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)

Signaling via the Ras pathway involves sequential activation of Ras, Raf-1, mitogen-activated protein kinase kinase (MKK), and the extracellular signal-regulated (ERK) group of mitogen-activated protein (MAP) kinases. Expression from the c-Fos, atrial natriuretic factor (ANF), and myosin light chain-2 (MLC-2) promoters during phenylephrine-induced cardiac muscle cell hypertrophy requires activation of this pathway. Furthermore, constitutively active Ras or Raf-1 can mimic the action of phenylephrine in inducing expression from these promoters. In this study, we tested whether constitutively active MKK, the molecule immediately downstream of Raf, was sufficient to induce expression. Expression of constitutively active MKK induce ERK2 kinase activity and caused expression from the c-Fos promoter, but did not significantly activate expression of reporter genes under the control of either the ANF or MLC-2 promoters. Expression of CL100, a phosphatase that inactivates ERKs, prevented expression from all of the promoters. Taken together, these data suggest that ERK activation is required for expression from the Fos, ANF, and MLC-2 promoters but MKK and ERK activation is sufficient for expression only from the Fos promoter. Constitutively active MKK synergized with phenylephrine to increase expression from a c-Fos- or an AP1-driven reporter. However, active MKK inhibited phenylephrine- and Raf-1-induced expression from the ANF and MLC-2 promoters. A DNA sequence in the MLC-2 promoter that is a target for inhibition by active MKK, but not CL100, was mapped to a previously characterized DNA element (HF1) that is responsible for cardiac specificity. Thus, activation of cardiac gene expression during phenylephrine-induced hypertrophy requires ERK activation but constitutive activation by MKK can inhibit expression by targeting a DNA element that controls the cardiac specificity of gene expression.
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PMID:Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase. 858 50

Protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine phosphatase present in most tissues and cell types, has been implicated in the regulation of cell cycle progression, DNA replication, transcription, and translation. Here we present genetic evidence suggesting that PP2A functions downstream of Ras1 in the Sevenless receptor tyrosine kinase (RTK) signal transduction pathway that specifies R7 photoreceptor cell fate in the developing Drosophila eye. Ras1 and downstream cytoplasmic kinases, Raf, MEK, and MAPK, comprise an evolutionarily conserved cascade that mediates the transmission of signals from RTKs at the plasma membrane to specific factors in the nucleus. Using transgenic flies expressing constitutively activated Ras1 or Raf proteins that function independently of upstream signaling events, we show that a reduction in the dose of the gene encoding the catalytic subunit of PP2A stimulates signaling from Ras1 but impairs signaling from Raf. This suggests that PP2A both negatively and positively regulates the Ras1 cascade by dephosphorylating factors that function at different steps in the cascade.
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PMID:Protein phosphatase 2A positively and negatively regulates Ras1-mediated photoreceptor development in Drosophila. 859 78

Hepatocyte growth factor (HGF) stimulated mitogen-activated protein (MAP) kinases and MAP kinase kinase in primary cultured rat hepatocytes. Inhibitors for protein kinase C (PKC), Ro31-8425, H-7, and calphostin C, reduced HGF-induced MAP kinase activity. A PKC activator, phorbol myristate acetate (PMA), induced MAP kinase activation in a concentration-dependent manner. Protein tyrosine kinase (PTK) inhibitors, genistein, and ST638 also inhibited HGF-induced MAP kinase activation. Furthermore, HGF increased formation of Ras guanosine triphosphate (GTP) complex, indicating Ras activation. Genistein inhibited HGF-induced Ras activation, but Ro31-8425 was without effect. On the other hand, Ro31-8425 decreased HGF-induced [3H]arachidonic acid (AA) release and [3H]thymidine incorporation. Genistein also prevented [3H]AA release and [3H]-thymidine incorporation. Moreover, a commonly used phospholipase A2 (PLA2) inhibitor, quinacrine, decreased HGF-induced [3H]AA release and [3H]thymidine incorporation. The inhibitory profile of [3H]AA release was well correlated with that of [3H]thymidine incorporation in Ro31-8425-, genistein-, and quinacrine-treated cells. A cyclooxygenase inhibitor, indomethacin, which suppressed HGF-induced DNA synthesis, had minimal effect on MAP kinase activation. In contrast, prostaglandin (PG) E1, E2, or F2 alpha, which stimulate [3H]thymidine incorporation to the same level as that caused by HGF in hepatocytes, caused very weak activation of MAP kinases. These results suggest that PTK, Ras, and PKC play roles in MAP kinase activation induced by HGF and that MAP kinase activation resulting in AA release is involved in DNA synthesis in rat hepatocytes.
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PMID:Mitogen-activated protein kinase activation in hepatocyte growth factor-stimulated rat hepatocytes: involvement of protein tyrosine kinase and protein kinase C. 862 Nov 60

