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 RAS gene product is normally a membrane-localized G protein (N-Ras, K-Ras and H-Ras) of 21 kDa classically described as a molecular off/on switch. It is inactive when bound to guanosine diphosphate and active when bound to GTP. When mutated, the gene produces an abnormal protein resistant to GTP hydrolysis by GTPase, resulting in a constitutively active GTP-bound protein that stimulates a critical network of signal transduction pathways that lead to cellular proliferation, survival and differentiation. At least three downstream effector pathways have been described, including Raf/MEK/ERK, PI3K/AKT and RalGDS, but they are not completely understood. Ras pathways are also important downstream effectors of several receptor tyrosine kinases localized in the cell membrane, most notably the BCR-ABL fusion protein seen in patients with Philadelphia chromosome positive chronic myelogenous leukemia. An important consideration in designing strategies to block Ras stimulatory effect is that Ras proteins are synthesized in the cytosol, but require post-translational modifications and attachment to anchor proteins or membrane binding sites in the cell membrane to be biologically active. Farnesyl transferase inhibitors (FTIs) are probably the best-studied class of Ras inhibitors in hematologic malignancies. They block the enzyme farnesyl-transferase (FTase), which is essential for post-translational modification. However, it has been observed that the Ras proteins also can be geranylgeranylated in the presence of FTIs, thus allowing membrane localization and activation, which limits their effectiveness. It is now hypothesized that their mechanism of action may be through FTase inhibition involving other signal transduction pathways. S-trans, trans-farnesylthiosalicylic acid, which was first designed as a prenylated protein methyltransferase inhibitor, has shown in vitro activity against all activated Ras proteins by dislodging them from their membrane-anchoring sites. Here, Ras biology, its signaling pathways and its implications as a therapeutic target in hematologic malignancies are reviewed.
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PMID:Ras as a therapeutic target in hematologic malignancies. 1760 1

Na+/K+-ATPase functions as both an ion pump and a signal transducer. Cardiac glycosides partially inhibit Na+/K+-ATPase, causing activation of multiple interrelated growth pathways via the Na+/K+-ATPase/c-Src/epidermal growth factor receptor complex. Such pathways include Ras/MEK/ERK and Ral/RalGDS cascades, which can lead to cardiac hypertrophy. In search of novel Ral-GTPase binding proteins, we used RalB as the bait to screen a human testes cDNA expression library using the yeast 2-hybrid system. The results demonstrated that 1 of the RalB interacting clones represented the C-terminal region of the beta1 subunit of Na+/K+-ATPase. Further analysis using the yeast 2-hybrid system and full-length beta1 subunit of Na+/K+-ATPase confirmed the interaction with RalA and RalB. In vitro binding and pull-down assays demonstrated that the beta1 subunit of Na+/K+-ATPase interacts directly with RalA and RalB. Ral-GTP pull-down assays demonstrated that short-term ouabain treatment of A7r5 cells, a rat aorta smooth muscle cell line, caused activation of Ral GTPase. Maximal activation was observed 10 min after ouabain treatment. Ouabain-mediated Ral activation was inhibited upon the stimulation of Na+/K+-ATPase activity by Ang II. We propose that Ral GTPase is involved in the signal transducing function of Na+/K+-ATPase and provides a possible molecular mechanism connecting Ral to cardiac hypertrophy during diseased conditions.
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PMID:Ral-GTPase interacts with the beta1 subunit of Na+/K+-ATPase and is activated upon inhibition of the Na+/K+ pump. 1761 54

Rac-dependent NADPH oxidases generate reactive oxygen species used in cell signaling and microbial killing or both. Whereas the mechanisms leading to NADPH oxidase activation are fairly well studied, the mechanisms that control downregulation of this enzyme complex remain unclear. We hypothesized that reactive oxygen species produced by NADPH oxidase may autoregulate the complex by inhibiting Rac activity. To this end, we searched for binding partners of Rac1 and identified a tyrosine-phosphorylated fragment of MKK6 that bound to Rac1 under redox-stress conditions. Constitutively active MKK6 interacted directly with Rac1 in vitro, and this interaction was enhanced when MKK6 was phosphorylated on tyrosine 219. Both Rac1 and Rac2 immunoprecipitated an MKK6 fragment under conditions that elevate cellular peroxide levels in 293 and RAW cells, respectively. Constitutively active and wild-type MKK6 enhanced Rac-GTPase activity in vitro, and their overexpression inhibited PMA-induced NADPH oxidase activation in RAW cells. In contrast, a Y219F mutant of MKK6 only partially enhanced Rac1 GTPase activity, and its overexpression did not alter PMA-induced NADPH oxidase activation in RAW cells. Last, MKK6 deficiency led to an increase in Rac1-GTP levels in brain tissue. Our findings suggest that MKK6 downregulates NADPH oxidase activity by enhancing Rac-GTPase activity.
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PMID:MKK6 phosphorylation regulates production of superoxide by enhancing Rac GTPase activity. 1785 74

