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)

Epidermal growth factor (EGF) stimulates gastric acid secretion and H(+)/K(+)-ATPase alpha-subunit gene expression. Because EGF activates the serine-threonine protein kinase Akt, we explored the role of Akt in gastric acid secretion. Akt phosphorylation and activation were measured by kinase assays and by Western blots with an anti-phospho-Akt antibody, using lysates of purified (>95%) canine gastric parietal cells in primary culture. EGF induced Akt phosphorylation and activation, whereas carbachol had no effect. LY294002, an inhibitor of phosphoinositide 3-kinase, completely blocked EGF induction of Akt phosphorylation, whereas the MEK1 inhibitor PD98059 and the protein kinase C inhibitor GF109203X had no effect. We examined the role of Akt in H(+)/K(+)-ATPase gene expression by Northern blotting using a canine H(+)/K(+)-ATPase alpha-subunit cDNA probe. The parietal cells were transduced with a multiplicity of infection of 100 of the adenoviral vector Ad.Myr-Akt, which overexpresses a constitutively active Akt gene, or with the control vector Ad.CMV-beta-gal, which expresses beta-galactosidase. Ad.Myr-Akt induced H(+)/K(+)-ATPase alpha-subunit gene expression 3-fold, whereas it failed to stimulate the gene cyclooxygenase-2, which was potently induced by carbachol in the same parietal cells. Ad.Myr-Akt induced aminopyrine uptake 4-fold, and it potentiated the stimulatory action of carbachol 3-fold. In contrast, Ad.Myr-Akt failed to induce changes in either parietal cell actin content, measured by Western blots with an anti-actin antibody or in the organization of the actin cellular cytoskeleton, visualized by fluorescein phalloidin staining and confocal microscopy. Transduction of the parietal cells with a multiplicity of infection of 100 of the adenoviral vector Ad.dom.neg.Akt, which overexpresses an inhibitor of Akt, blocked the stimulatory effect of EGF on both aminopyrine uptake and H(+)/K(+)-ATPase production, measured by Western blots with an anti-H(+)/K(+)-ATPase alpha-subunit antibody. Thus, EGF induces a cascade of events in the parietal cells that results in the activation of Akt. The functional role of Akt appears to be stimulation of gastric acid secretion through induction of H(+)/K(+)-ATPase expression.
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PMID:Functional role of protein kinase B/Akt in gastric acid secretion. 1156 30

Exposure of insulin-secreting RINm5F cells to the chemical nitric oxide donor sodium nitroprusside (SNP) resulted in apoptotic cell death, as detected by cytochrome c release from mitochondria and caspase 3 activation. SNP exposure also leads to phosphorylation and activation of enzymes involved in cellular response to stress such as signal-regulated kinase 2 (ERK2) and c-Jun NH(2)-terminal kinase 46 (JNK46). Both cytochrome c release and caspase 3 activation were abrogated in cells exposed to MEK and p38 inhibitors. Treatment of cells with the NO donors SNP, DETA-NO, GEA 5024, and SNAP resulted in phosphorylation of the antiapoptotic protein Bcl-2, which was resistant to blockade of MEK, p38, and JNK pathways and sensitive to phosphoinositide 3-kinase (PI3K) inhibition. In addition, transient transfection of cells with the wild-type PI3K gamma gene mimics the increased rate of Bcl-2 phosphorylation detected in NO-treated cells. The generation of phosphoinositides seems to participate in the process since Bcl-2 phosphorylation was not observed in cells overexpressing lipid-kinase-deficient PI3Kgamma. The potential of SNP toxicity directly from NO was supported by our finding that the NO scavenger carboxy-PTIO prevented cell death. We found no evidence to support the contention that oxygen radicals generated during cellular SNP metabolism mediate cell toxicity in RINm5F cells, since neither addition of catalase/superoxide dismutase nor transfection with superoxide dismutase prevented SNP-induced cell death. Thus, we propose that exposure to apoptotic concentrations of NO triggers ERK- and p38-dependent cytochrome c release, caspase 3 activation, and PI3K-dependent Bcl-2 phosphorylation.
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PMID:Sodium nitroprusside-induced mitochondrial apoptotic events in insulin-secreting RINm5F cells are associated with MAP kinases activation. 1157 Aug 14

