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) previously has been shown to stimulate short-term survival in vitro of cells derived from the native amphibian retinal pigment epithelium (RPE). In the present experiments, we have examined intracellular signaling pathways responsible for mediating these survival-specific growth factor effects, distinct from proliferative effects, using the human epithelial cell line RPE D407. When maintained as single cells in suspension culture in the absence of serum and exogenous survival factors, RPE D407 cell viability gradually declined over a 3-4 day period as a result of apoptotic cell death, a pattern similar to that seen for eye-derived RPE cells. Exposure to EGF (50 ng ml(-1)) enhanced cell survival by nearly 40% and caused a parallel increase in the tyrosine phosphate content of the EGF receptor (EGFR), as determined by immunoprecipitation and Western blotting. Both effects were completely blocked by 1 microm AG1478, an EGFR-selective tyrosine kinase inhibitor. EGF also stimulated phosphorylation of the phosphatidylinositol 3'-kinase (PI3K)-dependent effector kinase Akt, as well as that of the MEK-dependent mitogen-activated kinase (MAPK), extracellular signal-regulated kinase (ERK). Furthermore, EGF-induced protection was substantially reduced by either the PI3K inhibitor LY294002 (25 microm) or the MEK inhibitor U0126 (10 microm), under conditions in which phosphorylation of Akt and ERK1/2, respectively, was blocked. Our results indicate that EGF-stimulated survival of RPE D407 cells takes place as a result of signaling through both PI3K and ERK/MAPK pathways. Further, residual anti-apoptotic activity stimulated by EGF in the presence of both blockers suggests that additional as yet unidentified growth factor-dependent survival pathways exist.
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PMID:Epidermal growth factor stimulation of RPE cell survival: contribution of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. 1518

Elevated low density lipoprotein (LDL) cholesterol (LDL-C) levels represent one of the most important risk factors for atherosclerosis and therefore cardiovascular morbidity and mortality. LDL-C operates at different levels and through various classic and non-classic mechanisms. For example, it has been recently shown that both native and oxidized LDL are potent growth factors for several cell types such as vascular smooth muscle cells (VSMC) participating in the development and progression of atherosclerosis. Moreover, LDL-C modulates the expression of various growth factors and growth factor receptors that are involved in the process of atherosclerosis. More specifically, LDL-C can phosphorylate and therefore activate the epidermal growth factor (EGF) receptor and enhance the production of platelet derived growth factor (PDGF)-AA and of the PDGF receptors. LDL as well as oxidized LDL (oxLDL) signal transduction pathways involve trimeric G-proteins and cAMP, protein kinase C and ceramide, diacylglycerol and inositol-1,4,5-triphosphate, Ca(+2), Na(+)/H(+) exchange, c-fos and egr-1, phospholipases C, A2 and D, Raf-1, MEK1/2, the ERK1/2 (p42/44), SAP/JNK and p38 isoforms of the mitogen activated protein kinases (MAPK) as well as the signal transuding element gp 130. Furthermore, the mitogenic effects of oxLDL may be mediated by its oxidation products such as lysophosphatidylcholine (LPC), and lysophosphatidic acid (LPA), through LDL-induced lactosylceramide (LacCer) synthesis, and, as our group has recently shown, through LDL-adherent factors such as sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC). We review the various LDL-mediated signal transduction pathways implicated with the development and progression of atherosclerosis.
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PMID:Possible non-classic intracellular and molecular mechanisms of LDL cholesterol action contributing to the development and progression of atherosclerosis. 1532 Aug 16

