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)

Prostaglandin receptors may be activated by their cognate ligand or by free radical catalyzed isoprostanes, products of arachidonic acid peroxidation. For example, prostaglandin F2alpha (PGF2alpha) causes hypertrophy of neonatal rat ventricular myocytes, via the PGF2alpha receptor (FP). However, the FP may also be activated by the isoprostane, 8,12-iso-iPF2alpha-III (Kunapuli, P., Lawson, J. A., Rokach, J., and FitzGerald, G. A. (1997) J. Biol. Chem. 272, 27147-27154). Both ligands induce myocyte hypertrophy with overlapping potencies. Interestingly, the hypertrophic effects of these two agonists on cardiomyocytes are additive. Furthermore, the preference of these two agonists for activation of intracellular signal transduction pathways differs in several respects. Thus, PGF2alpha and 8,12-iso-iPF2alpha-III stimulate inositol phosphate formation with EC50 values of 50 +/- 12 nM and 3.5 +/- 0.6 microM, respectively. Moreover, PGF2alpha causes a robust activation ( approximately 50-fold) of Erk2, whereas 8,12-iso-iPF2alpha-III has no effect. Similarly, PGF2alpha causes translocation of cytosolic phospholipase A2 and also results in a 7-fold increment in the formation of 6-keto-PGF1alpha, whereas 8,12-iso-iPF2alpha-III exerts no effect on this pathway. On the other hand, both agonists are equally potent in activating JNK1 and c-Jun, whereas neither activates the p38 kinase. Both PGF2alpha and 8,12-iso-iPF2alpha-III activate the p70S6 kinase (p70(S6K)), but not Akt, downstream of phosphatidylinositol-3-kinase (PI3K). However, both wortmannin, a PI3K inhibitor, and rapamycin, an inhibitor of p70(S6K) activity, inhibit 8,12-iso-iPF2alpha-III -induced myocyte hypertrophy, with IC50 values of 60 +/- 12 and 3 +/- 1.7 nM, respectively, whereas neither compound abrogates the PGF2alpha-mediated response. Thus, both PGF2alpha and 8,12-iso-iPF2alpha-III induce myocyte hypertrophy via discrete signaling pathways. Although both agonists signal via the JNK pathway to initiate changes in c-Jun-dependent gene transcription, PGF2alpha preferentially activates the MEK-Erk2- cytosolic phospholipase A2 pathway. In contrast, the PI3K-p70(S6K) pathway appears to be essential for 8,12-iso-iPF2alpha-III-induced myocyte hypertrophy.
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PMID:Prostaglandin F2alpha (PGF2alpha) and the isoprostane, 8, 12-iso-isoprostane F2alpha-III, induce cardiomyocyte hypertrophy. Differential activation of downstream signaling pathways. 971 68

1. The effect of protein tyrosine kinase inhibitors on human adenosine A1 receptor-mediated [3H]-inositol phosphate ([3H]-IP) accumulation has been studied in transfected Chinese hamster ovary cells (CHO-A1) cells. 2. In agreement with our previous studies the selective adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) stimulated the accumulation of [3H]-IPs in CHO-A1 cells. Pre-treatment with the broad spectrum tyrosine kinase inhibitor genistein (100 microM; 30 min) potentiated the responses elicited by 1 microM (199+/-17% of control CPA response) and 10 microM CPA (234+/-15%). Similarly, tyrphostin A47 (100 microM) potentiated the accumulation of [3H]-IPs elicited by 1 microM CPA (280+/-32%). 3. Genistein (EC50 = 13.7+/-1.2 microM) and tyrphostin A47 (EC50 = 10.4+/-3.9 microM) potentiated the [3H]-IP response to 1 microM CPA in a concentration-dependent manner. 4. Pre-incubation with the inactive analogues of genistein and tyrphostin A47, daidzein (100 microM; 30 min) and tyrphostin A1 (100 microM; 30 min), respectively, had no significant effect on the accumulation of [3H]-IPs elicited by 1 microM CPA. 5. Genistein (100 microM) had no significant effect on the accumulation of [3H]-IPs produced by the endogenous thrombin receptor (1 u ml(-1); 100+/-10% of control response). In contrast, tyrphostin A47 produced a small augmentation of the thrombin [3H]-IP response (148+/-13%). 6. Genistein (100 microM) had no effect on the [3H]-IP response produced by activation of the endogenous Gq-protein coupled CCK(A) receptor with the sulphated C-terminal octapeptide of cholecystokinin (1 microM CCK-8; 96+/-6% of control). In contrast, tyrphostin A47 (100 microM) caused a small but significant increase in the response to 1 microM CCK-8 (113+/-3% of control). 7. The phosphatidylinositol 3-kinase inhibitor LY 294002 (30 microM) and the MAP kinase kinase inhibitor PD 98059 (50 microM) had no significant effect on the [3H]-IP responses produced by 1 microM CPA and 1 microM CCK-8. 8. These observations suggest that a tyrosine kinase-dependent pathway may be involved in the regulation of human adenosine A1 receptor mediated [3H]-IP responses in CHO-A1 cells.
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PMID:Potentiation of adenosine A1 receptor-mediated inositol phospholipid hydrolysis by tyrosine kinase inhibitors in CHO cells. 984 44

