Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Opioid peptides, particularly beta-endorphin, methionine- (MEK) and leucine-enkephalin, and dynorphin, are involved in the regulation of food intake in mammals. The precursor molecules of these peptides undergo differential processing in brain areas producing regional concentration differences in opioids. Intraregional concentration changes also accompany alterations in feeding states. For example, MEK concentrations decrease in the basomedial hypothalamus, amygdala, and olfactory bulb in fed sheep compared with fasted sheep. Moreover, these changes are species specific. In sheep, beta-endorphin decreases in the dorsomedial and posterior hypothalami after feeding, but in the rat it is increased in the ventromedial hypothalamus and decreased in the posterior hypothalamus. In addition, immunohistochemical localization of cell bodies shows interspecies differences in concentrations. For example, dynorphin is found predominantly in the suprachiasmatic area in sheep, but in the paraventricular nucleus in the rat. These observations indicate that regulation of food intake may be differentially controlled in these species. In sheep, kappa agonists increase food intake, whereas stimulation of delta receptors inhibits feeding. Further clarification of the receptors involved in food intake will necessitate studies with more specific agonists.
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PMID:Opioid peptides and the control of feeding in sheep. 302 55

Platelet-derived growth factor (PDGF) BB is a potent mitogen for renal mesangial cells and stimulates a biphasic mitogen-activated protein kinase (MAP kinase) activation. A rapid increase in activity (maximal at 10 min) is followed by a lower persistent level of activity which is maximal at 4-6 h. The second peak of MAP kinase activity is markedly attenuated by the protein synthesis inhibitor cycloheximide and, consequently, is paralleled by a marked de-novo synthesis of p42 and p44 MAP kinases, as measured by immunoprecipitation of [35S]methionine-labeled mesangial cells and by a 700% increase in total MAP kinase protein, as detected by Western-blot analysis. A 30-min treatment with PDGF-BB is sufficient to induce pronounced de-novo synthesis of MAP kinase. However, for maximal induction of MAP kinase synthesis, PDGF is required to be present for at least 4 h. In addition, an increased de-novo synthesis of MAP kinase kinase, the upstream activator of MAP kinase, is observed in response to PDGF stimulation. We propose that PDGF-induced de-novo synthesis of MAP kinase and MAP kinase kinase is important for the potent mitogenic activity of this growth factor.
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PMID:Platelet-derived growth factor stimulates de-novo synthesis of mitogen-activated protein kinase in renal mesangial cells. 785 88

Arg0-Met5-enkephalin (Arg0-MEK) was isolated from bovine striatum and purified to homogeneity. The peptide was extracted with trichloroacetic acid, followed by column chromatography successively on Bio-Sil C8, semipreparative HPLC Radial-Pak C18, fast protein liquid chromatography (FPLC) Mono S, HPLC Ultrasphere-ODS, Supelco C18, Lichromsorb C18, and mu Bondapak C18. The peptide content was followed by radioimmunoassay with an antibody against synthetic Met-enkephalin. For each of the six HPLC and FPLC systems, the elution time of the immunoreactive fractions coincided exactly with that of synthetic Arg0-MEK. The purified peptide showed a highly homogeneous profile in three different analytical HPLC systems. Its retention time and three-dimensional UV spectrum were identical to those of the synthetic Arg0-MEK. The structure of the purified material was identified by microsequencing as the hexapeptide Arg-Tyr-Gly-Gly-Phe-Met. Ninety percent of the purified peptide was in oxidized form containing equimolar amounts of Met-(R)- and Met-(S)-sulfoxide. The reduced Arg0-MEK inhibited aminoenkephalinase with a Ki of 2.2 microM, and its sulfoxide analogue inhibited it with a Ki of 8.9 microM. The reduced or oxidized peptide suppressed the electrically induced contraction of rat vas deferens with an ED50 of 5 microM, and the effect could be reversed by equimolar naloxone. Our data indicate that Arg0-MEK is an immediate Met-enkephalin precursor and an endogenous inhibitor.
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PMID:An endogenous aminoenkephalinase inhibitor: purification and characterization of Arg0-Met5-enkephalin from bovine striatum. 793 30

