Requirement of caspase-mediated cleavage of c-Abl during stress-induced apoptosis.

c-Abl protein tyrosine kinase plays an important role in cell cycle control and apoptosis. Furthermore, induction of apoptosis correlates with the activation of c-Abl. Here, we demonstrate the cleavage of c-Abl by caspases during apoptosis. Caspases separate c-Abl into functional domains including a Src-kinase, a fragment containing nuclear import sequences, a fragment with an actin-binding domain and nuclear export sequence. Caspase cleavage increases the kinase activity of c-Abl as demonstrated by in vitro kinase assays as well as by auto- and substrate phosphorylation. Cells in which c-Abl expression was knocked down by RNA interference resisted cisplatin- but not TNFalpha-induced apoptosis. A similar selective resistance against cisplatin-induced apoptosis was observed when cleavage resistant c-Abl was overexpressed in treated cells. Our data suggest the selective requirement of c-Abl cleavage by caspases for stress-induced, but not for TNFalpha-induced apoptosis.