Type-I phosphoinositide 3-kinases (PI3Ks) were characterized as a group of intracellular signalling proteins expressing both protein and lipid kinase activities. Recent studies implicate PI3Ks as mediators of oocyte maturation, but the molecular mechanisms are poorly defined. Here we used the Xenopus oocyte expression system as a model to investigate a possible contribution of the gamma-isoform of PI3K (PI3Kgamma) in the different pathways leading to cell-cycle progression by monitoring the time course of germinal vesicle breakdown (GVBD). Expression of a constitutive active PI3Kgamma (PI3Kgamma-CAAX) induced GVBD and increased the levels of phosphorylated Akt/protein kinase B and mitogen-activated protein kinase (MAPK). Furthermore, PI3Kgamma-CAAX accelerated progesterone-induced GVBD, but had no effect on GVBD induced by insulin. The effects of PI3Kgamma-CAAX could be suppressed by pre-incubation of the oocytes with LY294002, PD98059 or roscovitine, inhibitors of PI3K, MEK (MAPK/extracellular-signal-regulated protein kinase kinase) and cdc2/cyclin B kinase, respectively. Mutants of PI3Kgamma-CAAX, in which either lipid kinase or both lipid and protein kinase activities were altered or eliminated, did not induce significant GVBD. Our data demonstrate that expression of PI3Kgamma in Xenopus oocytes accelerates their progesterone-induced maturation and that lipid kinase activity is required to induce this effect.
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PMID:Phosphoinositide 3-kinase-gamma induces Xenopus oocyte maturation via lipid kinase activity. 1173 61

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are a group of kinases that play an important role in proliferation and differentiation. In megakaryocyte-like human erythroleukemia (HEL) cells, ERK2 was found to be predominantly expressed and strongly activated by prostaglandin (PG) E(2), thrombin, and epinephrine. On the other hand, adenosine, ADP, ATP, and UTP did not significantly increase ERK1/2 phosphorylation. However, of the agonists tested, only ADP was able to stimulate thymidine uptake. Pretreatment with pertussis toxin abolished the PGE(2) response but had less of an effect on thrombin. PGE(2)- and thrombin-induced ERK1/2 activation was mimicked by 4-beta-phorbol-12-myristate-13-acetate and ionomycin and blocked by mitogen-activated protein kinase kinase inhibitor 1,4 diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene but displayed differential sensitivity to protein kinase C inhibitor bisindolylmaleimide I and Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Analogs of cAMP or agents that stimulate cAMP production were either weak or ineffective activators. Further studies indicate that the effect of thrombin was blocked by the phosphoinositide 3-kinase inhibitor wortmannin but not by agents inhibiting tyrosine kinase activity. On the contrary, herbimycin, but not wortmannin, attenuated the effect of PGE(2). Collectively, these results indicate that ERK1/2 are selectively activated by G protein-coupled receptors and not functionally associated with proliferation in HEL cells. ERK1/2 activation in response to PGE(2) and thrombin is mediated by distinctive types of G proteins and is differentially regulated by multiple pathways, including calcium mobilization, protein kinase C, phosphoinositide 3-kinase, and tyrosine kinases.
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PMID:Extracellular signal-regulated kinases and g protein-coupled receptors in megakaryocytic human erythroleukemia cells: selective activation, differential regulation, and dissociation from mitogenesis. 1175 34

We hypothesized that glutathione transferases could be induced and may participate to cellular defenses against the oxidative stress occurring during liver regeneration. Here, we evidenced that murine GSTA1 (mGSTA1), A4, Pi, and Mu are up-regulated during mouse liver regeneration, exhibiting a biphasic pattern of induction correlating early G(1) phase and G(1)/S transition of the cell cycle. Using confocal microscopy immunolocalization and subcellular fractionation, mGSTA4 was demonstrated in both mitochondria and cytosol and found preferentially increased in cytosol during liver regeneration. In addition, mGSTA4 was induced in vivo and in cultured hepatocytes by tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6), and epidermal growth factor (EGF), factors that play crucial roles in hepatocyte survival and proliferation during liver regeneration. However, the mitogenic effect of EGF was not responsible for the induction of mGSTA4. In transient transfections, IL-6 and EGF, but not TNFalpha, transactivated the human GSTA4 (hGSTA4) promoter cloned upstream of the luciferase reporter gene suggesting that IL-6 and EGF up-regulated hGSTA4 at a transcriptional level, whereas TNFalpha could rather act at a post-transcriptional level. The inhibition of phosphoinositide 3-kinase, p38 MAPK, and MEK/ERK signaling pathways, using specific inhibitors, prevented EGF-dependent induction of mGSTA4 and transactivation of hGSTA4 promoter. Altogether, these data favor the conclusion that, in regenerating hepatocytes, several GST isoforms are induced and that cytokines TNFalpha and IL-6 and survival factor EGF positively regulate mGSTA4 via survival signaling pathways.
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PMID:Pro-inflammatory cytokines tumor necrosis factor alpha and interleukin-6 and survival factor epidermal growth factor positively regulate the murine GSTA4 enzyme in hepatocytes. 1188 96

