Stress-induced Inhibition of ERK1 and ERK2 by Direct Interaction with p38 MAP Kinase
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Bibliographic record
Abstract
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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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it