Adoptive cellular immunotherapy inducing a graft-versus-tumor (GVT) effect is the therapeutic mainstay of allogeneic hematopoietic stem cell transplantation (ASCT) for high-risk leukemias. Autologous immunotherapies using vaccines or adoptive transfer of ex vivo-manipulated lymphocytes are clinically explored in patients with various cancer entities. Main reason for failure of ASCT and cancer immunotherapy is progression of the underlying malignancy, which is more prevalent in patients with advanced disease. Elucidating the molecular mechanisms contributing to immune escape will help to develop strategies for the improvement of immunologic cancer treatment. To this end, we have undertaken functional screening and expression cloning of factors mediating resistance to antigen-specific cytotoxic T lymphocytes (CTLs). We have identified Cdc42, a GTPase regulating actin dynamics and growth factor signaling that is highly expressed in invasive cancers, as determinator of cancer cell susceptibility to antigen-specific CTLs in vitro and adoptively transferred immune effectors in vivo. Cdc42 prevents CTL-induced apoptosis via mitogen-activated protein kinase (MAPK) signaling and posttranscriptional stabilization of Bcl-2. Pharmacologic inhibition of MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) overcomes Cdc42-mediated immunoresistance and activation of Bcl-2 in vivo. In conclusion, Cdc42 signaling contributes to immune escape of cancer. Targeting Cdc42 may improve the efficacy of cancer immunotherapies.
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PMID:An immune escape screen reveals Cdc42 as regulator of cancer susceptibility to lymphocyte-mediated tumor suppression. 1797 88

Receptor Tyrosine Kinase (RTK)/Ras GTPase/MAP kinase (MAPK) signaling pathways are used repeatedly during metazoan development to control many different biological processes. In the nematode Caenorhabditis elegans, two different RTKs (LET-23/EGFR and EGL-15/FGFR) are known to stimulate LET-60/Ras and a MAPK cascade consisting of the kinases LIN-45/Raf, MEK-2/MEK and MPK-1/ERK. This Ras/MAPK cascade is required for multiple developmental events, including induction of vulval, uterine, spicule, P12 and excretory duct cell fates, control of sex myoblast migration and axon guidance, and promotion of germline meiosis. Studies in C. elegans have provided much insight into the basic framework of this RTK/Ras/MAPK signaling pathway, its regulation, how it elicits cell-type specific responses, and how it interacts with other signaling pathways such as the Wnt and Notch pathways.
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PMID:RTK/Ras/MAPK signaling. 1805 Apr 74

Prostaglandin (PG) E(2) may regulate invasiveness of human placenta because we previously reported stimulation of migration of placental trophoblasts by PGE(2) acting through PGE receptor (EP)-1 and activating calpain. RhoA GTPase and its important effector Rho kinase (ROCK) have also been previously shown to regulate trophoblast migration. Using immortalized HTR-8/SVneo trophoblast cells and first-trimester human chorionic villus explant cultures on matrigel, we further examined the role of RhoA/ROCK and MAPK (ERK1/2) pathways on PGE(2)-mediated stimulation of trophoblast migration. Migration of cytotrophoblasts was shown to be inhibited by treatment of the trophoblast cell line and chorionic villus explants with either cell-permeable C3 transferase or selective RhoA small interfering RNA. These inhibitions were significantly mitigated by the addition of PGE(2), an EP1/EP3 agonist or an EP3/EP4 agonist, suggesting that RhoA plays an important role in trophoblast migration but may not be obligatory for PGE(2) action. Treatment of HTR-8/SVneo cells with nonselective ROCK inhibitor Y27632 or ROCK small interfering RNAs inhibited migration of these cells, which could not be rescued with PGE(2) or the other two EP agonists, suggesting the obligatory role of ROCK in PGE(2)-induced migratory response. Furthermore, U0126, an inhibitor of MAPK kinases MEK1 and MEK2, abrogated PGE(2)-induced migration of trophoblasts, and PGE(2) or the other two EP agonists stimulated ERK1/2 activation in trophoblasts, which was not abrogated by pretreatment with C3 transferase, indicating that ERK signaling pathway is an efficient alternate pathway for RhoA in PGE(2)-mediated migration of trophoblasts. These results suggest that ROCK and ERK1/2 play more important roles than RhoA in PGE(2)-mediated migration stimulation of first-trimester trophoblasts.
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PMID:Roles of Rho guanosine 5'-triphosphatase A, Rho kinases, and extracellular signal regulated kinase (1/2) in prostaglandin E2-mediated migration of first-trimester human extravillous trophoblast. 1807 97