The Rac1/Cdc42 effector p21-activated kinase (PAK) is activated by various signaling cascades including receptor-tyrosine kinases and integrins and regulates a number of processes such as cell proliferation and motility. PAK activity has been shown to be required for maximal activation of the canonical Ras/Raf/MEK/ERK Map kinase signaling cascade, likely because of PAK co-activation of Raf and MEK. Herein, we found that adhesion signaling also stimulates an association between PAK1 and ERK1/2. PAK1 and ERK1/2 co-immunoprecipitated from rat aortic smooth muscle cells (SMC) plated on fibronectin, and the two proteins co-localized in membrane ruffles and adhesion complexes following PDGF-BB or sphingosine 1-phosphate treatment, respectively. Far Western analysis demonstrated a direct association between the two proteins, and peptide mapping identified an ERK2 binding site within the autoinhibitory domain of PAK1. Interestingly, deletion of a major ERK binding site in PAK attenuates activation of an ERK-dependent serum-responsive element (SRE)-luciferase reporter gene, indicating that association between PAK and ERK is required to facilitate ERK signaling. We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal to control coordinate activation of ERK by growth factor- and matrix-induced signals.
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PMID:Adhesion stimulates direct PAK1/ERK2 association and leads to ERK-dependent PAK1 Thr212 phosphorylation. 1554 7

Epidermal growth factor (EGF) is a potent mitogen for mesangial cells. The mechanism by which EGF induces DNA synthesis is not precisely understood. We investigated the role of phosphatidylinositol (PI)3-kinase in regulating mitogenesis. EGF increased PI3-kinase activity resulting in stimulation of PDK-1 and Akt kinase activities. Blocking of PI3-kinase activity using LY-294002 or adenoviral expression of PTEN, which dephosphorylates PI3,4,5-tris-phosphate and thus inactivates PI3-kinase signaling, significantly inhibits EGF-induced DNA synthesis. Expression of dominant-negative Akt kinase, however, had no effect on DNA synthesis. But it inhibited EGF-induced phosphorylation of FoxO3a transcription factor, thus demonstrating its functional consequences. These data indicate that EGF increases the DNA synthesis in a PI3-kinase-dependent but Akt-independent manner. In addition to activating PI3-kinase signaling, EGF increased Erk1/2 MAPK activity, leading to transcriptional activation of its nuclear target Elk-1 and resulting in c-fos expression. Inhibition of MAPK activity by MEK inhibitor U-0126 abolished EGF-induced DNA synthesis. Because EGF activates PI3-kinase, which also regulates DNA synthesis, the effect of PI3-kinase on MAPK activity was also examined. Inhibition of PI3-kinase signaling blocked EGF-induced MAPK activity as well as Elk-1-dependent reporter transcription and c-fos gene transcription. To further determine the mechanism of EGF-induced DNA synthesis, we investigated the effect of EGF on the cyclin-dependent kinase inhibitor p27(Kip1). EGF reduced the expression of p27(Kip1). Inhibition of PI3-kinase action or MAPK activity abolished the reduction in p27(Kip1) expression induced by EGF. These data provide the evidence that a linear signal transduction pathway involving PI3-kinase-dependent MAPK regulates EGF-induced DNA synthesis in mesangial cells by regulating c-fos and p27(Kip1) expression.
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PMID:EGF stimulates mesangial cell mitogenesis via PI3-kinase-mediated MAPK-dependent and AKT kinase-independent manner: involvement of c-fos and p27Kip1. 1570 16

We examined the effect of EGF on the proliferation of mouse embryonic stem (ES) cells and their related signal pathways. EGF increased [3H]thymidine and 5-bromo-2'-deoxyuridine incorporation in a time- and dose-dependent manner. EGF stimulated the phosphorylation of EGF receptor (EGFR). Inhibition of EGFR tyrosine kinase with AG-1478 or herbimycin A, inhibition of PLC with neomycin or U-73122, inhibition of PKC with bisindolylmaleimide I or staurosporine, and inhibition of L-type Ca2+ channels with nifedipine or methoxyverapamil prevented EGF-induced [3H]thymidine incorporation. PKC-alpha, -betaI, -gamma, -delta, and -zeta were translocated to the membrane and intracellular Ca2+ concentration ([Ca2+]i) was increased in response to EGF. Moreover, inhibition of EGFR tyrosine kinase, PLC, and PKC completely prevented EGF-induced increases in [Ca2+]i. EGF also increased inositol phosphate levels, which were blocked by EGFR tyrosine kinase inhibitors. Furthermore, EGF rapidly increased formation of H2O2, and pretreatment with antioxidant (N-acetyl-L-cysteine) inhibited EGF-induced increase of [Ca2+]i. In addition, we observed that p44/42 MAPK phosphorylation by EGF and inhibition of EGFR tyrosine kinase, PLC, PKC, or Ca2+ channels blocked EGF-induced phosphorylation of p44/42 MAPKs. Inhibition of p44/42 MAPKs with PD-98059 (MEK inhibitor) attenuated EGF-induced increase of [3H]thymidine incorporation. Finally, inhibition of EGFR tyrosine kinase, PKC, Ca2+ channels, or p44/42 MAPKs attenuated EGF-stimulated cyclin D1, cyclin E, cyclin-dependent kinase (CDK)2, and CDK4, respectively. In conclusion, EGF partially stimulates proliferation of mouse ES cells via PLC/PKC, Ca2+ influx, and p44/42 MAPK signal pathways through EGFR tyrosine kinase phosphorylation.
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PMID:EGF stimulates proliferation of mouse embryonic stem cells: involvement of Ca2+ influx and p44/42 MAPKs. 1610 8

