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)

To examine the specificity of MEKs for MAP kinase family members, we determined the abilities of several MEK isoforms to phosphorylate mutants of the MAP kinase ERK2 and the related kinase ERK3 which are modified in the phosphorylation loop. The ERK2 mutants included mutations of the two phosphorylation sites, mutations of the acidic residue between these two sites, and mutations that shorten the length of this loop. All mutants were tested for phosphorylation by six mammalian MEKs and compared with several wild type MAP kinases. MEK1 and MEK2 phosphorylate a majority of the ERK2 mutants. MEK2 but not MEK1 will phosphorylate ERK3. Alteration of the residue between the two phosphorylation sites neither dramatically affected the activity of MEK1 and MEK2 toward ERK2 nor conferred recognition by other MEKs. Likewise, reduction of the length of the phosphorylation loop only partially reduces recognition by MEK1 and MEK2 but does not promote recognition by other MEKs. Thus other yet to be identified factors must contribute to the specificity of MEK recognition of MAP kinases.
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PMID:Contributions of the mitogen-activated protein (MAP) kinase backbone and phosphorylation loop to MEK specificity. 893 8

Mammalian cells contain at least three signaling systems which are structurally related to the mitogen-activated protein kinase (MAPK) pathway. Growth factors acting through Ras primarily stimulate the Raf/MEK/MAPK cascade of protein kinases. In contrast, many stress-related signals such as heat shock, inflammatory cytokines, and hyperosmolarity induce the MEKK/SEK(MKK4)/SAPK(JNK) and/or the MKK3 or MKK6/p38(hog) pathways. Physiological agonists of these pathway types are either qualitatively or quantitatively distinct, suggesting few common proximal signaling elements, although past studies performed in vitro, or in cells using transient over-expression, reveal interaction between the components of all three pathways. These studies suggest a high degree of cross-talk apparently not seen in vivo. We have examined the possible molecular basis of the differing agonist profiles of these three MAPK pathways. We report preferential association between MAP kinases and their activators in eukaryotic cells. Furthermore, using the yeast 2-hybrid system, we show that association between these components can occur independent of additional eukaryotic proteins. We show that SAPK(JNK) or p38(hog) activation is specifically impaired by co-expression of cognate dominant negative MAP kinase kinase mutants, demonstrating functional specificity at this level. Further divergence and insulation of the stress pathways occurs proximal to the MAPK kinases since activation of the MAPK kinase kinase MEKK results in SAPK(JNK) activation but does not cause p38(hog) phosphorylation. Therefore, in intact cells, the three MAPK pathways may be independently regulated and their components show specificity in their interaction with cognate cascade members. The degree of intermolecular specificity suggests that mammalian MAPK signaling pathways may remain distinct without the need for specific scaffolding proteins to sequester components of individual pathways.
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PMID:Mammalian mitogen-activated protein kinase pathways are regulated through formation of specific kinase-activator complexes. 893 29

In order to elucidate the signal transduction pathway from external mechanical stress to nuclear gene expression in mechanical stress-induced cardiac hypertrophy, we examined the time course of activation of Raf-1 kinase (Raf-1), mitogen-activated protein kinase kinase (MAPKK) and MAP kinases (MAPKs) in neonatal rat cardiac myocytes. Mechanical stretch transiently activated Raf-1 and MAPKK with a peak at 2 and 5 min after stretch, respectively. In addition, MAPKs were maximally activated at 8 min after stretch. Next, the relationship between stretch-induced hypertrophy and the cardiac reninangiotensin system was investigated. When the stretch-conditioned culture medium was transferred to non-stretched cardiac myocytes, the medium activated MAPK activity slightly but significantly, and the activation was completely blocked by the type I angiotensin II (AngII) receptor antagonist, CV-11974. Moreover, in in vivo studies using spontaneously hypertensive rats, hypertension-induced cardiac hypertrophy was significantly reduced by treatment with subpressure doses of CV-11974. In addition, CV-11974 reduced the isozymic transition of MHC from VI to V3 and inhibited the accumulation of collagen fibers in the extracellular space of the myocardium. These results suggest that mechanical stress activates the protein kinase cascade of phosphorylation in cardiac myocytes in the order of Raf-1, MAPKK and MAPKs. AngII, which is secreted from stretched myocytes, possibly activates these protein kinases. Moreover, it was shown that CV-11974 causes regression of cardiac hypertrophy and has cardioprotective effects on hypertrophied myocardium in vivo.
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PMID:Angiotensin II mediates mechanical stress-induced cardiac hypertrophy. 896 84

