cells, at least in part, through the activation of p38 MAPK.
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PMID:Effect of MG132, a proteasome inhibitor, on the expression of growth related oncogene protein-alpha in human umbilical vein endothelial cells. 1458 Oct

It has been proposed that mitogen-activated protein kinase (MAPK) pathways may play a role in the regulation of pro-inflammatory cytokines, such as interlukine-1, during cerebral ischemia. Our previous study showed that extracellular-signal-regulated kinases 1 and 2 (ERK 1/2) were activated during focal cerebral ischemia in mice [J. Cereb. Blood Flow Metab. 20 (2000) 1320]. However, the effect of ERK 1/2 activation in focal cerebral ischemia is still unclear. In this study we reported that in vivo phospho-ERK 1/2 expression increased following 30 min of middle cerebral artery occlusion (MCAO) in the mouse brain in both the ischemic core and perifocal regions. Western blot analysis and immunohistochemistry demonstrated that pro-treatment with 1,4-diamino-2,3-dicyano-1,4-bis butadiene (U0126) [J. Biol. Chem. 273 (1998) 18623] could significantly inhibit mouse brain phospho-MEK 1/2 and phospho-ERK 1/2 expression after 1-2 h of MCAO (p<0.05). Compared to the control group of mice, brain infarct volume was significantly decreased after 24 h of MCAO in the U0126-treated mice (27+/-6 vs. 46+/-9 mm(2), p<0.05). Inhibition of the MEK/ERK 1/2 pathway also prevented downstream kinase Elk-1 phosphorylation, and further reduced cytokine IL-1beta mRNA, but not TNFalpha, IL-1alpha, or chemokine MIP-1alpha mRNA expression. Our data demonstrates that in vivo the close linking of MEK 1/2, ERK 1/2, Elk-1, and IL-1 mRNA expression in the cerebral ischemia animals suggests that ERK 1/2 pathway activation is important in pro-inflammatory cytokine IL-1beta signaling, which induces an inflammatory response and exacerbates ischemic brain injury. Inhibiting the ERK 1/2 pathway may therefore provide a novel approach for the reduction of ischemia-induced IL-1beta overexpression.
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PMID:Inhibition of MEK/ERK 1/2 pathway reduces pro-inflammatory cytokine interleukin-1 expression in focal cerebral ischemia. 1467 Jun 31

Hepatic stellate cells (HSC) coordinate the liver wound-healing response through secretion of several cytokines and chemokines, including CCL2 (formerly known as monocyte chemoattractant protein-1). In this study, we evaluated the role of different proteins of the MAPK family (ERK, p38(MAPK), and JNK) in the regulation of CCL2 expression by HSC, as an index of their proinflammatory activity. Several mediators activated all three MAPK, including TNF, IL-1, and PDGF. To assess the relative role of the different MAPKs, specific pharmacological inhibitors were used; namely, SB203580 (p38(MAPK)), SP600125 (JNK), and PD98059 (MEK/ERK). The efficacy and specificity of the different inhibitors in our cellular system were verified analyzing the enzymatic activity of the different MAPKs using in vitro kinase assays and/or testing the inhibition of phosphorylation of downstream substrates. SB203580 and SP600125 dose-dependently inhibited CCL2 secretion and gene expression induced by IL-1 or TNF. In contrast, inhibition of ERK did not affect the upregulation of CCL2 induced by the two cytokines. Finally, activin A was also found to stimulate CCL2 expression and to activate ERK, JNK, p38, and their downstream targets. Unlike in cells exposed to proinflammatory cytokines, all three MAPKs were required to induce CCL2 secretion in response to activin. We conclude that members of the MAPK family differentially regulate cytokine-induced chemokine expression in human HSC.
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PMID:Differential requirement of members of the MAPK family for CCL2 expression by hepatic stellate cells. 1501 14

The virally encoded chemokine receptors US28 from human cytomegalovirus and ORF74 from human herpesvirus 8 are both constitutively active. We show that both receptors constitutively activate the transcription factors nuclear factor of activated T cells (NFAT) and cAMP response element binding protein (CREB) and that both pathways are modulated by their respective endogenous receptor ligands. By addition of specific pathway modulators against the G protein subunit Galphai, phospholipase C, protein kinase C, calcineurin, p38 MAP kinase, and MEK1, we find that the constitutive and ligand-dependent inductions are mediated by multiple yet similar pathways in both receptors. The NFAT and CREB transcription factors and their upstream activators are known inducers of host and virally encoded genes. We propose that the activity of these virally encoded chemokine receptors coordinates host and potentially viral gene expression similarly. As ORF74 is a known inducer of neoplasia, these findings may have important implications for cytomegalovirus-associated pathogenicity.
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PMID:Similar activation of signal transduction pathways by the herpesvirus-encoded chemokine receptors US28 and ORF74. 1524 64


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