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 luteinizing hormone (LH) plays a critical role in steroidogenesis, by stimulating cAMP-dependent protein kinase A (PKA) and phospholipase A2 activity, and by mobilizing calcium and chloride ions. In contrast, whether the ERK 1, 2 mitogen-activated protein (MAP) kinases are involved in LH-induced steroidogenesis is less obvious. Here, we sought to clarify this point in rat primary Leydig cells, naturally bearing the LH receptor (LH-R) in male, and in the mouse tumoral Leydig cell line (MLTC 1). Pre-incubation of both cell types with the mitogen-activated protein kinase kinase (MEK) inhibitors U0126 and PD98059 reduced LH-induced steroidogenesis, and tonically enhanced the expression of the StAR protein. Furthermore, ERK1, 2 were inducibly phosphorylated following LH exposure of MLTC 1 cells. Altogether, our results indicate that in primary as well as in tumoral Leydig cells, inhibiting MEK dampened LH-induced steroidogenesis but enhanced basal as well as LH-induced StAR expression, suggesting that ERK1,2 could be involved in these responses.
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PMID:Extracellular signal-regulated kinases (ERK) 1, 2 are required for luteinizing hormone (LH)-induced steroidogenesis in primary Leydig cells and control steroidogenic acute regulatory (StAR) expression. 1586 56

The binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein Ib-IX (GPIb-IX) results in platelet activation. In this study, we sought to clarify previous conflicting reports and to elucidate the mechanism of activation and the precise role of extracellular signal-regulated kinase (Erk) in VWF-induced platelet activation. Erk2 is activated in platelets on stimulation with VWF/ristocetin in a time-dependent manner. VWF-induced Erk2 phosphorylation and thromboxane A2 (TXA2) release were completely blocked by PP2, an Src family kinase inhibitor, suggesting that Erk is downstream of Src family kinases. U73122, a phospholipase C inhibitor, also abolished TXA2 generation and Erk phosphorylation. Although VWF fostered the agglutination of platelets regardless of any additional treatment, the inhibition of mitogen-activated protein kinase kinase (MEK) with U0126 abolished VWF-induced platelet aggregation and thromboxane production in non-aspirin-treated washed platelets. However, in platelets treated with aspirin, VWF failed to cause any aggregation. Thus, we conclude that VWF stimulation of platelets results in phospholipase A2 activation through Erk stimulation and that Src family kinases and phospholipase C play essential roles in this event. We further conclude that VWF-induced platelet aggregation does not directly depend on Erk activation but has an absolute requirement for Src/Erk-mediated TXA2 generation.
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PMID:Src family kinase-mediated and Erk-mediated thromboxane A2 generation are essential for VWF/GPIb-induced fibrinogen receptor activation in human platelets. 1721 Aug 69

Apigenin is a nonmutagenic bioflavonoid that has been shown to be an inhibitor of mouse skin carcinogenesis induced by the two-stage regimen of initiation and promotion with dimethylbenzanthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). These DMBA/TPA-induced squamous cell carcinomas overexpress cyclooxygenase-2 (COX-2). Cyclooxygenases are key enzymes required for prostaglandin (PG) synthesis, converting the arachidonic acid (AA) released by phospholipase A2 into prostaglandins. A large body of evidence indicates that the inducible form of cyclooxygenase, COX-2, is involved in tumor promotion and carcinogenesis in a wide variety of tissue types, including colon, breast, lung, and skin. In the present study, we have determined that apigenin inhibited the TPA-induced increase in COX-2 protein and mRNA in the human keratinocyte cell line; HaCaT. The induction of COX-2 elicited by TPA correlated with increased activation of Akt kinase and cell treatment with the PI3 kinase inhibitor, LY294002, blocked TPA induction of COX-2. In cells treated with TPA and apigenin, the inhibition of COX-2 expression correlated with inhibition of Akt kinase activation. Apigenin-mediated inhibition of TPA-induced COX-2 expression was reversed by transient transfection with constitutively active Akt (CA-Akt). Chemical inhibitors of MEK (PD98059), p38 (SB202190), but not JNK (SP600125) blocked TPA induction of COX-2 although apigenin did not inhibit TPA-mediated COX-2 expression through these pathways. The TPA-induced release of AA from HaCaT cells was also inhibited by cell treatment with apigenin. These data show that apigenin inhibits TPA-mediated COX-2 expression by blocking signal transduction of Akt and that apigenin also blocks AA release, which may contribute to its chemopreventive activity.
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PMID:Inhibition of TPA-induced cyclooxygenase-2 (COX-2) expression by apigenin through downregulation of Akt signal transduction in human keratinocytes. 1604 7