PTP1C, an SH2 domain-containing protein-tyrosine phosphatase, is predominantly expressed in hematopoietic cells, in which it negatively regulates cellular signaling. However, this enzyme is also expressed in many non-hematopoietic cells. We demonstrate here that in non-hematopoietic 293 cells, overexpression of a catalytically inactive mutant of PTP1C strongly suppressed the stimulatory effects of the epidermal growth factor or serum on cell proliferation, early gene transcription, and DNA synthesis. Similarly, the phosphorylation of the mitogen-activated protein kinase and mitogen-activated protein kinase kinase activity was markedly inhibited by overexpression of mutant PTP1C. The inhibitory effect of mutant PTP1C was overcome by cotransfection with wild-type PTP1C, but not with the structurally related PTP2C. Furthermore, expression of the mutant phosphatase resulted in hyperphosphorylation on tyrosine of a 95-kDa protein that was co-immunoprecipitated with the mutant, but not with the wild-type protein. These results suggest that, unlike in hematopoietic cells, PTP1C in 293 cells plays a positive role in epidermal growth factor- or serum-activated mitogenesis. Thus, PTP1C participates in multiple signaling pathways, where the enzyme, depending on its target molecules, may function as either a positive or negative mediator.
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PMID:Positive effect of overexpressed protein-tyrosine phosphatase PTP1C on mitogen-activated signaling in 293 cells. 862 11

The serine/threonine protein kinase Raf-1 is a component of a conserved intracellular signaling cascade that controls responses to various extracellular stimuli. Transcription from several promoters, including the oncogene-responsive element in the polyomavirus enhancer, the c-fos promoter, as well as other AP-1- and Ets-dependent promoters, can be induced by Raf-1 kinase. Previously, we have shown that activated Raf-1 kinase transactivates the human immunodeficiency virus type 1 (HIV-1) long terminal repeat and have identified the NF-kappaB binding motif as a Raf-1-responsive element (RafRE). We now report that Raf-1 kinase-induced transactivation from the HIV RafRE involves the purine-rich-repeat-binding protein (GABP), which is composed of two distinct subunits (alpha and beta). GABP alpha is an Ets oncogene-related DNA-binding protein, and GABP beta contains four ankyrin-like repeats that have been shown to be essential in protein-protein interactions. In electrophoretic mobility shift assays using nuclear extracts from human Jurkat T cells, a protein-DNA complex which was supershifted with antiserum against GABP alpha and GABP beta was observed. Purified recombinant GABP alpha and beta interact with the HIV RafRE as judged from DNA binding assays. Cotransfection experiments with GABP alpha and beta and Raf-1 kinase demonstrate synergistic transactivation of the HIV-1 promoter. Point mutations in the HIV RafRE abolished the Raf-1 kinase as well as GABP alpha- and beta-induced transactivation. The observed Raf-1-GABP synergism presumably involves phosphorylation of GABP subunits, as treatment of cells with Raf-1 kinase activators serum and 12-O-tetradecanoylphorbol-13-acetate increases phosphorylation of GABP in vivo. However, GABP is not a target of Raf-1 kinase; instead, it is a substrate of mitogen-activated protein kinase (MAPK/ERK), since in vitro phosphorylation of GABP alpha and beta was achieved by the reconstituted protein kinase cascade but not with purified Raf-1 or MEK. These results suggest that Raf-1 kinase- induced activation of the HIV-1 promoter is mediated by the classical cytoplasmic cascade resulting in MAPK/ERK-mediated phosphorylation of GABP alpha and beta. Because the HIV RafRE corresponds to a region within the promoter which is essential for regulation of HIV-1 expression, the data indicate that in addition to NK-kappaB, GABP transcription factors are important for induced expression of HIV.
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PMID:Raf-1 kinase targets GA-binding protein in transcriptional regulation of the human immunodeficiency virus type 1 promoter. 864 52