To elucidate the signal transduction pathway from external stimuli to nuclear gene expression in mechanical stress-induced cardiac hypertrophy, we examined the time course of activation of protein kinases such as Raf-1 kinase (Raf-1), mitogen-activated protein kinase kinase (MAPKK), MAP kinases (MAPKs) and 90-kDa ribosomal S6 kinase (p90rsk) in neonatal rat cardiomyocytes. Mechanical stretch rapidly activated Raf-1 and its maximal activation was observed at 1-2 min after stretch. The activity of MAPKK was also increased by stretch, with a peak at 5 min after stretch. In addition, MAPKs and p90rsk were maximally activated at 8 min and at 10-30 min after stretch, respectively. Next, the relationship between mechanical stress-induced hypertrophy and the cardiac renin-angiotensin system was investigated. When the stretch-conditioned culture medium was transferred to the culture dish of non-stretched cardiac myocytes, the medium activated MAPK activity slightly but significantly, and the activation was completely blocked by the type 1 angiotensin II receptor antagonist, CV-11974. However, activation of Raf-1 and MAPKs provoked by stretching cardiomyocytes was only partially suppressed by pretreatment with CV-11974. These results suggest that mechanical stress activates the protein kinase cascade of phosphorylation in cardiac myocytes in the order of Raf-1, MAPKK, MAPKs and p90rsk, and that angiotensin II, which is secreted from stretched myocytes, activates a part of these protein kinases.
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PMID:Molecular aspects of mechanical stress-induced cardiac hypertrophy. 897 57

Results of this study document a biphasic activation of protein kinases of the MAP kinase cascade-MEK and MAP kinases-upon interleukin-1 stimulation in human HeLa cells. The specific activities of both MEK and MAP kinases were increased within 1 min, declined rapidly to control levels and increased again after 15 min of interleukin-1 stimulation. Inhibition by okadaic acid of serine/threonine specific phosphatases resulted in a marked increase in interleukin-1 stimulated MEK and MAP kinase activities. Elevation by interleukin-1 of the specific activities of MEK and MAP kinases correlated with suppression of serine/threonine phosphatases in the late phase of stimulation. The data indicate, that enhanced phosphorylation of cellular proteins by enzymes of the MAP kinase cascade might represent a fine balance between activated protein kinases and repressed phosphoprotein phosphatase 2A in interleukin-1 stimulated HeLa cells.
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PMID:Interleukin-1 induced signalling: biphasic activation of mitogen-activated protein kinase kinase and mitogen-activated protein kinases in HeLa cells. Involvement of phosphoprotein phosphatases. 901 Jun 81

The extracellular-signal-regulated kinase (ERK), the best described MAP kinase cascade, is a major signaling system by which cells transduce extracellular cues into intracellular responses. ERK is activated by phosphorylation both on tyrosine and threonine residues. Therefore, a new clas of protein-tyrosine phosphatases (PTPases) that exhibit dual catalytic activity toward both regulatory sites on ERK is of special interest in the control of intracellular signaling. This study examined the expression and regulation of the dual-specificity PTPases CL100, B23, and PAC1. Findings included differential expression of these phosphatases in diverse cell lines and an expression of all three dual-specificity PTPases in human mesangial cells (HMC), thereby allowing investigation of their regulation in a single cell line. The MEK antagonist PD 098059 and selective extracellular agonists of ERK were used to demonstrate the induction of CL100, PAC1, and B23 in response to activation of the ERK cascade. In contrast, anisomycin, an agonist of the recently described MAP kinases stress-activated protein kinase (SAPK) and p38 MAP kinase, stimulated CL100 gene expression but had little effect on PAC1 and B23. This effect of anisomycin was partly inhibited in the presence of the p38 MAP kinase antagonist SB 203580. This study suggests a potential mechanism to regulate ERK activity through feedback inhibition by demonstrating the ERK cascade's induction of the dual-specificity PTPases CL100, PAC1, and B23. Moreover, this study suggests an ERK-independent induction of CL100 following stimulation of SAPK and p38 MAP kinase. This mode of induction of a phosphatase capable of inactivating ERK may play an important role in the cellular stress response.
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PMID:Differential regulation of the dual-specificity protein-tyrosine phosphatases CL100, B23, and PAC1 in mesangial cells. 901 47

