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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In rat 1 fibroblasts, insulin has little or no stimulatory effect on the activities of either MAP2 protein kinase or ribosomal protein S6 kinase. In contrast, in rat 1 cells that overexpress the normal human insulin receptor (rat 1 HIRc B; McClain et al. (1987) J. Biol. Chem. 262, 14663-14671), insulin activates both MAP2 and S6 kinase activities close to 5-fold. A MAP2 kinase has been purified from insulin-treated rat 1 HIRc B cells over 6300-fold by chromatography on Q-Sepharose, phenyl-Sepharose, S-Sepharose, phosphocellulose, QAE-Sepharose, UltrogelAcA54, DEAE-cellulose, and a second Q-Sepharose. Its specific activity is approximately 0.8-1 mumol.min-1.mg-1 with MAP2 and 3 mumol.min-1.mg-1 with myelin basic protein. The enzyme preparation contains one major band of Mr = 43,000 upon SDS-polyacrylamide gel electrophoresis, which is immunoblotted by antibodies to phosphotyrosine. A sequence from the 43-kDa band led to the isolation of a cDNA encoding the enzyme, which we have named ERK1 for extracellular signal-regulated kinase (Boulton et al. (1990) Science 249, 64-67).
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PMID:Purification and properties of extracellular signal-regulated kinase 1, an insulin-stimulated microtubule-associated protein 2 kinase. 184 91

Mitogen-activated protein kinase (MAP kinase) is a 42 kd serine/threonine protein kinase whose enzymatic activity requires phosphorylation of both tyrosyl and threonyl residues. As a step in elucidating the mechanism(s) for activation of this enzyme, we have determined the sites of regulatory phosphorylation. Following proteolytic digestion of 32P-labeled pp42/MAP kinase with trypsin, only a single phosphopeptide was detected by two-dimensional peptide mapping, and this peptide contained both phosphotyrosine and phosphothreonine. The amino acid sequence of the peptide, including the phosphorylation sites, was determined using a combination of Fourier transform mass spectrometry and collision-activated dissociation tandem mass spectrometry with electrospray ionization. The sequence for the pp42/MAP kinase tryptic phosphopeptide is similar (but not identical) to a sequence present in the ERK1- and KSS1-encoded kinases. The two phosphorylation sites are separated by only a single residue. The regulation of activity by dual phosphorylations at closely spaced threonyl and tyrosyl residues has a functional correlate in p34cdc2, and may be characteristic of a family of protein kinases regulating cell cycle transitions.
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PMID:Identification of the regulatory phosphorylation sites in pp42/mitogen-activated protein kinase (MAP kinase). 184 75

Staurosporine, a potent inhibitor of protein kinase C, arrests fission yeast cell elongation specifically at a stage immediately after cell division. We isolated two genes, which, when carried on multicopy plasmids, confer drug resistance in fission yeast. One, spk1+, encodes a protein kinase highly similar (54% identity) to those encoded by the mammalian ERK1/MAP2 kinase and the budding yeast KSS1 and FUS3 genes. It is not essential for vegetative growth of Schizosaccharomyces pombe cells but is required for conjugation. The spk1+ gene product is a 45-kD protein enriched in the nucleus, and its level increases 10-fold after addition of staurosporine. The other gene pap1+ encodes an AP-1-like transcription factor that contains a region rich in basic amino acids followed by a "leucine zipper" motif. The pap1+ gene is required for spk1(+)-conferred staurosporine resistance. These two genes appear to function as a part of the fission yeast growth control pathway.
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PMID:Fission yeast genes that confer resistance to staurosporine encode an AP-1-like transcription factor and a protein kinase related to the mammalian ERK1/MAP2 and budding yeast FUS3 and KSS1 kinases. 189 30

Two epidermal growth factor-stimulated protein kinases that correspond to ERK1 and ERK2 have been purified from human epidermoid carcinoma cells (Northwood, I. C., Gonzalez, F. A., Wartmann, M., Raden, D. L., and Davis, R. J. (1991) J. Biol. Chem. 266, 15266-15276). A consensus primary sequence for substrates of ERK1 has been identified as -Pro-Leu-Ser/Thr-Pro- (Alvarez, E., Northwood, I. C., Gonzalez, F. A., Latour, D. A., Seth, A., Abate, C., Curran, T., and Davis, R. J. (1991) J. Biol. Chem. 266, 15277-15285). However, the structural determinants for substrate recognition are not understood. We performed a systematic analysis of the effect of point mutations in the primary sequence of peptide substrates on the rate of phosphorylation by ERK1 and ERK2. The results of this investigation demonstrate that the substrate specificities of the ERK1 and ERK2 protein kinases are very similar. We propose that the primary sequence of substrates for ERK1 and ERK2 protein kinases can be generalized as -Pro-Xaan-Ser/Thr-Pro- (where Xaa is a neutral or basic amino acid and n = 1 or 2).
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PMID:Identification of substrate recognition determinants for human ERK1 and ERK2 protein kinases. 193 37

