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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)

Mitogen-activated protein (MAP) kinase cascades represent one of the major signal systems used by eukaryotic cells to transduce extracellular signals into cellular responses. Four MAP kinase subgroups have been identified in humans: ERK, JNK (SAPK), ERK5 (BMK), and p38. Here we characterize a new MAP kinase, p38beta. p38beta is a 372-amino acid protein most closely related to p38. It contains a TGY dual phosphorylation site, which is required for its kinase activity. Like p38, p38beta is activated by proinflammatory cytokines and environmental stress. A comparison of events associated with the activation of p38beta and p38 revealed differences, most notably in the preferred activation of p38beta by MAP kinase kinase 6 (MKK6), whereas p38 was activated nearly equally by MKK3, MKK4, and MKK6. Moreover, in vitro and in vivo experiments showed a strong substrate preference by p38beta for activating transcription factor 2 (ATF2). Enhancement of ATF2-dependent gene expression by p38beta was approximately20-fold greater than that of p38 and other MAP kinases tested. The data reported here suggest that while closely related, p38beta and p38 may be regulated by differing mechanisms and may exert their actions on separate downstream targets.
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PMID:Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). 866 24

Kss1 and Fus3 are mitogen-activated protein kinases (MAPKs or ERKs), and Ste7 is their activating MAPK/ERK kinase (MEK), in the pheromone response pathway of Saccharomyces cerevisiae. To investigate the potential role of specific interactions between these enzymes during signaling, their ability to associate with each other was examined both in solution and in vivo. When synthesized by in vitro translation, Kss1 and Fus3 could each form a tight complex (Kd of approximately 5 nM) with Ste7 in the absence of any additional yeast proteins. These complexes were specific because neither Hog1 nor Mpk1 (two other yeast MAPKs), nor mammalian Erk2, was able to associate detectably with Ste7. Neither the kinase catalytic core of Ste7 nor the phosphoacceptor regions of Ste7 and Kss1 were necessary for complex formation. Ste7-Kss1 (and Ste7-Fus3) complexes were present in yeast cell extracts and were undiminished in extracts prepared from a ste5delta-ste11delta double mutant strain. In Ste7-Kss1 (or Ste7-Fus3) complexes isolated from naive or pheromone-treated cells, Ste7 phosphorylated Kss1 (or Fus3), and Kss1 (or Fus3) phosphorylated Ste7, in a pheromone-stimulated manner; dissociation of the high-affinity complex was shown to be required for either phosphorylation event. Deletions of Ste7 in the region required for its stable association with Kss1 and Fus3 in vitro significantly decreased (but did not eliminate) signaling in vivo. These findings suggest that the high-affinity and active site-independent binding observed in vitro facilitates signal transduction in vivo and suggest further that MEK-MAPK interactions may utilize a double-selection mechanism to ensure fidelity in signal transmission and to insulate one signaling pathway from another.
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PMID:Signaling in the yeast pheromone response pathway: specific and high-affinity interaction of the mitogen-activated protein (MAP) kinases Kss1 and Fus3 with the upstream MAP kinase kinase Ste7. 866 80

Constitutive stimulation of the mitogen-activated protein kinase (MAPK) activator MAPK/ERK kinase (MEK) is sufficient to promote long-term events such as cell differentiation, proliferation, and transformation. To evaluate a possible mechanism for the chronic regulation of MEK and p42 MAPK, we studied the long-term effects of fetal bovine serum (FBS), the G protein-coupled receptor agonist endothelin-1 (ET-1), and the protein tyrosine kinase-coupled receptor agonist platelet-derived growth factor BB (PDGF BB) on MEK and p42 MAPK in glomerular mesangial cells (GMC). FBS, ET-1, and PDGF BB led to a time-dependent increase in MEK-1 mRNA and protein expression without altering p42 MAPK mRNA and protein levels. FBS also induced MEK-1 mRNA expression in diverse cell types, including NIH/3T3 fibroblasts, A7r5 vascular smooth muscle cells, and Chinese hamster ovary cells. In GMC, cycloheximide inhibited MEK-1 mRNA induction but stimulated p42 MAPK mRNA expression in the absence and presence of FBS, ET-1, or PDGF. The FBS-induced increase in MEK-1 mRNA was accompanied by a sustained enhancement of MEK activity, as assessed by the ability of immunoprecipitated p45 MEK to activate recombinant p42 MAPK and hence phosphorylate myelin basic protein, and p42 MAPK activity. We conclude that, in GMC, MEK-1 acts like a delayed-early gene and that it can be chronically induced at the mRNA and protein level.
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PMID:Differential long-term regulation of MEK and of p42 MAPK in rat glomerular mesangial cells. 877 28