We investigated whether GABA activates phospholipase A2 (PLA2) during acrosomal exocytosis, and if the MEK-ERK1/2 pathway modulates PLA2 activation initiated by GABA, progesterone or zona pellucida (ZP). In guinea pig spermatozoa prelabelled with [14C]arachidonic acid or [14C]choline chloride, GABA stimulated a decrease in phosphatidylcholine (PC), and release of arachidonic acid and lysoPC, during exocytosis. These lipid changes are indicative of PLA2 activation and appear essential for exocytosis since inclusion of aristolochic acid (a PLA2 inhibitor) abrogated them, along with exocytosis. GABA activation of PLA2 seems to be mediated, at least in part, by diacylglycerol (DAG) and protein kinase C since inclusion of the DAG kinase inhibitor R59022 enhanced PLA2 activity and exocytosis stimulated by GABA, whereas exposure to staurosporine decreased both. GABA-, progesterone- and ZP-induced release of arachidonic acid and exocytosis were prevented by U0126 and PD98059 (MEK inhibitors). Taken together, our results suggest that PLA2 plays a fundamental role in agonist-stimulated exocytosis and that MEK-ERK1/2 are involved in PLA2 regulation during this process.
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PMID:GABA, progesterone and zona pellucida activation of PLA2 and regulation by MEK-ERK1/2 during acrosomal exocytosis in guinea pig spermatozoa. 1609 15

Elevation of the intracellular cAMP concentration in agonist-activated human neutrophils (PMN) leads to the concomitant inhibitions of arachidonic acid (AA) release, 5-lipoxygenase (5-LO) translocation, and leukotriene (LT) biosynthesis. We report herein that exogenous AA completely prevents cAMP-dependent inhibition of 5-LO translocation and LT biosynthesis in agonist-activated PMN. Moreover, the group IVA phospholipase A2 inhibitor pyrrophenone and the MEK inhibitor U-0126 inhibited AA release and 5-LO translocation in activated PMN, and these effects were also prevented by exogenous AA, demonstrating a functional link between AA release and 5-LO translocation. Polyunsaturated fatty acids of the C18 and C20 series containing at least three double bonds located from carbon 9 (or closer to the carboxyl group) were equally effective as AA in restoring 5-LO translocation in pyrrophenone-treated agonist-activated PMN. Importantly, experiments with the 5-LO-activating protein inhibitor MK-0591 and the intracellular Ca2+ chelator BAPTA-AM demonstrated that the AA-regulated 5-LO translocation is FLAP- and Ca2+-dependent. Finally, the redox and competitive 5-LO inhibitors L-685,015, L-739,010, and L-702,539 (but not cyclooxygenase inhibitors) efficiently substituted for AA to reverse the pyrrophenone inhibition of 5-LO translocation, indicating that the site of regulation of 5-LO translocation by AA is at or in the vicinity of the catalytic site. This report demonstrates that AA regulates the translocation of 5-LO in human PMN and unravels a novel mechanism of the cAMP-mediated inhibition of LT biosynthesis.
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PMID:Arachidonic acid regulates the translocation of 5-lipoxygenase to the nuclear membranes in human neutrophils. 1627 40