The MAP kinase pathway impinging on ERK2 has been shown to be integrally associated with mitogenic signalling in many cell types. Previously, we and others have demonstrated that oncogenic forms of Raf-1 kinase, when expressed in fibroblasts, lead to the constitutive activation of ERK2, the de-regulation of c-fos expression and increased cell proliferation. Here we describe an exception to this scenario. In Rat6 cells, although both ERK1 and ERK2 are activated in response to mitogens that induce c-fos expression, such as Epidermal Growth Factor (EGF), lysophosphatidic acid (LPA) or serum, expression of v-Raf fails to induce c-fos expression and increase proliferation. However, ERK2 is activated by v-Raf expression. The co-transfection of an interfering mutant of ERK2 has no effect on the level of c-fos reporter expression in Rat6 cells whereas the analogous ERK1 mutant reduces its expression. Furthermore, the spontaneous focus formation observed in Rat6 cells is susceptible to the interfering mutant of ERK1 but resistant to that of ERK2. Thus, not only do mitogenic signals appear to by-pass both Raf-1 kinase and ERK2, the Raf-1-ERK2 pathway seems to be functionally compromised in Rat6 cells as its activation leads neither to c-fos expression nor to increased proliferation.
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PMID:Raf-1 kinase and ERK2 uncoupled from mitogenic signals in rat fibroblasts. 747 30

Formation of a complex of the nucleotide exchange factor Sos, the SH2 and SH3 containing adaptor protein Grb2/Sem-5 and tyrosine phosphorylated EGF receptor and Shc has been implicated in the activation of Ras by epidermal growth factor (EGF) in fibroblasts: related mechanisms for activation of Ras operate in other cell types. An increase in the apparent molecular weight of Sos has been reported to occur after several minutes of receptor stimulation due to phosphorylation by mitogen-activated protein (MAP) kinases. We report here that treatment of human peripheral blood T lymphoblasts with phorbol esters causes a similar shift in mobility of Sos. This modification of Sos does not alter its ability to bind Grb2, but correlates with strong inhibition of the binding of the Sos/Grb2 complex to tyrosine phosphorylated sequences, either a tyrosine phosphopeptide in cell lysates or p36 in intact cells. This effect, along with the mobility shift of Sos, can be mimicked in vitro by phosphorylation of Sos by the mitogen-activated protein kinase, ERK1. A novel negative feedback mechanism therefore exists whereby activation of MAP kinases through Ras results in the uncoupling of the Sos/Grb2 complex from tyrosine kinase substrates without blocking the interaction of Sos with Grb2.
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PMID:Downregulation of the Ras activation pathway by MAP kinase phosphorylation of Sos. 747 53

Several cellular signal transduction pathways activated by middle-T in polyomavirus-transformed cells are required for viral oncogenicity. Here we focus on the role of phosphatidylinositol 3-kinase (PI 3-kinase) and Ras and address the question how these signaling molecules cooperate during cell cycle activation. Ras activation is mediated through association with SHC.GRB2.SOS and leads to increased activity of several members of the mitogen-activated protein (MAP) kinase family, while activation of PI 3-kinase results in the generation of D3-phosphorylated phosphatidylinositides whose downstream targets remain elusive. PI 3-kinase activation might also ensue as a direct consequence of Ras activation. Oncogenicity of middle-T requires stimulation of both Ras- and PI 3-kinase-dependent pathways. Mutants of middle-T incapable to bind either SHC.GRB2.SOS or PI 3-kinase are not oncogenic. Sustained activation and nuclear localization of one of the MAP kinases, ERK1, was observed in wild type but not in mutant middle-T-expressing cells. Wortmannin, an inhibitor of PI 3-kinase, prevented MAP kinase activation and nuclear localization in middle-T-transformed cells. PI 3-kinase activity was also required for activation of the MAP kinase pathway in normal serum-stimulated cells, generalizing the concept that signaling through MAP kinases requires not only Ras-but also PI 3-kinase-mediated signals.
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PMID:Activation and nuclear translocation of mitogen-activated protein kinases by polyomavirus middle-T or serum depend on phosphatidylinositol 3-kinase. 749 60

