RRC ID 78185
Author Moriizumi H, Kubota Y, Tsuchiya T, Naka R, Takekawa M.
Title Caspase 3-specific cleavage of MEK1 suppresses ERK signaling and sensitizes cells to stress-induced apoptosis.
Journal FEBS Open Bio
Abstract Proper regulation of apoptotic cell death is crucial for normal development and homeostasis in multicellular organisms and is achieved by the balance between pro-apoptotic processes, such as caspase activation, and pro-survival signaling, such as extracellular signal-regulated kinase (ERK) activation. However, the functional interplay between these opposing signaling pathways remains incompletely understood. Here, we identified MAPK/ERK kinase (MEK) 1, a central component of the ERK pathway, as a specific substrate for the executioner caspase-3. During apoptosis, MEK1 is cleaved at an evolutionarily conserved Asp282 residue in the kinase domain, thereby losing its catalytic activity. Gene knockout experiments showed that MEK1 cleavage was mediated by caspase-3, but not by the other executioner caspases, caspase-6 or -7. Following exposure of cells to osmotic stress, elevated ERK activity gradually decreased, and this was accompanied by increased cleavage of MEK1. In contrast, the expression of a caspase-uncleavable MEK1(D282N) mutant in cells maintained stress-induced ERK activity and thereby attenuated apoptotic cell death. Thus, caspase-3-mediated, proteolytic inhibition of MEK1 sensitizes cells to apoptosis by suppressing pro-survival ERK signaling. Furthermore, we found that a RASopathy-associated MEK1(Y130C) mutation prevented this caspase-3-mediated proteolytic inactivation of MEK1 and efficiently protected cells from stress-induced apoptosis. Our data reveal the functional crosstalk between ERK-mediated cell survival and caspase-mediated cell death pathways and suggest that its dysregulation by a disease-associated MEK1 mutation is at least partly involved in the pathophysiology of congenital RASopathies.
Volume 13(4)
Pages 684-700
Published 2023-4-1
DOI 10.1002/2211-5463.13574
PMID 36776127
PMC PMC10068311
MeSH Apoptosis / physiology Caspase 3 / metabolism Caspases / metabolism Extracellular Signal-Regulated MAP Kinases* / metabolism Signal Transduction* / physiology
Human and Animal Cells Jurkat(RCB3052) 293(RCB1637) A549(RCB3677) 293gp(RCB2354)