Stimulation of mammalian cells results in subcellular relocalization of Ras pathway enzymes, in which extracellular signal-regulated protein kinases rapidly translocate to nuclei. In this study, we define conditions for nuclear localization of mitogen-activated protein kinase kinase 1 (MKK1) by examining effects of perturbing the nuclear export signal (NES), the regulatory phosphorylation sites Ser218 and Ser222, and a regulatory domain at the N terminus. After disrupting the NES (Delta32-37), nuclear uptake of MKK was enhanced when quiescent cells were activated with serum-phorbol 12-myristate 13-acetate or BXB-Raf-1 cotransfection. Uptake was enhanced by mutation of Ser218 and Ser222 to Glu and Asp, respectively, and blocked by mutation of these residues to Ala, although mutation of Lys97 to Met, which renders MKK catalytically inactive, did not interfere with uptake. Therefore, nuclear uptake of MKK requires incorporation of phosphate or negatively charged residues at the activation lip but not enzyme activity. On the other hand, uptake of an active MKK mutant with disrupted NES (Delta32-51) was elevated in quiescent as well as stimulated cells, and pretreatment of cells with the MKK inhibitor 1,4-diamino-2, 3-dicyano-1,4-bis[2-aminophenylthio]butadiene blocked nuclear uptake. Thus, signaling downstream of MKK is also necessary for translocation. Finally, wild type MKK containing an intact NES translocates to nuclei during mitosis before envelope breakdown. Comparison of mutants with Ser to Glu and Asp or Ala substitutions indicates that Ser phosphorylation is also required for mitotic nuclear uptake of MKK.
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PMID:Nuclear localization of mitogen-activated protein kinase kinase 1 (MKK1) is promoted by serum stimulation and G2-M progression. Requirement for phosphorylation at the activation lip and signaling downstream of MKK. 1003 1

In mouse embryo NIH 3T3 fibroblasts, ethanol (60-80 mM) was found to enhance the stimulatory effects of sphingosine 1-phosphate (S1P) on both DNA synthesis and cell proliferation. Well-detectable potentiating effects of ethanol on S1P-induced mitogenesis required the presence of calcium (>1 mM) and zinc (20-40 microM) in the incubation medium. The amphibian tetrapeptide bombesin, which is known to mobilize intracellular calcium in fibroblasts, had no effect alone, but it approximately doubled the combined stimulatory effects of ethanol and S1P on DNA synthesis. The synergistic mitogenic effects of ethanol and S1P were also slightly enhanced, rather than inhibited, by the alcohol dehydrogenase inhibitor 4-methylpyrazole (5 mM). Of the various growth regulatory enzymes examined, ethanol detectably enhanced the stimulatory effects of S1P on the phosphosphorylation (activation) of p42/p44 mitogen-activated protein (MAP) kinases, but not of p38 MAP kinase. Cotreatment of fibroblasts with ethanol for 10 min also enhanced the stimulatory effects of S1P on the activities of c-Raf-1 kinase and p70 S6 kinase, but neither S1P nor ethanol had effects on phosphatidylinositol 3'-kinase and Akt/PKB kinase activities. Ethanol-plus-S1P-induced DNA synthesis was partially inhibited by both PD 98059 (50 microM) and rapamycin (10 nM), inhibitors of p42/p44 MAP kinase kinase and mTOR/p70 S6 kinases, respectively. The results indicate that in NIH 3T3 fibroblasts, ethanol can enhance the mitogenic effects of S1P by a zinc- and calcium-dependent mechanism involving both the rapamycin-sensitive p70 S6 kinase-dependent and the c-Raf-1/MAP kinase-dependent growth regulatory pathways.
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PMID:Ethanol potentiates the mitogenic effects of sphingosine 1-phosphate by a zinc- and calcium-dependent mechanism in fibroblasts. 1033 73

