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

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.

Characterization of p38α autophosphorylation inhibitors that target the non-canonical activation pathway

“…We performed TSA in intact cells to test whether NC-p38i compounds could bind to the endogenous p38α protein, which is normally forming complexes with other proteins such as MK2 36 . Cells were treated with compounds NC-37 or NC-38 or with the vehicle DMSO, and then heated in a temperature range between 39 °C and 52 °C to monitor protein unfolding and aggregation.…”

Modulating p38 MAPK signaling by proteostasis mechanisms supports tissue integrity during growth and aging

“…Previous work established a key role of the nervous system in regulating stress responses in other tissues including the UPR in intestine 71 . More recent studies have illuminated that MAPK-dependent regulation of hyaluronidase (TMEM2) promotes ER homeostasis 72 and degradation of the p38 target MK2 functions as a feedback signal critical for stress-induced cell fate 73 as well as emerging evidence that p38 signaling has a crucial role in synaptic plasticity and neurodegenerative processes 74 . Our previous findings revealed that PMK-1 coordinates growth rate with stress responsiveness during larval development.…”

A new negative feedback mechanism for MAPK pathway inactivation through Srk1 MAPKAP kinase

“…Furthermore, Srk1 and MK2, although they have differences, they share functional characteristics. They regulate the cell cycle through Cdc25, form a complex with MAPK p38, and are degraded to terminate or modulate the stress response [28][29][30] . Our preliminary data also suggest a conservation of the negative feedback regulation of p38 by MK2 in mammalian cells.…”