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)

One Ras-dependent protein kinase cascade leading from growth factor receptors to the ERK (extracellular signal-regulated kinases) subgroup of mitogen-activated protein kinases (MAPKs) is dependent on the protein kinase Raf-1, which activates the MEK (MAPK or ERK kinase) dual specificity kinases. A second protein kinase cascade leading to activation of the Jun kinases (JNKs) is dependent on MEKK (MEK kinase). A dual-specificity kinase that activates JNK, named JNKK, was identified that functions between MEKK and JNK. JNKK activated the JNKs but did not activate the ERKs and was unresponsive to Raf-1 in transfected HeLa cells. JNKK also activated another MAPK, p38 (Mpk2; the mammalian homolog of HOG1 from yeast), whose activity is regulated similarly to that of the JNKs.
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PMID:Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. 771 21

Mitogen-activated protein (MAP) kinase lies at the convergence of various extracellular ligand-mediated signaling pathways. It is activated by the dual-specificity kinase, MAP kinase kinase or MEK. MAP kinase inactivation is mediated by dephosphorylation via specific MAP kinase phosphatases (MKPs). One MKP (MKP-1 (also known as 3CH134, Erp, or CL100)) has been reported to be expressed in a wide range of tissues and cells. We report the identification of a second widely expressed MKP, termed MKP-2, isolated from PC12 cells. MKP-2 showed significant homology with MKP-1 (58.8% at the amino acid level) and, like MKP-1, displayed vanadate-sensitive phosphatase activity against MAP kinase in vitro. Overexpression of MKP-2 in vivo inhibited MAP kinase-dependent gene transcription in PC12 cells. MKP-2 differed from MKP-1 in its tissue distribution and in its extent of induction by growth factors and agents that induce cellular stress, suggesting that these MKPs may have distinct physiological functions.
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PMID:A novel mitogen-activated protein kinase phosphatase. Structure, expression, and regulation. 778 22

Mitogen-activated protein (MAP) kinase and its direct activator, MAP kinase kinase (MAPKK), comprise the MAPKK/MAP kinase cascade, which may play a pivotal role in a variety of intracellular signal transduction pathways from yeast to human. Vertebrate MAPKK, a dual-specificity kinase, is activated by serine phosphorylation catalyzed by upstream serine/threonine kinases, MAPKK kinases (MAPKK-Ks). MAPKK is, on the other hand, threonine phosphorylated by MAP kinase, although a physiological role of this MAP kinase-mediated phosphorylation of MAPKK is unknown. Biochemical fractionation of extracts from Xenopus mature oocytes revealed two major and one minor peaks for the MAPKK-K activity. One of the major peaks contained a proto-oncogene product c-Mos, while the other peaks did not. These observations, together with a recent finding that several MAPKK-Ks such as Raf-1 and MEKK may function within a cell, suggest a diversity of MAPKK-Ks. A variety of extracellular signals converge at the MAPKK/MAP kinase cascade through different MAPKK-Ks and elicit a wide spectrum of cellular responses. Therefore, mechanisms that control activation of the MAP kinase cascade temporally and spatially may be important for specification of cellular responses.
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PMID:Signaling pathways mediated by the mitogen-activated protein (MAP) kinase kinase/MAP kinase cascade. 796 62

The features of three distinct protein phosphorylation cascades in mammalian cells are becoming clear. These signalling pathways link receptor-mediated events at the cell surface or intracellular perturbations such as DNA damage to changes in cytoskeletal structure, vesicle transport and altered transcription factor activity. The best known pathway, the Ras-->Raf-->MEK-->ERK cascade [where ERK is extracellular-signal-regulated kinase and MEK is mitogen-activated protein (MAP) kinase/ERK kinase], is typically stimulated strongly by mitogens and growth factors. The other two pathways, stimulated primarily by assorted cytokines, hormones and various forms of stress, predominantly utilize p21 proteins of the Rho family (Rho, Rac and CDC42), although Ras can also participate. Diagnostic of each pathway is the MAP kinase component, which is phosphorylated by a unique dual-specificity kinase on both tyrosine and threonine in one of three motifs (Thr-Glu-Tyr, Thr-Phe-Tyr or Thr-Gly-Tyr), depending upon the pathway. In addition to activating one or more protein phosphorylation cascades, the initiating stimulus may also mobilize a variety of other signalling molecules (e.g. protein kinase C isoforms, phospholipid kinases, G-protein alpha and beta gamma subunits, phospholipases, intracellular Ca2+). These various signals impact to a greater or lesser extent on multiple downstream effectors. Important concepts are that signal transmission often entails the targeted relocation of specific proteins in the cell, and the reversible formation of protein complexes by means of regulated protein phosphorylation. The signalling circuits may be completed by the phosphorylation of upstream effectors by downstream kinases, resulting in a modulation of the signal. Signalling is terminated and the components returned to the ground state largely by dephosphorylation. There is an indeterminant amount of cross-talk among the pathways, and many of the proteins in the pathways belong to families of closely related proteins. The potential for more than one signal to be conveyed down a pathway simultaneously (multiplex signalling) is discussed. The net effect of a given stimulus on the cell is the result of a complex intracellular integration of the intensity and duration of activation of the individual pathways. The specific outcome depends on the particular signalling molecules expressed by the target cells and on the dynamic balance among the pathways.
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PMID:Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex signalling. 883 13