Thromboxane A(2) (TXA(2)) stimulates mitogenic growth of vascular smooth muscle. In humans, TXA(2) signals through two TXA(2) receptor (TP) isoforms, termed TPalpha and TPbeta. To investigate the mechanism of TXA(2)-mediated mitogenesis, regulation of extracellular signal-regulated kinase (ERK) signaling was examined in human embryonic kidney 293 cells stably overexpressing the individual TP isoforms. The TXA(2) mimetic 9,11-dideoxy-9alpha,11alpha-methano epoxy prostaglandin F(2alpha) (U46619) elicited concentration- and time-dependent activation of ERK1 and -2 through both TPs with maximal TPalpha- and TPbeta-mediated ERK activation observed after 10 and 5 min, respectively. U46619-mediated ERK activation was inhibited by the TP antagonist [1S-[1alpha,2beta-(5Z)-3beta,4alpha-]]-7-[3-[[2-(phenylamino)carbonyl]hydrazine] methyl]-7-oxabicyclo[-2,2,1-]hept-2yl]-5-heptenoic acid (SQ29,548), and by the mitogen-activated protein kinase kinase inhibitor 2'-amino-3'-methoxyflavone (PD 98059). Although ERK activation through TPalpha was dependent on 2-[1-(dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide (GF 109203X)-sensitive protein kinase (PK) Cs, ERK activation through TPbeta was only partially dependent on PKCs. ERK activation through both TPalpha and TPbeta was dependent on PKA and phosphoinositide 3-kinase (PI3K) class 1(A), but not class 1(B), and was modulated by Harvey-Ras, A-Raf, c-Raf, and Rap1B/B-Raf and also involved transactivation of the epidermal growth factor receptor. Additionally, PKB/Akt was activated through TPalpha and TPbeta in a PI3K-dependent manner. In conclusion, we have defined the key components of TXA(2)-mediated ERK signaling and have established that both TPalpha and TPbeta are involved. TXA(2)-mediated ERK activation through the TPs is a complex event involving PKC-, PKA-, and PI3K-dependent mechanisms in addition to transactivation of the EGF receptor. TPalpha and TPbeta mediate ERK activation through similar mechanisms, although the time frame for maximal ERK activation and PKC dependence differs.
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PMID:Regulation of extracellular signal-regulated kinase cascades by alpha- and beta-isoforms of the human thromboxane A(2) receptor. 1190 Dec 21

The matricellular protein thrombospondin (TSP) stimulates stress fiber and focal adhesion disassembly through a sequence (hep I) in its heparin-binding domain. TSP/hep I signals focal adhesion disassembly by binding cell surface calreticulin (CRT) and activating phosphoinositide 3-kinase (PI3K). However, other components of this signaling pathway have not been identified. We now show that TSP induces focal adhesion disassembly through activation of pertussis toxin (PTX)-sensitive G proteins and ERK phosphorylation. PTX pretreatment inhibits TSP/hep I-mediated focal adhesion disassembly as well as PI3K activation. In addition, membrane-permeable Galpha(i2)- and Gbetagamma-blocking peptides inhibit hep I-mediated focal adhesion disassembly. Hep I stimulates a transient increase in ERK activation, which is abrogated by both PTX and PI3K inhibitors. Inhibiting ERK activation with MEK inhibitors blocks hep I-mediated focal adhesion disassembly, indicating that ERK activation is required for cytoskeletal reorganization. G protein signals and ERK phosphorylation are induced by TSP binding to cell surface CRT, because CRT null mouse embryonic fibroblasts (MEF) fail to stimulate ERK phosphorylation in response to TSP/hep I treatment. These data show that G(i) protein and ERK, in concert with PI3K, are stimulated by TSP.CRT interactions at the cell surface to induce de-adhesive changes in the cytoskeleton.
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PMID:Thrombospondin stimulates focal adhesion disassembly through Gi- and phosphoinositide 3-kinase-dependent ERK activation. 1192 91