The roles of growth factor receptors and numerous downstream growth regulatory pathways are of increasing interest in neuro-oncology. These pathways have been extensively studied in gliomas but only recently analyzed in meningiomas. This article reviews current research on the growth factor receptor-Ras-Raf-1-MEK-1-MAPK, PI3K-Akt/PKB, PLC-gamma1-PKC, phospholipase A2-cyclooxygenase, and TGF-beta receptor-Smad pathways that appear to regulate meningioma growth and inhibit apoptosis. Sites along these receptor/kinase cascades that might be targeted by novel therapies are also discussed.
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PMID:Mitogenic signal transduction pathways in meningiomas: novel targets for meningioma chemotherapy? 1631 13

We investigated the mechanism of contraction induced by S1P in esophageal smooth muscle cells. Western blot analysis demonstrated that S1P(1), S1P(2), S1P(3), and S1P(5) receptors existed in the cat esophagus. Only penetration of EDG-5 (S1P(2)) antibody into permeabilized cells inhibited S1P-induced contraction. Pertussis toxin (PTX) also inhibited contraction, suggesting that it was mediated by S1P(2) receptors coupled to a PTX-sensitive G(i) protein. Specific antibodies to G(i2), G(q) and G(beta) inhibited contraction, implying that the S1P-induced contraction depends on PTX-insensitive G(q) and G(beta) dimers as well as the PTX-sensitive G(i2). Contraction was not affected by the phospholipase A2 inhibitor DEDA, or the PLD inhibitor rho-chloromer-curibenzoate, but it was abolished by the PLC inhibitor U73122. Incubation of permeabilized cells with PLCb3 antibody also inhibited contraction. Contraction involved the activation of a PKC pathway since it was affected by GF109203X and chelerythrine. Since PKCepsilon antibody inhibited contraction, PKCe may be required. Preincubation of the muscle cells with the MEK inhibitor PD98059 blocked S1P-induced contraction, but the p38 MAP kinase inhibitor SB202190 did not. In addition, co-treatment of cells with GF 109203X and PD98059 did not have a synergistic effect, suggesting that these two kinases are involved in the same signaling pathway. Our data suggest that S1P-induced contraction in esophageal smooth muscle cells is mediated by S1P(2) receptors coupled to PTX-sensitive G(i2) proteins, and PTX-insensitive G(q) and G(beta) proteins, and that the resulting activation of the PLCb3 and PKCepsilon pathway leads to activation of a p44/p42 MAPK pathway.
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PMID:Sphingosine 1-phosphate-induced signal transduction in cat esophagus smooth muscle cells. 1651 46

Bacterial infection triggers an acute inflammatory response that might alter phospholipid metabolism. We have investigated the acute-phase response of murine lung epithelia to Pseudomonas aeruginosa infection. Ps. aeruginosa triggered secretion of the pro-inflammatory lipase, sPLA2 IB (phospholipase A2 IB), from lung epithelium. Ps. aeruginosa and sPLA2 IB each stimulated basolateral PtdCho (phosphatidylcholine) efflux in lung epithelial cells. Pre-treatment of cells with glyburide, an inhibitor of the lipid-export pump, ABCA1 (ATP-binding cassette transporter A1), attenuated Ps. aeruginosa and sPLA2 IB stimulation of PtdCho efflux. Effects of Ps. aeruginosa and sPLA2 IB were completely abolished in human Tangier disease fibroblasts, cells that harbour an ABCA1 genetic defect. Ps. aeruginosa and sPLA2 IB induced the heterodimeric receptors, PPARa (peroxisome-proliferator-activated receptor-a) and RXR (retinoid X receptor), factors known to modulate ABCA1 gene expression. Ps. aeruginosa and sPLA2 IB stimulation of PtdCho efflux was blocked with PD98059, a p44/42 kinase inhibitor. Transfection with MEK1 (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase 1), a kinase upstream of p44/42, increased PPARa and RXR expression co-ordinately with increased ABCA1 protein. These results suggest that pro-inflammatory effects of Ps. aeruginosa involve release of an sPLA2 of epithelial origin that, in part, via distinct signalling molecules, transactivates the ABCA1 gene, leading to export of phospholipid.
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PMID:Pseudomonas aeruginosa and sPLA2 IB stimulate ABCA1-mediated phospholipid efflux via ERK-activation of PPARalpha-RXR. 1722 97