Although the involvement of protein kinase C (PKC) in the activation of the mitogen-activated protein (MAP) kinase pathway has been implicated through experiments using 12-O-tetradecanoylphorbol-13-acetate (TPA), there has been no direct demonstration that PKC activates the MAP kinase pathway. A Raf-dependent intact cell assay system for monitoring the activation of MAPK/ERK kinase (MEK) and extracellular signal-related kinase (ERK) permitted us to evaluate the role of PKC isotypes in MAP kinase activation. Treatment of cells with TPA or epidermal growth factor resulted in the activation of MEK and ERK. The activation of the MAP kinase pathway triggered by epidermal growth factor was completely inhibited by dominant-negative Ras (RasN17), whereas the activation triggered by TPA was not, consistent with previous observations. The introduction of an activated point mutant of PKCdelta, but not PKCalpha or PKCepsilon, resulted in the activation of the MAP kinase pathway. The activation of MEK and ERK by an activated form of PKCdelta requires the presence of c-Raf and is independent of RasN17. These results demonstrate that activation of PKCdelta is sufficient for the activation of MEK and ERK and that the pathway operates in a manner dependent on c-Raf and independent of Ras.
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PMID:Protein kinase C activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf. 879 60

Raf-1 is a serine/threonine specific kinase that integrates signaling by a large number of mitogens to elicit a transcriptional response in the nucleus. Activated Raf-1 phosphorylates and activates MAPK/ERK kinase Mek), thus initiating the Mek--> MAP kinase cascade, which ultimately results in the phosphorylation and activation of transcription factors by MAP kinase. Here we have characterized the mechanism by which monoclonal antibody URP26K, which binds to an epitope in the Raf-1 kinase domain, inhibits intracellular signal transduction. This antibody preferentially immunoprecipitated the underphosphorylated, non-activated form of Raf-1 from quiescent cells. Baculovirus-expressed Raf-1 immunoprecipitated with URP26K was largely refractory to phosphorylation and activation mediated by protein kinase C (PKC)alpha or the tyrosine kinase Lck. In addition, URP26K reduced the binding of Raf-1 to its substrate Mek in vitro, but did not disturb the association of Raf-1 with Ras. Microinjection of URP26K into Rat-1 cells blocked DNA synthesis initiated by serum, insulin and various purified growth factors, but it did not block DNA synthesis initiated by v-ras. Microinjected URP26K also impaired the expression of stably transfected beta-galactosidase reporter genes regulated by minimal promoter elements. These results demonstrate, (i) that the URP26K monoclonal antibody inhibits Raf-1 by preventing activating Raf-1 phosphorylation and/or association with its substrate Mek, (ii) that inhibition of Raf-1 by URP26K does not interfere with Ras-induced DNA synthesis. In contrast to dominant negative Raf-1 mutants, which also block Ras signaling by binding to the Ras effector domain, antibody mediated Raf-1 inhibition thus reveals a branchpoint of mitogenic signaling at the level of Ras.
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PMID:Inhibition of Raf-1 signaling by a monoclonal antibody, which interferes with Raf-1 activation and with Mek substrate binding. 880 5

A conserved MAP kinase cascade is central to signal transduction in both simple and complex eukaryotes. In the yeast Schizosaccharomyces pombe, Byr2, a homolog of mammalian MAPK/ERK kinase kinase and Saccharomyces cerevisiae STE11, is required for pheromone-induced sexual differentiation. A screen for S. pombe proteins that interact with Byr2 in a two-hybrid system led to the isolation of Ste4, a protein that is known to be required for sexual function. Ste4 binds to the regulatory region of Byr2. This binding site is separable from the binding site for Ras1. Both Ste4 and Ras1 act upstream of Byr2 and act at least partially independently. Ste4 contains a leucine zipper and is capable of homotypic interaction. Ste4 has regions of homology with STE50, an S. cerevisiae protein required for sexual differentiation that we show can bind to STE11.
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PMID:Identification of Ste4 as a potential regulator of Byr2 in the sexual response pathway of Schizosaccharomyces pombe. 881 72

Stimulation of mitogenic signaling pathways results in transient activation of the extracellular signal-regulated kinase (ERK) subfamily of mitogen-activated protein kinases (MAPK) in normal cells. We demonstrate here that activation of ERKs in response to serum or phorbol ester stimulation was markedly repressed in three different rodent fibroblast cell lines stably transformed by v-Src. Activation of the MAPK/ERK kinase (MEK) was also repressed in v-Src-transformed cells, indicating that the repression occurs upstream of ERK. Consistent with repression occurring predominantly at the level of MEK, the phosphatase inhibitor orthovanadate could restore ERK activation to a limited extent in some but not all v-Src-transformed cell lines. A similar repression of ERK activation was observed in v-Ras- and v-Raf-transformed cells. In addition, ERK activity was not constitutively elevated in exponentially growing cells transformed by v-Src, v-Ras, or v-Raf as compared with normal cells. These results establish that the ERK activation pathway is repressed in rodent fibroblasts stably transformed by viral oncoproteins that chronically stimulate receptor tyrosine kinase signaling pathways. Furthermore, our findings suggest that elevated ERK activity above basal levels is not required for maintaining cell transformation by these oncoproteins. Taken together, these results indicate that ERK signaling pathways are subject to negative feedback regulation upstream of ERK as a consequence of oncogenic transformation.
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PMID:Activation of extracellular signal-regulated kinase (ERK) by mitogenic stimuli is repressed in v-Src-transformed cells. 899 40