Endocytosis is required for efficient mitogen-activated protein kinase (MAPK) activation by activated growth factor receptors. We examined if H-Ras and K-Ras proteins, which are distributed across different plasma membrane microdomains, have equal access to the endocytic compartment and whether this access is necessary for downstream signaling. Inhibition of endocytosis by dominant interfering dynamin-K44A blocked H-Ras but not K-Ras-mediated PC12 cell differentiation and selectively inhibited H-Ras- but not K-Ras-mediated Raf-1 activation in BHK cells. H-Ras- but not K-Ras-mediated Raf-1 activation was also selectively dependent on phosphoinositide 3-kinase activity. Stimulation of endocytosis and endocytic recycling by wild-type Rab5 potentiated H-Ras-mediated Raf-1 activation. In contrast, Rab5-Q79L, which stimulates endocytosis but not endocytic recycling, redistributed activated H-Ras from the plasma membrane into enlarged endosomes and inhibited H-Ras-mediated Raf-1 activation. Rab5-Q79L expression did not cause the accumulation of wild-type H-Ras in enlarged endosomes. Expression of wild-type Rab5 or Rab5-Q79L increased the specific activity of K-Ras-activated Raf-1 but did not result in any redistribution of K-Ras from the plasma membrane to endosomes. These results show that H-Ras but not K-Ras signaling though the Raf/MEK/MAPK cascade requires endocytosis and endocytic recycling. The data also suggest a mechanism for returning Raf-1 to the cytosol after plasma membrane recruitment.
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PMID:H-Ras signaling and K-Ras signaling are differentially dependent on endocytosis. 1207 41

The tumor suppressor PTEN possesses lipid and protein phosphatase activities. It has been well established that the lipid phosphatase activity is essential for its tumor-suppressive function via the phosphoinositide 3-kinase (PI3K) and Akt pathways. The precise role of the protein phosphatase activity is still unclear. In the current study, we demonstrate that overexpression of wild-type PTEN in the MCF-7 breast cancer line results in phosphatase activity-dependent decreases in the phosphorylation of ETS-2, which is a transcription factor whose DNA-binding ability is controlled by phosphorylation. Exposure of MCF-7 cells to insulin, insulin-like growth factor 1 (IGF-1) or epidermal growth factor (EGF) can lead to the phosphorylation of ETS-2, Akt and ERK1/2. The MEK inhibitor PD590089 abrogates insulin-stimulated phosphorylation of ETS-2. In contrast, the PI3K inhibitor LY492002 has no effect on insulin-stimulated phosphorylation of ETS-2, despite the fact that it diminishes insulin-stimulated phosphorylation of Akt. Interestingly, overexpression of PTEN in MCF-7 leads to blockade of insulin-stimulated, but not EGF-stimulated, phosphorylation of ERK, accompanied by dramatic decreases in ETS-2 phosphorylation. We further show that the relationship of PTEN and ETS-2 has functional significance by demonstrating that PTEN abrogates activation of the uPA Ras-responsive enhancer, a target of ETS-2 action, in a phosphatase-dependent manner, irrespective of the presence or absence of insulin. Our observations, therefore, suggest that PTEN blocks insulin-stimulated ETS-2 phosphorylation through inhibition of the ERK members of the MAP kinase family independently of PI3K, and that the PTEN effect on the phosphorylation status of ETS-2 may be mediated through PTEN's protein phosphatase activity.
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PMID:PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway. 1209 11

In the diaphragm muscle we tested the hypothesis that MAP kinase signaling pathways are activated by mechanical stress and such signaling pathways are dependent on the direction in which mechanical stress is applied. Although equal magnitudes of mechanical stress were applied axially and transversely a greater level of activation of ERK1/2, p38, Raf-1, p90 RSK, Elk-1, and the DNA binding activity of AP-1 transcription factor was produced when the muscle was stretched transversely than when stretched axially. A significant up-regulation in protein tyrosine phosphorylation was observed in axially or transversely loaded diaphragm muscles and the activation of ERK1/2 was completely inhibited by genistein (protein-tyrosine kinase inhibitor). Pretreatment of muscles with wortmannin (phosphoinositide 3-kinase inhibitor), TMB-8 (antagonist of intracellular calcium release), GF109203X (PKC inhibitor), or PD98059 (MEK1/2 inhibitor) blocked the activation of ERK1/2 kinases in response to axial but not to transverse loading. On the other hand, pretreatment of muscles with protein kinase A inhibitors H-7 and KT5720 completely suppressed the activation of ERK1/2 in response to transverse loading only. Taken together with the alterations of MAP kinases and the findings of elevations of downstream transcription targets, our data are consistent with two distinct MAP kinase signal transduction pathways in response to mechanical stress.
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PMID:Distinct signaling pathways are activated in response to mechanical stress applied axially and transversely to skeletal muscle fibers. 1222 Oct 78


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