Stress-induced Inhibition of ERK1 and ERK2 by Direct Interaction with p38 MAP Kinase
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Notice bibliographique
Résumé
We have identified a direct physical interaction between the stress signaling p38α MAP kinase and the mitogen-activated protein kinases ERK1 and ERK2 by affinity chromatography and coimmunoprecipitation studies. Phosphorylation and activation of p38α enhanced its interaction with ERK1/2, and this correlated with inhibition of ERK1/2 phosphotransferase activity. The loss of epidermal growth factor-induced activation and phosphorylation of ERK1/2 but not of their direct activator MEK1 in HeLa cells transfected with the p38α activator MKK6(E) indicated that activated p38α may sequester ERK1/2 and sterically block their phosphorylation by MEK1. We have identified a direct physical interaction between the stress signaling p38α MAP kinase and the mitogen-activated protein kinases ERK1 and ERK2 by affinity chromatography and coimmunoprecipitation studies. Phosphorylation and activation of p38α enhanced its interaction with ERK1/2, and this correlated with inhibition of ERK1/2 phosphotransferase activity. The loss of epidermal growth factor-induced activation and phosphorylation of ERK1/2 but not of their direct activator MEK1 in HeLa cells transfected with the p38α activator MKK6(E) indicated that activated p38α may sequester ERK1/2 and sterically block their phosphorylation by MEK1. mitogen-activated protein extracellular signal-regulated kinase MAP/ERK kinase MAP kinase kinase glutathioneS-transferase polyacrylamide gel electrophoresis Dulbecco's minimum essential medium dithiothreitol myelin basic protein 3-(N-morpholino)propanesulfonic acid epidermal growth factor Mitogen-activated protein (MAP)1 kinase modules are involved in the signal transduction of a wide variety of cellular responses in all eukaryotic organisms including proliferation, differentiation, and apoptosis (1English J. Pearson G. Wilsbacher J. Swantek J. Karandikar M. Xu S. Cobb M.H. Exp. Cell Res. 1999; 253: 255-270Crossref PubMed Scopus (377) Google Scholar). At least four distinct and parallel MAP kinase cascades have been identified, including extracellular signal-regulated kinases 1 and 2 (ERK1/2), the p38 MAP kinases, c-jun N-terminal or stress-activated protein kinases (JNK/SAPK), and ERK5/big MAP kinase 1 (BMK1). It is well established that ERK1/2 are typically stimulated by growth-related stimuli through the Raf1/B-MEK1/2-ERK1/2 protein kinase cascade. The JNK and p38 MAP kinases are primarily activated by stress-related signals such as heat and osmotic shock, UV irradiation, and proinflammatory cytokines by means of the MAP kinase kinases, MKK3, -4, -6, and -7 (2Ono K. Han J. Cell. Signal. 2000; 12: 1-13Crossref PubMed Scopus (1382) Google Scholar, 3Ichijo H. Oncogene. 1999; 18: 6087-6093Crossref PubMed Scopus (472) Google Scholar, 4Leppa S. Bohmann D. Oncogene. 1999; 18: 6158-6162Crossref PubMed Scopus (437) Google Scholar). Whereas the selective activation of distinct MAP kinase pathways in response to different extracellular stimuli has been extensively documented, there is increasing evidence for cross-talk between distinct MAP kinase pathways. A p38-dependent ERK1/2 activation was observed in several mammalian cell lines including the human embryonic kidney cell line HEK293 upon arsenite treatment (5Ludwig S. Hoffmeyer A. Goebeler M. Kilian K. Hafner H. Neufeld B. Han J. Rapp U.R. J. Biol. Chem. 1998; 273: 1917-1922Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar). It was also found that inactivation of p38 by SB202190 treatment resulted in a delayed and prolonged activation of ERK1/2 in the human hepatoma cell line, HepG2 (6Singh R.P. Dhawan P. Golden C. Kapoor G.S. Mehta K.D. J. Biol. Chem. 1999; 274: 19593-19600Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). In both cases, MEK1 was implicated in the activation of ERK1/2. Here we report that in HeLa and HEK293 cells, stress stimuli lead to an inhibition of ERK1/2 via p38α. Phosphorylated p38α is capable of forming a complex with ERK1/2, and it prevents their phosphorylation by MEK1/2. Mitogen-activated protein (MAP)1 kinase modules are involved in the signal transduction of a wide variety of cellular responses in all eukaryotic organisms including proliferation, differentiation, and apoptosis (1English J. Pearson G. Wilsbacher J. Swantek J. Karandikar M. Xu S. Cobb M.H. Exp. Cell Res. 1999; 253: 255-270Crossref PubMed Scopus (377) Google Scholar). At least four distinct and parallel MAP kinase cascades have been identified, including extracellular signal-regulated kinases 1 and 2 (ERK1/2), the p38 MAP kinases, c-jun N-terminal or stress-activated protein kinases (JNK/SAPK), and ERK5/big MAP kinase 1 (BMK1). It is well established that ERK1/2 are typically stimulated by growth-related stimuli through the Raf1/B-MEK1/2-ERK1/2 protein kinase cascade. The JNK and p38 MAP kinases are primarily activated by stress-related signals such as heat and osmotic shock, UV irradiation, and proinflammatory cytokines by means of the MAP kinase kinases, MKK3, -4, -6, and -7 (2Ono K. Han J. Cell. Signal. 2000; 12: 1-13Crossref PubMed Scopus (1382) Google Scholar, 3Ichijo H. Oncogene. 1999; 18: 6087-6093Crossref PubMed Scopus (472) Google Scholar, 4Leppa S. Bohmann D. Oncogene. 1999; 18: 6158-6162Crossref PubMed Scopus (437) Google Scholar). Whereas the selective activation of distinct MAP kinase pathways in response to different extracellular stimuli has been extensively documented, there is increasing evidence for cross-talk between distinct MAP kinase pathways. A p38-dependent ERK1/2 activation was observed in several mammalian cell lines including the human embryonic kidney cell line HEK293 upon arsenite treatment (5Ludwig S. Hoffmeyer A. Goebeler M. Kilian K. Hafner H. Neufeld B. Han J. Rapp U.R. J. Biol. Chem. 1998; 273: 1917-1922Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar). It was also found that inactivation of p38 by SB202190 treatment resulted in a delayed and prolonged activation of ERK1/2 in the human hepatoma cell line, HepG2 (6Singh R.P. Dhawan P. Golden C. Kapoor G.S. Mehta K.D. J. Biol. Chem. 1999; 274: 19593-19600Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). In both cases, MEK1 was implicated in the activation of ERK1/2. Here we report that in HeLa and HEK293 cells, stress stimuli lead to an inhibition of ERK1/2 via p38α. Phosphorylated p38α is capable of forming a complex with ERK1/2, and it prevents their phosphorylation by MEK1/2. We thank Dr. J. Han, the Scripps Research Institute (La Jolla, CA) for pcDNA3-flagp38α wild-type and p38α (AF) dominant negative mutant. Constructs of constitutively active MKK6(E) mutants, pGEX-MKK6(E) and pcDNA3-MKK6(E), were provided by Dr. C. Glembotski, San Diego State University and Dr. R. Davis, University of Massachusetts, respectively.
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découle