ArticleProceedings of the National Academy of Sciences of the United States of America2021
MK2 degradation as a sensor of signal intensity that controls stress-induced cell fate.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 16 citations in OpenAlex.
- Chronic activation of p38α in skeletal muscle causes necrotic changes, but also abolishes expression of MK2, MK3, and MKK6 and the muscle recovers.The Journal of biological chemistry · 2026Article
- Metabolic stress conditions dictate MAPKAPK2-dependent efficiency of MEK1/2 inhibition in colorectal carcinoma.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Ceramide kinase suppresses ferroptosis and protects against alcohol-associated liver disease through the p38 MAPK-HSPB1 pathway.Hepatology communications · 2025Article
- Article
- Modulating p38 MAPK signaling by proteostasis mechanisms supports tissue integrity during growth and aging.Nature communications · 2023Article
- Characterization of p38α autophosphorylation inhibitors that target the non-canonical activation pathway.Nature communications · 2023Article
- Article
- The bridge between cell survival and cell death: reactive oxygen species-mediated cellular stress.EXCLI journal · 2023Review
- A new negative feedback mechanism for MAPK pathway inactivation through Srk1 MAPKAP kinase.Scientific reports · 2022Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cell survival in response to stress is determined by the coordination of various signaling pathways. The kinase p38α is activated by many stresses, but the intensity and duration of the signal depends on the stimuli. How different p38α-activation dynamics may impact cell life/death decisions is unclear. Here, we show that the p38α-signaling output in response to stress is modulated by the expression levels of the downstream kinase MK2. We demonstrate that p38α forms a complex with MK2 in nonstimulated mammalian cells. Upon pathway activation, p38α phosphorylates MK2, the complex dissociates, and MK2 is degraded. Interestingly, transient p38α activation allows MK2 reexpression, reassembly of the p38α-MK2 complex, and cell survival. In contrast, sustained p38α activation induced by severe stress interferes with p38α-MK2 interaction, resulting in irreversible MK2 loss and cell death. MK2 degradation is mediated by the E3 ubiquitin ligase MDM2, and we identify four lysine residues in MK2 that are directly ubiquitinated by MDM2. Expression of an MK2 mutant that cannot be ubiquitinated by MDM2 enhances the survival of stressed cells. Our results indicate that MK2 reexpression and binding to p38α is critical for cell viability in response to stress and illustrate how particular p38α-activation patterns induced by different signals shape the stress-induced cell fate.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.