Exposure of rat glomerular mesangial cells to transforming growth factor beta 2 (TGF beta 2) stimulates a biphasic mitogen-activated protein kinase (MAP kinase) activation. A rapid increase in activity (maximal at 10 min) is followed by a second persistent level of activity which steadily increases over 24 h. The second peak of MAP kinase activity is markedly attenuated by the protein synthesis inhibitor cycloheximide and consequently is paralleled by a pronounced de-novo synthesis of p42 and p44 MAP kinase as measured by immunoprecipitation of [35S]methionine-labeled mesangial cells. In addition, an increased de-novo synthesis of MAP kinase kinase (MEK), the upstream activator of MAP kinase, is observed in response to TGF beta 2 stimulation. We propose that TGF beta-induced activation and de-novo synthesis of MAP kinases and MEK is important for the multifunctional actions of this cytokine in mesangial cells and its role in disease states characterized by excessive fibrosis.
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PMID:Transforming growth factor beta 2 stimulates acute and chronic activation of the mitogen-activated protein kinase cascade in rat renal mesangial cells. 795 34

The chemotactic peptide f-Met-Leu-Phe (fMLP) stimulates leukocyte functions through binding and activation of a specific G-protein-coupled formyl peptide receptor (FPR). Recent studies have shown that stimulation of neutrophils with fMLP induces the activation of two members of the mitogen-activated protein kinase (MAP kinase) family, ERK1 and ERK2, through mechanisms that are not completely understood but may involve the phosphorylation of the adapter protein SHC by the Src-related kinase Lyn. In this study, transfected fibroblasts expressing the rabbit FPR were used to investigate further the role of Lyn and SHC phosphorylation in fMLP-stimulated MAP kinase activation. Stimulation of transfected cells with fMLP resulted in the time- and dose-dependent increase in tyrosine phosphorylation and activation of ERK1 and ERK2 and the activation of MEK, the MAP kinase/ERK kinase. The activation of both ERKs and MEK was inhibited by preincubation of the cells with pertussis toxin, indicating that activation was dependent upon a Gi/Go-like protein that couples to the receptor. Our data also show that, unlike neutrophils, FPR-transfected fibroblasts do not express the Src-related kinase Lyn. In the absence of Lyn, fMLP stimulation did not result in an increased tyrosine phosphorylation of the adapter protein SHC, whereas it was still able to induce MAP kinase activation. These data suggest that Lyn and SHC are not the only upstream signals for activation of the MAP kinase/ERK pathway by fMLP and demonstrate the potential application of the FPR-transfected cells for the delineation of additional signaling mechanisms stimulated by fMLP.
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PMID:Activation of the mitogen-activated protein kinase pathway by fMet-leu-Phe in the absence of Lyn and tyrosine phosphorylation of SHC in transfected cells. 866 60

Mechanisms of neutrophil activation in response to chemoattractants remain incompletely understood. We have recently reported a Ras-mediated c-Raf pathway leading to the activation of mitogen-activated protein (MAP) kinase in human neutrophils stimulated with the chemoattractant formyl-Met-Leu-Phe (FMLP). However, concern that Raf activation may not fully account for the early FMLP-mediated human neutrophil responses prompted us to investigate the activation of MAP kinase/ERK kinase (MEK) by MEK kinase (MEKK). In cell lysates we identified protein species at 180, 160, 110, 72, and 54 kDa with a monoclonal antibody to MEKK. Activation of MEKK was determined on immunoprecipitates from FMLP-stimulated neutrophils by in vitro kinase assay, which utilized both MEK1 and MEK2 as substrates. It was rapid, detectable at 30 s and reaching a plateau at 5 min, and it was inhibited in a dose-dependent fashion by a specific phosphatidylinositol 3-kinase inhibitor, wortmannin. Partial inhibition by pertussis toxin was observed. We were unable to show inhibition of the MEKK response by GF 109203X, a protein kinase C-specific inhibitor. These data indicate that in neutrophils activation of MEKK in addition to Raf may underlie stimulation of MAP kinase and other MAP kinase homologues by FMLP.
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PMID:Activation of MEKK by formyl-methionyl-leucyl-phenylalanine in human neutrophils. Mapping pathways for mitogen-activated protein kinase activation. 896 28

Mutations in Met have been identified in human papillary renal carcinomas. We have shown previously that these mutations deregulate the enzymatic activity of Met and that NIH 3T3 cells expressing mutationally activated Met are transformed in vitro and are tumorigenic in vivo. In the present investigation, we find that mutant Met induces the motility of Madin-Darby canine kidney cells in vitro and experimental metastasis of NIH 3T3 cells in vivo, and that the Ras-Raf-MEK-ERK signaling pathway, which has been implicated previously in cellular motility and metastasis, is constitutively activated by the Met mutants. We also report that transgenic mice harboring mutationally activated Met develop metastatic mammary carcinoma. These data confirm the tumorigenic activity of mutant Met molecules and demonstrate their ability to induce the metastatic phenotype.
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PMID:The mutationally activated Met receptor mediates motility and metastasis. 982 15

Promyelocytic human leukemia HL60 cells can be differentiated into neutrophil-like cells that exhibit an NADPH oxidase activity through direct stimulation of protein kinase C (PKC) with PMA or through formyl peptide receptor activation. We have isolated a variant HL60 clone that exhibited a conditional PMA-induced oxidative response depending on the agent used for the differentiation. While cells differentiated with DMSO responded to either PMA or N-formyl peptide (N-formyl-Met-Leu-Phe-Lys or fMLFK), cells differentiated with dibutyryl-cAMP (Bt2cAMP) responded to fMLFK but very poorly to PMA. However, in Bt2cAMP-differentiated cells, the expression of the different PKC isoforms was similar to that observed in DMSO-differentiated cells. Moreover, PMA was able to induce a normal phosphorylation of the cytosolic factor p47phox and to fully activate extracellular signal-regulated kinases (Erk1/2). Interestingly, Bt2cAMP-differentiated cells exhibited a strong and sustained O2- production when costimulated with PMA and suboptimal concentrations of fMLFK which were, per se, ineffective. This sustained response was only slightly reduced by the conjunction of the mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor PD98059 and wortmannin, a phosphatidylinositol-3 kinase (PI3K) inhibitor. Variant HL60 cells that were stably transfected with a constitutively active form of Rac1 were able, when differentiated with Bt2cAMP, to secrete oxidant following PMA stimulation. Altogether, the results suggest that, in addition to the phosphorylation of p47phox, the activation of NADPH oxidase requires the activation of a Rac protein through a pathway that diverges at a point upstream of MEK and that is independent of the activation of wortmannin sensitive PI3K.
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PMID:Isolation and characterization of a variant HL60 cell line defective in the activation of the NADPH oxidase by phorbol myristate acetate. 986 21

In the present study, we investigated the involvement of Ca2+-signaling and protein kinases in the effect of Ca2+-ATPase inhibitors on the activation of cytosolic phospholipase A2 (cPLA2) in human polymorphonuclear neutrophils. We found that activity and mobility on electrophoresis gels of the cPLA2 protein were significantly increased by f-Met-Leu-Phe (fMLP), 12-myristate 13-acetate (PMA) and the Ca2+-ATPase inhibitors, thapsigargin and cyclopiazonic acid. This effect was completely suppressed by staurosporine. Calphostin C partially inhibited the fMLP- and PMA-induced cPLA 2 activation, but had no influence on thapsigargin- and cyclopiazonic acid-treated cells. Thapsigargin and cyclopiazonic acid also showed no effect on protein kinase C activity. However, the thapsigargin- and cyclopiazonic acid-induced cPLA2 activation was completely inhibited by the tyrosine kinase inhibitor, erbstatin, and Ca2+ chelator, EGTA. In addition, the cPLA2 activity was reduced after pretreatment with the mitogen-activated protein kinase kinase inhibitor PD98059. The arachidonic acid release was significantly reduced in cells pretreated with the cPLA2 inhibitor, AACOCF3. Furthermore, we found that the human neutrophil cPLA2 cDNA contain a Ca2+-dependent-lipid binding domain which shares homology to several other enzymes such as protein kinase C and phospholipase C. Our results suggest that tyrosine kinases and the MAP kinase cascade are involved in Ca2+-ATPase inhibitor-induced activation and phosphorylation of cPLA2. Protein kinase C is not required in this event.
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PMID:Role of Ca2+-ATPase inhibitors in activation of cytosolic phospholipase A2 in human polymorphonuclear neutrophils. 993 28

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


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