The propensity of T cells to generate coordinated cytokine responses is critical for the host to develop resistance to pathogens while maintaining the state of immunotolerance to self-antigens. The exact mechanisms responsible for preventing the overproduction of proinflammatory cytokines including interferon (IFN)-gamma are not fully understood, however. In this study, we examined the role of a recently described Ras GTPase effector and repressor of the Raf/MEK/ERK cascade called impedes mitogenic signal propagation (Imp) in limiting the induction of T-cell cytokines. We found that stimulation of the T cell receptor complex leads to the rapid development of a physical association between Ras and Imp. Consistent with the hypothesis that Imp inhibits signal transduction, we also found that disengagement of this molecule by the Ras(V12G37) effector loop mutant or RNA interference markedly enhances the activation of the NFAT transcription factor and IFN-gamma secretion. A strong output of IFN-gamma is responsible for the distinct lymphocyte traffic pattern observed in vivo because the transgenic or retroviral expression of Ras(V12G37) caused T cells to accumulate preferentially in the lymph nodes and delayed their escape from the lymphoid tissue, respectively. Together, our results describe a hitherto unrecognized negative regulatory role for Imp in the production of IFN-gamma in T cells and point to Ras-Imp binding as an attractive target for therapeutic interventions in conditions involving the production of this inflammatory cytokine.
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PMID:p21 Ras/impedes mitogenic signal propagation regulates cytokine production and migration in CD4 T cells. 1857 12

Infection with hepatitis C virus (HCV) is still a major public health problem, and the events leading to hepatocyte infection are not yet fully understood. Combining confocal microscopy with biochemical analysis and studies of infection requirements using pharmacological inhibitors and small interfering RNAs, we show here that engagement of CD81 activates the Rho GTPase family members Rac, Rho, and Cdc42 and that the block of these signaling pathways drastically reduces HCV infectivity. Activation of Rho GTPases mediates actin-dependent relocalization of the HCV E2/CD81 complex to cell-cell contact areas where CD81 comes into contact with the tight-junction proteins occludin, ZO-1, and claudin-1, which was recently described as an HCV coreceptor. Finally, we show that CD81 engagement activates the Raf/MEK/ERK signaling cascade and that this pathway affects postentry events of the virus life cycle. In conclusion, we describe a range of cellular events that are manipulated by HCV to coordinate interactions with its multiple coreceptors and to establish productive infections and find that CD81 is a central regulator of these events.
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PMID:CD81 is a central regulator of cellular events required for hepatitis C virus infection of human hepatocytes. 1857 6

The epithelial Na(+) channel (ENaC) is an essential channel responsible for Na(+) reabsorption. Coexpression of Rab11a and Rab3a small G proteins with ENaC results in a significant increase in channel activity. In contrast, coexpression of Rab5, Rab27a, and Arf-1 had no effect or slightly decreased ENaC activity. Inhibition of MEK with PD98059, Rho-kinase with Y27632 or PI3-kinase with LY294002 had no effect on ENaC activity in Rab11a-transfected CHO cells. Fluorescence imaging methods demonstrate that Rab11a colocalized with ENaC. Rab11a increases ENaC activity in an additive manner with dominant-negative dynamin, which is a GTPase responsible for endocytosis. Brefeldin A, an inhibitor of intracellular protein translocation, blocked the stimulatory action of Rab11a on ENaC activity. We conclude that ENaC channels, present on the apical plasma membrane, are being exchanged with channels from the intracellular pool in a Rab11-dependent manner.
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PMID:Regulation of ENaC expression at the cell surface by Rab11. 1892 97

Anthrax lethal factor (LF), secreted by Bacillus anthracis, interacts with protective antigen to form a bipartite toxin (lethal toxin [LT]) that exerts pleiotropic biological effects resulting in subversion of the innate immune response. Although the mitogen-activated protein kinase kinases (MKKs) are the major intracellular protein targets of LF, the pathology induced by LT is not well understood. The statin family of HMG-coenzyme A reductase inhibitors have potent anti-inflammatory effects independent of their cholesterol-lowering properties, which have been attributed to modulation of Rho family GTPase activity. The Rho GTPases regulate vesicular trafficking, cytoskeletal dynamics, and cell survival and proliferation. We hypothesized that disruption of Rho GTPase function by statins might alter LT action. We show here that statins delay LT-induced death and MKK cleavage in RAW macrophages and that statin-mediated effects on LT action are attributable to disruption of Rho GTPases. The Rho GTPase-inactivating toxin, toxin B, did not significantly affect LT binding or internalization, suggesting that the Rho GTPases regulate trafficking and/or localization of LT once internalized. The use of drugs capable of inhibiting Rho GTPase activity, such as statins, may provide a means to attenuate intoxication during B. anthracis infection.
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PMID:Inactivation of rho GTPases by statins attenuates anthrax lethal toxin activity. 1893 76


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