Partial cleavage of RasGAP by caspases is required for cell survival in mild stress conditions.
Tight control of apoptosis is required for proper development and maintenance of homeostasis in multicellular organisms. Cells can protect themselves from potentially lethal stimuli by expressing antiapoptotic factors, such as inhibitors of apoptosis, FLICE (caspase 8)-inhibitory proteins, and members of the Bcl2 family. Here, we describe a mechanism that allows cells to survive once executioner caspases have been activated. This mechanism relies on the partial cleavage of RasGAP by caspase 3 into an amino-terminal fragment called fragment N. Generation of this fragment leads to the activation of the antiapoptotic Akt kinase, preventing further amplification of caspase activity. Partial cleavage of RasGAP is required for cell survival under stress conditions because cells expressing an uncleavable RasGAP mutant cannot activate Akt, cannot prevent amplification of caspase 3 activity, and eventually undergo apoptosis. Executioner caspases therefore control the extent of their own activation by a feedback regulatory mechanism initiated by the partial cleavage of RasGAP that is crucial for cell survival under adverse conditions.
Yang
Jiang-Yan
JY
Department of Cellular Biology, Lausanne University, 1005 Lausanne, Switzerland.
Michod
David
D
Walicki
Joël
J
Murphy
Brona M
BM
Kasibhatla
Shailaja
S
Martin
Seamus J
SJ
Widmann
Christian
C
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018274:Electroporation; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D019169:Jurkat Cells; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008957:Models, Genetic; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013312:Stress, Physiological; D013997:Time Factors; D014162:Transfection; D020703:ras GTPase-Activating Proteins / Q000737:chemistry* / Q000378:metabolism
D020703:ras GTPase-Activating Proteins; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin