Antiapoptotic signaling generated by caspase-induced cleavage of RasGAP

Activation of caspases 3 and 9 is thought to commit a cell irreversibly to apoptosis. There are, however, several documented situations (e.g., during erythroblast differentiation) in which caspases are activated and caspase s ubstrates are cleaved with no associated apoptotic response. Why the cleava ge of caspase substrates leads to cell death in certain cases but not in ot hers is unclear. One possibility is that some caspase substrates generate a ntiapoptotic signals when cleaved. Here we show that RasGAP is one such pro tein. Caspases cleave RasGAP into a C-terminal fragment (fragment C) and an N-terminal fragment (fragment N). Fragment C expressed alone induces apopt osis, but this effect could be totally blocked by fragment N. Fragment N co uld also block apoptosis induced by low levels of caspase 9. As caspase act ivity increases, fragment N is further cleaved into fragments N1 and N2. Ap optosis induced by high levels of caspase 9 or by cisplatin was strongly po tentiated by fragment N1 or N2 but not by fragment N. The present study sup ports a model in which RasGAP functions as a sensor of caspase activity to determine whether or not a cell should survive. When caspases are mildly ac tivated, the partial cleavage of RasGAP protects cells from apoptosis. When caspase activity reaches levels that allow completion of RasGAP cleavage, the resulting RasGAP fragments turn into potent proapoptotic molecules.