The pleiotropic cytokine tumor necrosis factor-alpha (TNF alpha) controls the expression of multiple gene products in macrophages and plays an important role in host defense. TNF alpha is recognized by the receptors, CD120a (p55) and CD120b (p75). Ligation of CD120a (p55) by TNF alpha or by anti-receptor agonistic antibodies initiates signal transduction leading to the activation of mitogen-activated protein kinases (MAPKs) (p42mapk/erk2 and p44mapk/erk1). Phosphorylation and activation of MAPK are mediated by MAPK kinase (MEK), a family of Thr/Tyr kinases. In this study, we investigated the preferential involvement of the MEK isoforms MEK1 and MEK2 in the activation of p42mapk/erk2 in mouse macrophages stimulated with TNF alpha. Exposure of macrophages to TNF alpha stimulated a time-dependent increase in the activity of MEK1 as measured by an in vitro kinase assay using kinase-inactive p42mapk/erk2 (rMAPKkd) as substrate in the presence of gamma-[32P]ATP. Maximal activation of MEK1 was detected at 10 min poststimulation and coincided with maximal transphosphorylation of Tyr and Thr residues of rMAPKkd. By contrast, there was no evidence of MEK2 activation in macrophages in response to TNF alpha. These data suggest that MEK1 is the preferred substrate for MEK kinase, the upstream kinase implicated in activation of the MAPK pathway in macrophages by TNF alpha.
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PMID:Preferential involvement of MEK1 in the tumor necrosis factor-alpha-induced activation of p42mapk/erk2 in mouse macrophages. 749 90

A consensus cyclic AMP response element (CRE) in the murine prostaglandin synthase-2 (PGS2) promoter is essential for pgs2 gene expression induced by pp60v-src, the v-src oncogene product. In this study, we investigate (i) the transcription factors active at the PGS2 "CRE site" in response to v-src activation and (ii) the signal transduction pathways by which pp60v-src activates these transcription factors. Transient transfection assays with pgs2 promoter/luciferase reporter chimeric genes suggest that c-Jun mediates v-src-induced pgs2 gene expression. Antibody supershift experiments demonstrate that c-Jun can participate in a complex with the pgs2 promoter CRE site. Moreover, in vitro immuno-complex assays demonstrate that pp60v-src expression strongly activates c-Jun N-terminal kinase (JNK1) enzyme activity. Serines 63 and 73, the sites of c-Jun phosphorylation by JNK, are essential for v-src-induced, pgs2 promoter-mediated luciferase expression. Cotransfection studies with plasmids expressing wild-type JNK, dominant-negative JNK, and dominant-negative MEKK-1 confirm that activation of the Ras/MEKK-1/JNK/c-Jun pathway is required for v-src-induced pgs2 gene expression. Overexpression of either wild-type ERK-1 or ERK-2 proteins also potentiate v-src-mediated luciferase expression driven by the pgs2 promoter, and expression of dominant-negative mutants of ERK-1, ERK-2, or Raf-1 attenuate this response. Thus, in response to v-src expression, a Ras/MEKK-1/JNK signal transduction pathway activating c-Jun and a Ras/Raf-1/ERK pathway converge to mediate pgs2 gene expression via the CRE site in the pgs2 promoter.
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PMID:v-src induces prostaglandin synthase 2 gene expression by activation of the c-Jun N-terminal kinase and the c-Jun transcription factor. 749 26

The prototype mitogen-activated protein (MAP) kinase module is a three-kinase cascade consisting of the MAP kinase, extracellular signal-regulated protein kinase (ERK) 1 or ERK2, the MAP/ERK kinase (MEK) MEK1 or MEK2, and the MEK kinase, Raf-1 or B-Raf. This and other MAP kinase modules are thought to be critical signal transducers in major cellular events including proliferation, differentiation, and stress responses. To identify novel mammalian MAP kinase modules, polymerase chain reaction was used to isolate a new MEK family member, MEK5, from the rat. MEK5 is more closely related to MEK1 and MEK2 than to the other known mammalian MEKs, MKK3 and MKK4. MEK5 is thought to lie in an uncharacterized MAP kinase pathway, because MEK5 does not phosphorylate the ERK/MAP kinase family members ERK1, ERK2, ERK3, JNK/SAPK, or p38/HOG1, nor will Raf-1, c-Mos, or MEKK1 highly phosphorylate it. Alternative splicing results in a 50-kDa alpha and a 40-kDa beta isoform of MEK5. MEK5 beta is ubiquitously distributed and primarily cytosolic. MEK5 alpha is expressed most highly in liver and brain and is particulate. The 23 amino acids encoded by the 5' exon in the larger alpha isoform are similar to a sequence found in certain proteins believed to associate with the actin cytoskeleton; this alternatively spliced modular domain may lead to the differential subcellular localization of MEK5 alpha.
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PMID:Isolation of MEK5 and differential expression of alternatively spliced forms. 749 18


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