Synovial fluid basic calcium phosphate (BCP) crystals are markers of severe joint degeneration in osteoarthritis. These crystals are mitogenic and induce protooncogene expression and matrix metalloproteinase (MMP) synthesis and secretion in human fibroblasts, effects that are specifically blocked by phosphocitrate (PC). We have recently determined that crystals transduce signals to the nucleus via the activation of the p42 and p44 mitogen-activated protein (MAP) kinases (Nair et al., 1997, J Biol Chem 272:18920-18925). Treatment of human fibroblasts (HF) with BCP induces phosphorylation of p42/44 MAPK, which is inhibited by PC in a dose-dependent manner. Blocking of p42/44 MAPK signal transduction with an inhibitor (PD98059) of MEK1, an upstream activator of MAPKs, reduces crystal-induced p42/44 MAPK activation and significantly inhibits crystal-induced cell proliferation. Based on these findings, we sought to determine the role of the p42/44 MAPK signal transduction pathway in crystal-induced expression of matrix MMPs. We demonstrate suppression of crystal-induced MMPs via the utilization of two different MEK inhibitors: PD98059 and the recently described U0126, a novel inhibitor of MEK1 and MEK2. Treatment of HF with PD98059 blocks the induction of crystal-stimulated collagenase 1 (MMP-1) and stromelysin (MMP-3) expression. PD98059 and PC reduced the level of crystal-induced MMP-1 and MMP-3 mRNA expression to that observed in nonstimulated cells. Likewise, PD98059 treatment of HF blocked the epidermal growth factor (EGF)- and crystal-induced increases in MMP-1 and MMP-3 protein expression and secretion as demonstrated by Western blotting and zymography. Treatment of HF with U0126 inhibits EGF-induced phosphorylation of p42/44 MAPK as well as crystal- and EGF-induced upregulation of MMP-1 mRNA. Additionally, we demonstrate that treatment of HF with BCP, EGF, or PD98059 does not significantly alter levels of gelatinase A (MMP-2) mRNA and protein expression.
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PMID:Basic calcium phosphate crystal induction of collagenase 1 and stromelysin expression is dependent on a p42/44 mitogen-activated protein kinase signal transduction pathway. 1039 91

Endothelial differentiation gene-encoded G protein-coupled receptors (Edg Rs) Edg-1, Edg-3, and Edg-5 bind sphingosine 1-phosphate (S1P), and Edg-2 and Edg-4 Rs bind lysophosphatidic acid (LPA). LPA and S1P initiate ras- and rho-dependent signaling of cellular growth. Cultured lines of human breast cancer cells (BCCs) express Edg-3 > Edg-4 > Edg-5 > or = Edg-2, without detectable Edg-1, by both assessment of mRNA and Western blots with rabbit and monoclonal mouse anti-Edg R antibodies. BCC proliferation was stimulated significantly by 10(-9) M to 10(-6) M LPA and S1P. Luciferase constructs containing the serum response element (SRE) of growth-related gene promoters reported mean activation of BCCs by LPA and S1P of up to 85-fold. LPA and S1P stimulated BCC secretion of type II insulin-like growth factor (IGF-II) by 2-7-fold, to levels at which exogenous IGF-II stimulated increased proliferation and SRE activation of BCCs. All BCC responses to LPA and S1P were suppressed similarly by pertussis toxin, mitogen-activated protein kinase kinase inhibitors, and C3 exoenzyme inactivation of rho, suggesting mediation by Edg Rs. Monoclonal anti-IGF-II and anti-IGFR1 antibodies suppressed proliferation and SRE reports of BCCs to LPA and S1P by means of up to 65%. Edg Rs thus transduce LPA and S1P enhancement of BCC growth, both directly through SRE and indirectly by enhancing the contribution of IGF-II.
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PMID:Dual mechanisms for lysophospholipid induction of proliferation of human breast carcinoma cells. 1049 33

Parathyroid hormone (PTH), a major physiologic regulator of proximal renal tubule cell sodium-phosphate cotransport, stimulates several signal transduction pathways including extracellular signal-regulated kinases (ERK). The physiologic role of PTH-stimulated ERK is unknown. The purpose of the present study was to identify signaling components involved in PTH-stimulated ERK activity and to determine the role of PTH-stimulated ERK activity in regulation of phosphate transport. PTH-stimulated ERK activity was measured in opossum kidney (OK) cell lysates as phosphorylation of myelin basic protein by an in vitro kinase assay. PTH stimulated a dose-dependent increase in ERK activity with a peak at 10(-7) M. The time course was biphasic with an early peak at 10 min and a later peak at 20 min. Pretreatment of OK cells with the nonreceptor tyrosine kinase inhibitors genistein and herbimycin A or with the phosphatidylinositol 3-kinase (PI-3K) inhibitors wortmannin and LY294002 blocked the early and late peaks of PTH-stimulated ERK activity. Pretreatment with the protein kinase C inhibitor calphostin C blocked only the later phase of PTH-stimulated ERK. To determine the role of ERK in regulation of phosphate transport, PTH inhibition of phosphate uptake and PTH regulation of sodium-phosphate cotransporter (NaPi-4) expression were measured in OK cells pretreated with the MEK inhibitor PD098059. PD098059 significantly attenuated PTH inhibition of phosphate uptake but did not prevent PTH downregulation of NaPi-4. It is concluded that PTH stimulates ERK through two signal transduction pathways: an early pathway dependent on tyrosine kinase and PI-3K and a late pathway dependent on protein kinase C. PTH-stimulated ERK regulates phosphate transport by a mechanism other than downregulation of NaPi-4 expression.
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PMID:Parathyroid hormone stimulates extracellular signal-regulated kinase (ERK) activity through two independent signal transduction pathways: role of ERK in sodium-phosphate cotransport. 1066 29

Receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) can both activate mitogen-activated protein kinase (MAPK), a critical intermediate in the transduction of proliferative signals. Numerous observations have demonstrated that integrin-mediated cell anchorage can regulate the efficiency of signaling from RTKs to MAPK. Recently, a relationship between integrins and GPCR signaling has also emerged; however, little is understood concerning the mechanisms involved. Here, we investigate integrin regulation of GPCR signaling to MAPK, focusing on the P2Y class of GPCRs that function through activation of phospholipase Cbeta. P2Y receptor signaling to the downstream components mitogen-activated protein kinase kinase and MAPK is highly dependent on integrin-mediated cell anchorage. However, activation of upstream events, including inositol phosphate production and generation of calcium transients, is completely independent of cell anchorage. This indicates that integrins regulate the linkage between upstream and downstream events in this GPCR pathway, just as they do in some aspects of RTK signaling. However, the P2Y pathway does not involve cross-activation of a RTK, nor a role for Shc or c-Raf; thus, it is quite distinct from the classical RTK-Ras-Raf-MAPK cascade. Rather, integrin-modulated P2Y receptor stimulation of MAPK depends on calcium and on the activation of protein kinase C.
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PMID:Integrins regulate the linkage between upstream and downstream events in G protein-coupled receptor signaling to mitogen-activated protein kinase. 1077 98

There is increasing evidence that sphingolipids are involved in cell survival, differentiation or commitment to death. The effect of different sphingolipids and inhibitors of mitogen-activated protein kinase (MAPK) cascade on SH-SY5Y neuroblastoma cell death has been studied. Permeant ceramide analogues C2-Cer, C8-Cer, and C8-Cer-1-phosphate, but not dihydro C2-Cer induce apoptosis, as shown by Hoechst staining. Inhibition of ceramidase and sphingosine kinase, as well as incubation with sphingosine, decreases cell viability, measured as 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide reduction, whereas addition of sphingosine-1-phosphate increases proliferation. Both PD98059 (MAPKK inhibitor) and SB202190 (p38 MAPK inhibitor) decreased viability, but only SB202190 abolished the effect of ceramide. These results suggest that in SH-SY5Y neuroblastoma cells, death is signalled by increases in ceramide, ceramide-phosphate or sphingosine content through p38 MAPK pathway while survival requires MAPK and high sphingosine-1-phosphate/ceramide ratio.
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PMID:Sphingomyelinase metabolites control survival and apoptotic death in SH-SY5Y neuroblastoma cells. 1080 17

The authors have examined the role of the src-family of protein tyrosine kinases in leukotriene B(4) (LTB(4))-induced activation of guinea-pig eosinophils. Western blot analysis identified the src-like protein tyrosine kinases p53(lyn), p56(lyn), p56/59(hck), p55(fgr), and p56(lck) whereas p60(src), p62(yes), p55(blk), and p59(fyn) were not detected. LTB(4) promoted a rapid increase in p53/56(lyn) activity in eosinophils, which peaked at 5 seconds and remained elevated at 60 seconds; hck, fgr, and lck were not activated. A role for p53/56(lyn) in eosinophil activation was investigated with the use of the src-selective inhibitor PP1 (1 micromol/L to 10 micromol/L), which attenuated LTB(4)-stimulated p53/56(lyn) activity and the phosphorylation of extracellular signal-regulated kinase-2 in intact cells. At comparable concentrations, PP1 was also shown to attenuate LTB(4)-induced nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) oxidase activation, chemotaxis, and Ca(++)-dependent [(3)H]arachidonic acid (AA) release. Moreover, an inhibitor of mitogen-activated protein kinase kinase-1, PD 098059, significantly inhibited LTB(4)-induced chemotaxis but had no effect on oxidant production or [(3)H]AA release. Collectively, these results implicate lyn kinase in LTB(4)-induced eosinophil activation through the recruitment of divergent cell-signaling pathways.
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PMID:Pleiotropic role of lyn kinase in leukotriene B(4)-induced eosinophil activation. 1082 41


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