Rat T lymphoblasts arrested in the G1 phase of the cell cycle by interleukin-2 (IL-2) deprivation can be forced to proceed to the S phase when they are stimulated with IL-2 or the phorbol ester phorbol 12,13-dibutyrate (PDBu). When PDBu is used as a stimulus, extracellular regulated kinase 2 (ERK2) is activated by threonine and tyrosine phosphorylation by the dual-specificity kinase MEK. Here we have studied the regulation of ERK2 dephosphorylation as a mechanism for inactivation of this kinase. In vivo inhibition of ERK2 dephosphorylation observed after preincubation with translation or transcription inhibitors (cycloheximide or actinomycin, respectively) indicates the involvement of at least one inducible phosphatase, the best candidate for which is the dual-specificity phosphatase PAC-1. Other noninducible phosphatases must act as well, however, because sodium orthovanadate is a more effective dephosphorylation blocker than cycloheximide. In addition, the okadaic acid effect in ERK2 dephosphorylation indicates that Ser/Thr phosphatases are also involved, directly and/or indirectly.
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PMID:Regulation of ERK2 dephosphorylation in G1-stimulated rat T lymphoblasts. 941 90

Vascular smooth muscle cells respond to the purinergic agonist ATP by increasing intracellular calcium concentration and increasing the rate of cell proliferation. In many cells the extracellular signal-regulated kinase (ERK) cascade plays an important role in cellular proliferation. We have studied the effect of extracellular ATP on ERK activation and cell proliferation. ATP binding to a UTP-sensitive P2Y nucleotide receptor activates ERK1/ERK2 in a time- and dose-dependent manner in coronary artery smooth muscle cells (CASMC). ATP-induced activation of ERK1/ERK2 is dependent on the dual-specificity kinase mitogen-activated protein kinase/ERK kinase (i.e., MEK) but independent of phosphatidylinositol 3-kinase (PI3K) activity. We provide evidence that both ERK1/ERK2 and PI3K activities are required for CASMC proliferation. Thus ATP-stimulation of CASMC proliferation requires independent activation of both the ERK and PI3K signaling pathways.
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PMID:ATP-stimulated smooth muscle cell proliferation requires independent ERK and PI3K signaling pathways. 974 68

The modulation of mitogen-activated protein kinase (MAPK) activity regulates many intracellular signaling processes. In animal and yeast cells, MAP kinases are activated via phosphorylation by the dual-specificity kinase MEK (MAP kinase kinase). Several plant homologs of MEK and MAPK have been identified, but the biochemical events underlying the activation of plant MAPKs remain unknown. We describe the in vitro activation of an Arabidopsis homolog of MAP kinase, ATMPK4. ATMPK4 was phosphorylated in vitro by an Arabidopsis MEK homolog, AtMEK1. This phosphorylation occurred principally on threonine (Thr) residues and resulted in elevated ATMPK4 kinase activity. A second Arabidopsis MEK isoform, ATMAP2Kalpha, failed to phosphorylate ATMPK4 in vitro. Tyr dephosphorylation by the Arabidopsis Tyr-specific phosphatase AtPTP1 resulted in an almost complete loss of ATMPK4 activity. Immunoprecipitates of Arabidopsis extracts with anti-ATMPK4 antibodies displayed myelin basic protein kinase activity that was sensitive to treatment with AtPTP1. These results demonstrate that a plant MEK can phosphorylate and activate MAPK, and that Tyr phosphorylation is critical for the catalytic activity of MAPK in plants. Surprisingly, in contrast to the animal enzymes, AtMEK1 may not be a dual-specificity kinase but, rather, the required Tyr phosphorylation on ATMPK4 may result from autophosphorylation.
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PMID:ATMPK4, an Arabidopsis homolog of mitogen-activated protein kinase, is activated in vitro by AtMEK1 through threonine phosphorylation. 1075 27

