Caspase-dependent cleavage and inactivation of the Vav1 proto-oncogene product during apoptosis prevents IL-2 transcription

Here we identify the hematopoietic proto-oncogene Vav1 as a caspase substra te during apoptosis in lymphoid cells. Cleavage of Vav1 is prevented by the caspase inhibitors zDEVD and zVAD as well as by expression of CrmA, Vav1 i s cleaved in vivo at the evolutionary conserved caspase consensus cleavage site (DLYDC)-C-161, generating the carboxy-terminal cleavage product Vav1p7 6 of intermediate stability. In vitro caspase assays reveal cleavage of Vav 1 at position 161 either by apoptotic cell lysates or by recombinant caspas e-3, Mutation of Asp 161 to Ala leads to the usage of the adjacent alternat ive cleavage sequence DQID(150)D. Mutation of both cleavage sites at positi on 150 and 161 protects Vav1 from caspase-mediated proteolysis in vitro and in vivo. The cleavage product Vav1p76 is capable of activating JNK in T-ce lls, but fails to induce the phosphorylation of p38/HOG1, Vav1p76 displays a diminished capacity to activate the transcription factors NF-AT, AP-1 and NF-kappa B, and thus completely fails to activate IL-2 transcription. Sinc e Vav1 is essential for IL-2 production and plays a central role for cytosk eletal reorganization, its proteolytic inactivation during apoptosis affect s multiple downstream targets.