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

Cell survival in response to stress is determined by the coordination of various signaling pathways. The kinase p38? is activated by many stresses, but the intensity and duration of the signal depends on the stimuli. How different p38?-activation dynamics may impact cell life/death decisions is unclear. Here, we show that ...
the p38?-signaling output in response to stress is modulated by the expression levels of the downstream kinase MK2. We demonstrate that p38? forms a complex with MK2 in nonstimulated mammalian cells. Upon pathway activation, p38? phosphorylates MK2, the complex dissociates, and MK2 is degraded. Interestingly, transient p38? activation allows MK2 reexpression, reassembly of the p38?-MK2 complex, and cell survival. In contrast, sustained p38? activation induced by severe stress interferes with p38?-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? is critical for cell viability in response to stress and illustrate how particular p38?-activation patterns induced by different signals shape the stress-induced cell fate.
Mesh Terms:
Animals, Cell Differentiation, Cell Line, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mitogen-Activated Protein Kinase 14, Protein Binding, Protein Serine-Threonine Kinases, Proteolysis, Proto-Oncogene Proteins c-mdm2, Signal Transduction, Stress, Physiological, Ubiquitination
Proc Natl Acad Sci U S A
Date: Dec. 20, 2020
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