A plethora of extracellular signals leads to the stimulation of Ras, which triggers intracellular protein kinase cascades, resulting in activation of transcription factors and thus in enhanced gene activity. In this report, it is demonstrated that the ETS transcription factor ER81, which appears to be localized within the cell nucleus by virtue of its DNA binding domain, is transcriptionally activated by oncogenic Ras. Since this activation was dependent on the presence of Raf-1 and ERK-1, ER81 is a target of the Ras/Raf/MEK/ERK signaling cascade. Consistently, activated ERK-1 is capable to phosphorylate ER81. However, the carboxy-terminal region of ER81, which contains no potential ERK phosphorylation sites, is also transcriptionally activated by ERK-1, suggesting that an ERK-stimulated protein kinase phosphorylates and thus stimulates ER81 activity. Two acidic stretches of amino acids, which are conserved in the related PEA3 and ERM proteins, are localized within the amino-and carboxy-terminal transactivation domains of ER81. In addition, an inhibitory domain may dampen the activation function of these two domains. In conclusion, ER81 is a target of Ras-dependent signaling cascades and may thus contribute to the nuclear response upon stimulation of cells and also to cellular transformation due to oncogenic Ras.
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PMID:Analysis of the ERK-stimulated ETS transcription factor ER81. 865 29

The modulation of the activity of mitogen-activated protein kinase (MAPK) by endogenous growth factors or growth inhibitors provides a potential means of regulating cell proliferation. We determined the effect of the endogenous anti-proliferative peptide, atrial natriuretic peptide (ANP), on the ability of MAPK to phosphorylate myelin basic protein. In astrocytes, MAPK activity was significantly stimulated (up to 3-fold) by three known glial mitogens, endothelin-3, platelet-derived growth factor, or phorbol 12-myristate 13-acetate. ANP inhibited by 55-70% the ability of each of these mitogens to activate MAPK. The effects of ANP were equipotent to those caused by C-ANP 4-23, a peptide that specifically binds to the natriuretic peptide clearance receptor. Additionally, both natriuretic peptides caused a 70-80% inhibition of the sodium vanadate-stimulated MAPK activity, complete inhibition of the okadaic acid-stimulated activity, and inhibition of the mitogen-stimulated phosphorylation of MAPK. To understand the potential mechanism by which the natriuretic peptides act, we found that both ANP and C-ANP inhibited the mitogen-stimulated activity of the immediate upstream kinase in the cascade, MAPK kinase (MEK). C-ANP also strongly inhibited the endothelin-3-, platelet-derived growth factor-, and phorbol 12-myristate 13-acetate-induced stimulation of DNA synthesis in the astrocytes, while both okadaic acid and sodium vanadate significantly reversed these anti-proliferative actions. Our results identify ANP as a peptide hormone that inhibits growth factor-stimulated MAPK. These data suggest that the ability of the natriuretic peptides to inhibit MAPK may be important for their anti-growth actions. This effect likely occurs via the inhibition of upstream kinase(s), including MEK, uniquely resulting from ligand binding to the natriuretic peptide clearance receptor.
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PMID:Atrial natriuretic peptide inhibits mitogen-activated protein kinase through the clearance receptor. Potential role in the inhibition of astrocyte proliferation. 866 98