The structures of phosphoglycolipids PGL1 and PGL2 from the thermophilic bacteria Meiothermus taiwanensis, Meiothermus ruber, Thermus thermophilus, and Thermus oshimai are determined recently (Yang et al. in J Lipid Res. 47:1823-1932, 2006). These bacteria belong to Gram-negative bacteria that do not contain lipopolysaccharide, but high amounts of phosphoglycolipids and glycoglycerolipids. Here we show that PGL1/PGL2 mixture (PGL1: PGL2 = 10:1 ~ 10:2) from M. taiwanensis and T. oshimai, but not T. thermophilus and M. ruber, up-regulate interleukin-1beta (IL-1beta) production in human THP-1 monocytes and blood-isolated primary monocytes. PGL2 was purified after phospholipase A2 hydrolysis of PGL1 in the PGL1/PGL2 mixture followed by column chromatography. PGL2 did not induce proIL-1 production, even, partially (35-40%) inhibited PGL1-mediated proIL-1 production, showing that PGL1 is the main inducer of proIL-1 production in PGL1/PGL2 mixture. The production of proIL-1 stimulated by phosphoglycolipids was strongly inhibited by specific PKC-alpha, MEK1/2, and JNK inhibitors, but not by p38-specific inhibitor. The intracellular calcium influx was involved in phosphoglycolipids-mediated proIL-1 production. Using blocking antibody and Toll-like receptor (TLR)-linked NF-kappaB luciferase assays, we found that the cellular receptor(s) for phosphoglycolipids on proIL-1 production was TLR-independent. Further, phosphoglycolipids isolated from T. thermophilus and M. ruber did not induce proIL-1 production, even though T. thermophilus possess more PGL1 than PGL2 (6:4). Specially, the fatty acid composition of phosphoglycolipids from both T. thermophilus and M. ruber consists of a low percentage of C15 (<10%) and a high percentage of C17 (>75%). It suggests, the C15 percentage of PGL may play a critical role in PGL-mediated proIL-1 induction.
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PMID:TLR-independent induction of human monocyte IL-1 by phosphoglycolipids from thermophilic bacteria. 1816 Oct 25

It was demonstrated previously that a positive feedback loop, including protein kinase C (PKC) and mitogen-activated protein kinase (MAPK), is required for the gradual expression of cerebellar long-term depression (LTD). PKC and MAPK are mutually activated in this loop. MAPK-dependent PKC activation is likely to be mediated by phospholipase A2. On the other hand, it is not clear how PKC activates MAPK. Therefore, the entire picture of this loop was not fully understood. We here test the hypothesis that this loop is completed by the PKC substrate, Raf kinase inhibitory protein (RKIP). To test this hypothesis, we used a mutant form of RKIP that is not phosphorylated by PKC and thus constitutively inhibits Raf-1 and MEK, upstream kinases of MAPK. When this RKIP mutant was introduced into Purkinje cells of mouse cerebellar slices through patch-clamp electrodes, LTD was blocked, while wild-type (WT) RKIP had no effect on LTD. Physiological epistasis experiments demonstrated that RKIP works downstream of PKC and upstream of MAPK during LTD induction. Furthermore, biochemical analyses demonstrated that endogenous RKIP dissociates from Raf-1 and MEK during LTD induction in a PKC-dependent manner, suggesting that RKIP binding-dependent inhibition of Raf-1 and MEK is removed upon LTD induction. We therefore conclude that PKC-dependent regulation of RKIP leads to MAPK activation, with RKIP completing the positive feedback loop that is required for LTD.
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PMID:Raf kinase inhibitory protein is required for cerebellar long-term synaptic depression by mediating PKC-dependent MAPK activation. 2305 94


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