IL-4 and mast cells (MCs) mediate mucosal defense against helminths and are central to allergic inflammation. Lysophosphatidic acid (LPA), an abundant, potent lipid growth factor, stimulates the growth of cultured human MCs (hMCs) in vitro through a pathway involving LPA receptors 1 and 3 (termed the LPA(1) and LPA(3) receptors, respectively) and peroxisome proliferator-activated receptor-gamma. We now report that LPA potently induces the generation of proinflammatory chemokines (MIP-1beta, IL-8, and MCP-1) by hMCs by a mechanism that absolutely requires IL-4. The de novo expression of chemokine mRNA and protein generation involves synergistic actions of calcium flux-dependent NFAT transcription factors and ERK. ERK phosphorylation and chemokine production in response to LPA require IL-4-dependent up-regulation of MEK-1 expression by a pathway involving PI3K. Although receptor-selective agonists for both the LPA(2) and LPA(3) receptors induce calcium fluxes by hMCs, only the LPA(2) receptor-selective agonist fatty alcohol phosphate-12 mimics the IL-4-dependent effect of LPA on chemokine generation. The fact that LPA, an endogenous lipid mediator, activates hMCs by an LPA(2) receptor-dependent pathway indicates functional distinctions between different LPA receptor family members that are expressed constitutively by cells of a single hemopoietic lineage. Moreover, the regulation of MEK-dependent signaling is a mechanism by which IL-4 could amplify inflammation in mucosal immune responses through receptor systems for endogenous ligands such as LPA.
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PMID:IL-4 regulates MEK expression required for lysophosphatidic acid-mediated chemokine generation by human mast cells. 1621 Jun 50

We evaluated the effects of d-myo-inositol 1,4,5-tris-phosphate on cardiac hypertrophy. d-myo-inositol 1,4,5-tris-phosphate augmented cardiac hypertrophy as evidenced by its effects on DNA synthesis, protein synthesis, and expression of immediate-early genes c-myc and c-fos, beta-myosin heavy chain, and alpha-actin. The administration of d-myo-inositol 1,4,5-tris-phosphate increased the expression of nuclear factor of activated T-cells and cardiac-restricted zinc finger transcription factor (GATA4). Real-time quantitative RT-PCR showed that d-myo-inositol 1,4,5-tris-phosphate-induced GATA4 mRNA was significantly enhanced even in the presence of the calcineurin inhibitor, cyclosporine A. The effect of d-myo-inositol 1,4,5-tris-phosphate was blocked after inhibition of inositol-trisphosphate receptors but not after inhibition of c-Raf/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (ERK) or p38 mitogen-activated protein kinase pathways. The study shows that d-myo-inositol 1,4,5-tris-phosphate-induced cardiac hypertrophy is mediated by GATA4 but independent from the calcineurin pathway.
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PMID:GATA4-mediated cardiac hypertrophy induced by d-myo-inositol 1,4,5-tris-phosphate. 1625 52

