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12541_6524836_gutierrez-prat__2021_proc_natl_acad_sci_usa.pdf (7.4 MB)

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Article

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Accepted version

Publication date

2021-07-20

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Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/180160

MK2 degradation as a sensor of signal intensity that controls stress-induced cell fate

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https://doi.org/10.1073/pnas.2024562118

Abstract

Cell survival in response to stress is determined by the coordination of various signaling pathways. The kinase p38 alpha is activated by many stresses, but the intensity and duration of the signal depends on the stimuli. How different p38 alpha-activation dynamics may impact cell life/death decisions is unclear. Here, we show that the p38 alpha signaling output in response to stress is modulated by the expression levels of the downstream kinase MK2. We demonstrate that p38 alpha forms a complex with MK2 in nonstimulated mammalian cells. Upon pathway activation, p38 alpha phosphorylates MK2, the complex dissociates, and MK2 is degraded. Interestingly, transient p38 alpha activation allows MK2 reexpression, reassembly of the p38 alpha-MK2 complex, and cell survival. In contrast, sustained p38 alpha activation induced by severe stress interferes with p38 alpha-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 p38 alpha is critical for cell viability in response to stress and illustrate how particular p38 alpha-activation patterns induced by different signals shape the stress-induced cell fate.

Subject

Neuroimmunologia, Mort cel·lular

Subject (English)

Neuroimmunology, Cell death

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Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citation

GUTIERREZ PRAT, Núria, et al. MK2 degradation as a sensor of signal intensity that controls stress-induced cell fate. Proceedings Of The National Academy Of Sciences Of The United States Of America. 2021. Vol. 118, num. 29. ISSN 1091-6490. [consulted: 19 of August of 2026]. Available at: https://hdl.handle.net/2445/180160

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