The extracellular signal-regulated kinase (ERK) pathway, the stress-activated protein kinase (SAPK) pathway, and the p38 pathway are three major mitogen-activated protein kinase (MAPK) cascades known to participate in the regulation of cellular responses to a variety of extracellular signals. Upstream regulatory components of these kinase cascades, the MAPK/ERK kinase kinases (MEKK), have been described in several systems. We have isolated a cDNA encoding human MEKK3. Transfected MEKK3 has the ability to activate both SAPK and ERK pathways, but does not induce p38 activity, in agreement with a previous report on murine MEKK3 (Blank, J. L., Gerwins, P., Elliott, E. M., Sather, S., and Johnson, G. L. (1996) J. Biol. Chem. 271, 5361-5368). We now demonstrate that MEKK3 activates SEK and MEK, the known kinases targeting SAPK and ERK, respectively. Utilizing an estrogen ligand-activated MEKK3 derivative, we furthermore demonstrate that MEKK3 regulates the SAPK and the ERK pathway directly. Consistent with the fact that several SAPK-inducing agents activate the transcription factor NFkappaB, we now show that MEKK3 also enhances transcription from an NFkappaB-dependent reporter gene in cotransfection assays. The ability of MEKK3 to simultaneously activate the SAPK and ERK pathways is remarkable, given that they have divergent roles in cellular homeostasis.
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PMID:Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein Kinase/ERK kinase kinase 3 (MEKK) derivative. 900 2

Regulation of the mitogen-activated protein kinase (MAPK) family members - which include the extracellular response kinases (ERKs), p38/HOG1, and the c-Jun amino-terminal kinases (JNKs) - plays a central role in mediating the effects of diverse stimuli encompassing cytokines, hormones, growth factors and stresses such as osmotic imbalance, heat shock, inhibition of protein synthesis and irradiation. A rapidly increasing number of kinases that activate the JNK pathways has been described recently, including the MAPK/ERK kinase kinases, p21-activated kinases, germinal center kinase, mixed lineage kinases, tumor progression locus 2, and TGF-beta-activated kinase. Thus, regulation of the JNK pathway provides an interesting example of how many different stimuli can converge into regulating pathways critical for the determination of cell fate.
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PMID:MEKKs, GCKs, MLKs, PAKs, TAKs, and tpls: upstream regulators of the c-Jun amino-terminal kinases? 902 36

Peroxisome proliferators (PPs) are a class of nongenotoxic carcinogens in the rodent liver. The induction of immediate-early gene expression in immortalized mouse liver cells by the PPs Wy-14, 643, monoethylhexyl phthalate, ciprofibrate ethyl ester, and clofibrate suggested that they may be activating growth-regulatory signal transduction pathways. We report that incubation of quiescent ML457 cells with Wy-14,643 resulted in the appearance of two tyrosine-phosphorylated bands of approximately 44 and 42 kDa with maximal phosphorylation at 20 min. These two proteins were identified as extracellular signal-regulated kinases (ERKs) ERK1 and ERK2 (also known as mitogen-activated protein kinases, or MAPKs). Stimulation of quiescent ML457 cells with monoethylhexyl phthalate, ciprofibrate ethyl ester, and clofibrate also resulted in tyrosine phosphorylation of ERK1 and ERK2; however, the steroid PP dehydroepiandrosterone sulfate, which does not induce immediate-early gene expression, did not induce phosphorylation of ERK1 and ERK2. Kinase activity of ERK1 and ERK2 was stimulated by the PPs, consistent with their phosphorylation. The PPs also induced phosphorylation of the upstream regulator MAPK/ERK kinase (MEK). Preincubation of quiescent cells with MEK inhibitor PD98059 blocked activation of ERK1 and ERK2 by the PPs, implicating MEK activation as a requirement for PP-induced ERK activation. In addition, pretreatment with PD98059 greatly reduced the PP-induced expression of immediate-early genes c-fos, egr-1, and to a lesser extent junB. Induction of ERK phosphorylation and junB expression by Wy-14,643 was also seen in rat hepatocytes. These results attribute many of the effects of PPs on immediate-early gene expression to the activation of the MEK/ERK signal transduction pathway and add the PPs to the growing number of tumor promoters that modulate signaling proteins.
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PMID:Peroxisome proliferators activate extracellular signal-regulated kinases in immortalized mouse liver cells. 914 71


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