Herein we report that the prosurvival sphingolipid sphingosine 1-phosphate regulates the activities of both Bad and Bax during apoptosis of Jurkat cells. First, sphingosine 1-phosphate treatment results in Bad inactivation via the ERK/Rsk-1 pathway. Second, sphingosine 1-phosphate blocks the translocation of Bax to the mitochondria induced by Fas ligation. MEK inhibition by PD98059 or U0126 not only abrogates sphingosine 1-phosphate-induced Bad phosphorylation, but also its cytoprotective effect. Furthermore, inhibition of both mitochondrial cytochrome c efflux and Bax translocation to the mitochondria by sphingosine 1-phosphate could be overcome by PD98059 or U0126. Hence, the MEK/ERK pathway seems to be crucial for the survival effects initiated by sphingosine 1-phosphate.
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PMID:Regulation by sphingosine 1-phosphate of Bax and Bad activities during apoptosis in a MEK-dependent manner. 1641 56

Perifosine is a synthetic novel alkylphospholipid, a new class of antitumor agents which targets cell membranes and inhibits Akt activation. Here we show that baseline phosphorylation of Akt in multiple myeloma (MM) cells is completely inhibited by perifosine [octadecyl-(1,1-dimethyl-piperidinio-4-yl)-phosphate] in a time- and dose-dependent fashion, without inhibiting phosphoinositide-dependent protein kinase 1 phosphorylation. Perifosine induces significant cytotoxicity in both MM cell lines and patient MM cells resistant to conventional therapeutic agents. Perifosine does not induce cytotoxicity in peripheral blood mononuclear cells. Neither exogenous interleukin-6 (IL-6) nor insulinlike growth factor 1 (IGF-1) overcomes Perifosine-induced cytotoxicity. Importantly, Perifosine induces apoptosis even of MM cells adherent to bone marrow stromal cells. Perifosine triggers c-Jun N-terminal kinase (JNK) activation, followed by caspase-8/9 and poly (ADP)-ribose polymerase cleavage. Inhibition of JNK abrogates perifosine-induced cytotoxicity, suggesting that JNK plays an essential role in perifosine-induced apoptosis. Interestingly, phosphorylation of extracellular signal-related kinase (ERK) is increased by perifosine; conversely, MEK inhibitor synergistically enhances Perifosine-induced cytotoxicity in MM cells. Furthermore, perifosine augments dexamethasone, doxorubicin, melphalan, and bortezomib-induced MM cell cytotoxicity. Finally, perifosine demonstrates significant antitumor activity in a human plasmacytoma mouse model, associated with down-regulation of Akt phosphorylation in tumor cells. Taken together, our data provide the rationale for clinical trials of perifosine to improve patient outcome in MM.
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PMID:Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. 1641 32

Sphingosine kinase (SK) is an oncogenic sphingolipid-metabolizing enzyme that catalyzes the formation of the mitogenic second messenger sphingosine-1-phosphate (S1P) at the expense of proapoptotic ceramide. Thus, SK is an attractive target for cancer therapy because blockage of S1P formation leads to inhibition of proliferation, as well as the induction of apoptosis in cancer cells. We have recently identified novel SK inhibitors with nanomolar to low micromolar potencies toward recombinant human SK. This study describes the continuing analysis of these inhibitors through in vitro and in vivo experiments. All three structurally diverse SK inhibitors tested showed antitumor activity in mice without exhibiting toxicity. Blood and tumor inhibitor concentrations exceeded in vitro potency levels. Cell signaling analyses in vitro revealed mixed inhibition of mitogen-activated protein kinase kinase and Akt phosphorylation by the SK inhibitors. Importantly, 4-[4-(4-chloro-phenyl)-thiazol-2-ylamino]-phenol (SKI-II) is orally bioavailable, detected in the blood for at least 8 h, and showed a significant inhibition of tumor growth in mice. These compounds are the first examples of nonlipid selective inhibitors of SK with in vivo antitumor activity and provide leads for further development of inhibitors of this important molecular target.
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PMID:Antitumor activity of sphingosine kinase inhibitors. 1663 40


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