To investigate the molecular basis of the hypertrophic action of angiotensin II (AII) in vascular smooth muscle cells (SMC), we have examined the ability of the hormone to regulate the function of the translational repressor 4E-binding protein 1 (4E-BP1). Addition of AII to quiescent aortic SMC potently increased the phosphorylation of 4E-BP1 as revealed by a decreased electrophoretic mobility and an increased phosphate content of the protein. The stimulation of 4E-BP1 phosphorylation was maximal at 15 min and persisted up to 120 min. Results from affinity chromatography on m7GTP-agarose demonstrated that AII-induced phosphorylation of 4E-BP1 promotes its dissociation from eIF4E in target cells. Further characterization of 4E-BP1 phosphorylation by phosphoamino acid analysis and phosphopeptide mapping revealed that 4E-BP1 is phosphorylated on eight distinct peptides containing serine and threonine residues in AII-treated cells. The combination of results obtained from kinetics experiments, phosphopeptide analysis of in vitro and in vivo phosphorylated 4E-BP1, and pharmacological studies with the MAP kinase kinase inhibitor PD 98059 provided strong evidence that the MAP kinases ERK1/ERK2 are not involved in the regulation of 4E-BP1 phosphorylation in aortic SMC. Together, our results demonstrate that AII treatment of vascular SMC leads to hyperphosphorylation of the translational regulator 4E-BP1 and to its dissociation from eIF4E by a MAP kinase-independent mechanism.
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PMID:Angiotensin II stimulates phosphorylation of the translational repressor 4E-binding protein 1 by a mitogen-activated protein kinase-independent mechanism. 902 Jan 7

Stimulation of human neutrophils with chemoattractants FMLP or platelet activating factor (PAF) results in different but overlapping functional responses. We questioned whether these differences might reflect patterns of intracellular signal transduction. Stimulation with either PAF or FMLP resulted in equivalent phosphorylation and activation of the mitogen-activated protein kinase (MAPk) homologue 38-kD murine MAP kinase homologous to HOG-1 (p38) MAPk. Neither FMLP nor PAF activated c-jun NH2-terminal MAPk (JNKs). Under identical conditions, FMLP but not PAF, resulted in significant p42/44 (ERK) MAPk activation. Both FMLP and PAF activated MAP kinase kinase-3 (MKK3), a known activator of p38 MAPk. Both MAP ERK kinase kinase-1 (MEKK1) and Raf are activated strongly by FMLP, but minimally by PAF. Pertussis toxin blocked FMLP-induced activation of the p42/44 (ERK) MAPk cascade, but not that of p38 MAPk. A specific p38 MAPk inhibitor (SK&F 86002) blocked superoxide anion production in response to FMLP and reduced adhesion and chemotaxis in response to PAF or FMLP. These results demonstrate distinct patterns of intracellular signaling for two chemoattractants and suggest that selective activation of intracellular signaling cascades may underlie different patterns of functional responses.
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PMID:Common and distinct intracellular signaling pathways in human neutrophils utilized by platelet activating factor and FMLP. 906 56

MEK kinase 1 (MEKK1) shares sequence identity with the yeast kinases Ste11 and Byr2, and is capable of phosphorylation and activation of both mitogen-activated protein/extracellular signal-related protein kinase (MAP/ERK) kinase (MEK) and stress-activated protein kinase (SAPK)/ERK kinase (SEK) in vitro. In vivo, however, MEKK1 predominantly activates the SEK/SAPK kinase cascade. Mechanisms of activation of MEKK1 are unclear. We have identified a major site of autophosphorylation (Thr-575) within the 'activation loop' of MEKK1 between the kinase subdomains VII and VIII. Phosphatase treatment of a constitutively active MEKK1 decreased kinase activity by 59%. Dephosphorylated T575 was rapidly re-(auto)phosphorylated by MEKK1. Mutation of T575 to alanine decreased MEKK1 transphosphorylation activity with a SEK substrate to approx. 30% of wild-type. Mutation of a second threonine residue (Thr-587) to alanine eliminated the phosphorylation of MEK or SEK substrate but not autophosphorylation. MEKK1 autophosphorylation is an intramolecular reaction because active MEKK1 cannot transphosphorylate a kinase-inactive MEKK1. Inactive MEKK1 was not phosphorylated on Thr-575 within cells, suggesting that the phosphorylation of Thr-575 in vivo results from autophosphorylation rather than phosphorylation by an upstream kinase. Autoactivation of MEKK1 via autophosphorylation of Thr-575 might be an immediate response to initial kinase activation through non-phosphorylation mechanisms.
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PMID:Regulation of the activity of MEK kinase 1 (MEKK1) by autophosphorylation within the kinase activation domain. 907 60

In this study we investigated the effect of Listeria monocytogenes infection on the activation of the Raf-MEK-MAP kinase pathway in eukaryotic host cells. HeLa cell infection with L. monocytogenes EGD resulted in a rapid, but transient, phosphorylation of the MAP kinases erk-1 and erk-2, a transient phosphorylation of the MAP kinase kinase MEK-1, and a transient activation of the MAP kinase kinase kinase Raf. In parallel to the transient phosphorylation of the MAP kinases, we detected induced expression of the MAP kinase phosphatase MKP-1. Additionally we present evidence that listeriolysin O is the inducing agent for activation of the Raf-MEK-MAP kinase pathway.
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PMID:Listeria monocytogenes infection of HeLa cells results in listeriolysin O-mediated transient activation of the Raf-MEK-MAP kinase pathway. 908 47


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