Bufalin, an active principle of Chinese medicine, chan'su, induced typical apoptosis in human leukemia U937 cells. When U937 cells were treated with 10(-8) M bufalin in the absence of serum, mitogen-activated protein (MAP) kinase activity was markedly increased 6 h after the start of treatment and elevated so for 12 h. Prior to the activation of MAP kinase, increased activities of Ras, Raf-1, and MAP kinase kinase were found, but these enzymes were transiently activated by the treatment with bufalin. These results suggest that the signal was transmitted sequentially from Ras, Raf-1, and MAP kinase kinase to MAP kinase. In association with this signal transduction, the concentration of cAMP in the cells decreased markedly, suggesting that Raf-1 was also activated by a decrease in the extent of phosphorylation by protein kinase A. In fact, pretreatment of U937 cells with forskolin and 3-isobutyl-1-methylxanthine, which are known to increase the concentration of cAMP in the cells, and subsequent treatment with bufalin resulted in a decrease in both Raf-1 activity and DNA fragmentation. To confirm the participation of MAP kinase in the apoptotic process, antisense cDNA for MAP kinase kinase 1 was expressed in U937 cells. The transformants were significantly resistant to both DNA fragmentation and cell death in response to bufalin. Our findings suggest that a pathway with the persistent activation of MAP kinase in U937 cells in response to bufalin is at least one of the signal transduction pathways involved in the induction of apoptosis.
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PMID:The cooperative interaction of two different signaling pathways in response to bufalin induces apoptosis in human leukemia U937 cells. 866 6

Bombesin induced a marked and persistent activation of the mitogen-activated protein kinase kinase-1 (MEK-1), p42(mapk) and p90(rsk) in Swiss 3T3 cells by a pathway that was independent of p74(raf-1) but dependent on the activity of protein kinase C. Pretreatment of the cells with a specific inhibitor of MEK-1, PD 098059, markedly reduced the early and abolished the sustained phase of bombesin-induced p42(mapk) activation. In addition, PD 098059 prevented bombesin-induced DNA synthesis and progression of the cells through the cell cycle, indicating that the mitogenic effect of bombesin is dependent on the activation of p42(mapk). However, in the presence of insulin, which neither stimulated p42(mapk) activation nor DNA synthesis on its own in Swiss 3T3 cells, bombesin potently stimulated DNA synthesis even at concentrations of PD 098059 (15 microM) that completely abolished the mitogenic effect of bombesin alone. Furthermore, Swiss 3T3 cells stably transfected with interfering mutants of MEK-1 showed a marked decrease in the mitogenic effect of bombesin. In contrast, the combination of bombesin and insulin strongly stimulated DNA synthesis in these cells to levels comparable with that obtained in the wild type cells. Thus, our data demonstrate that insulin dramatically reduced the requirement for the mitogen-activated protein kinase pathway for reinitiation of DNA synthesis in bombesin-treated Swiss 3T3 cells and consequently indicate that the contribution of the mitogen-activated protein kinase cascade to mitogenesis depends on the combination of extracellular signals that are used to stimulate these cells.
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PMID:Reduced requirement of mitogen-activated protein kinase (MAPK) activity for entry into the S phase of the cell cycle in Swiss 3T3 fibroblasts stimulated by bombesin and insulin. 870 30

The HBx protein of hepatitis B virus is a dual-specificity activator of transcription, stimulating signal transduction pathways in the cytoplasm and transcription factors in the nucleus, when expressed in cell lines in culture. In the cytoplasm, HBx was shown to stimulate the Ras-Raf-mitogen-activated protein kinase (MAP kinase) cascade, which is essential for activation of transcription factor AP-1. Here we show that HBx protein stimulates two independently regulated members of the MAP kinase family when expressed transiently in cells. HBx protein stimulates the extracellular signal-regulated kinases (ERKs) and the c-Jun N-terminal kinases (JNKs). HBx activation of ERKs and JNKs leads to induction and activation of AP-1 DNA binding activity involving transient de novo synthesis of c-Fos protein and prolonged synthesis of c-Jun, mediated by N-terminal phosphorylation of c-Jun carried out by HBx-activated JNK. New c-Jun synthesis was blocked by coexpression with a dominant-negative MAP kinase kinase (MEK kinase, MEKK-1), confirming that HBx stimulates the prolonged synthesis of c-Jun by activating JNK signalling pathways. Activation of the c-fos gene was blocked by coexpression with a Raf-C4 catalytic mutant, confirming that HBx induces c-Fos by acting on Ras-Raf linked pathways. HBx activation of ERK and JNK pathways resulted in prolonged accumulation of AP-1-c-Jun dimer complexes. HBx activation of JNK and sustained activation of c-jun, should they occur in the context of hepatitis B virus infection, might play a role in viral transformation and pathogenesis.
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PMID:Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases. 876 4


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