MEK is a dual-specificity kinase that activates the extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase upon agonist binding to receptors. The ERK/MAP kinase cascade is involved in cell fate determination in many organisms. In mammals, this pathway is proposed to regulate cell growth and differentiation. Genetic studies have shown that although a single Mek gene is present in Caenorhabditis elegans, Drosophila melanogaster, and Xenopus laevis, two Mek homologs, Mek1 and Mek2, are present in the mammalian cascade. The inactivation of the Mek1 gene leads to embryonic lethality and has revealed the unique role played by Mek1 during embryogenesis. To investigate the biological function of the second homolog, we have generated mice deficient in Mek2 function. Mek2 mutant mice are viable and fertile, and they do not present flagrant morphological alteration. Although several components of the ERK/MAP kinase cascade have been implicated in thymocyte development, no such involvement was observed for MEK2, which appears to be nonessential for thymocyte differentiation and T-cell-receptor-induced proliferation and apoptosis. Altogether, our findings demonstrate that MEK2 is not necessary for the normal development of the embryo and T-cell lineages, suggesting that the loss of MEK2 can be compensated for by MEK1.
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PMID:Mek2 is dispensable for mouse growth and development. 1283 65

Advances in clinical, translational, and basic studies of metastasis have identified molecular changes associated with specific facets of the metastatic process. Studies of metastasis suppressor gene function are providing a critical mechanistic link between signaling cascades and biological outcomes. We have previously identified c-Jun NH2-terminal kinase (JNK) kinase 1/mitogen-activated protein kinase (MAPK) kinase 4 (JNKK1/MKK4) as a prostate cancer metastasis suppressor gene. The JNKK1/MKK4 protein is a dual-specificity kinase that has been shown to phosphorylate and activate the JNK and p38 MAPKs in response to a variety of extracellular stimuli. In this current study, we show that the kinase activity of JNKK1/MKK4 is required for suppression of overt metastases and is sufficient to prolong animal survival in the AT6.1 model of spontaneous metastasis. Ectopic expression of the JNK-specific kinase MKK7 suppresses the formation of overt metastases, whereas the p38-specific kinase MKK6 has no effect. In vivo studies show that both JNKK1/MKK4 and MKK7 suppress the formation of overt metastases by inhibiting the ability of disseminated cells to colonize the lung (secondary site). Finally, we show that JNKK1/MKK4 and MKK7 from disseminated tumor cells are active in the lung but not in the primary tumor, providing a biochemical explanation for why their expression specifically suppressed metastasis while exerting no effect on the primary tumor. Taken together, these studies contribute to a mechanistic understanding of the context-dependent function of metastasis regulatory proteins.
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PMID:Suppression of metastatic colonization by the context-dependent activation of the c-Jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7. 1632 47

Long-term memory formation is regulated by many distinct molecular mechanisms that control gene expression. An emerging model for effecting a stable, coordinated pattern of gene transcription involves epigenetic tagging through modifications of histones or DNA. In this study, we investigated the regulation of histone phosphorylation in the hippocampus by the ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) pathway. We found that activation of ERK/MAPK in vitro significantly increased histone H3 phosphorylation in hippocampal area CA1. Furthermore, we found that contextual fear conditioning in vivo leads to a rapid time-dependent increase in histone H3 phosphorylation in area CA1. This increase paralleled the time course of contextual fear-dependent activation of ERK, and was inhibited in vivo by a latent inhibition paradigm as well as by injection of an N-methyl-d-aspartic acid receptor (NMDA-R) antagonist. Finally, injection of an inhibitor of MEK (MAP kinase/ERK kinase), the unique dual-specificity kinase upstream of ERK, blocked the increase in histone H3 phosphorylation seen after contextual fear conditioning. These results demonstrate that changes in histone phosphorylation in the hippocampus are regulated by ERK/MAPK following a behavioral fear conditioning paradigm.
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PMID:ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning. 1674 Dec 77


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