Functional Interaction between the c-Abl and Arg Protein-tyrosine Kinases in the Oxidative Stress Response

The Abl family of mammalian nonreceptor tyrosine kinases consists of c-Abl and Arg. Recent work has shown that c-Abl and Arg are activated in the cellular response to oxidative stress. The present studies demonstrate that reactive oxygen species (ROS) induce the formation of c-Abl and Arg heterodimers. The results show that the c-Abl SH3 domain binds directly to a proline-rich site (amino acids 567–576) in the Arg C-terminal region. Formation of c-Abl·Arg heterodimers also involves direct binding of the Arg Src homology 3 domain to the C-terminal region of c-Abl. The results further demonstrate that the interaction between c-Abl and Arg involves c-Abl-mediated phosphorylation of Arg. The functional significance of the c-Abl-Arg interaction is supported by the demonstration that both c-Abl and Arg are required for ROS-induced apoptosis. These findings indicate that ROS induce c-Abl·Arg heterodimers and that both c-Abl and Arg are necessary as effectors in the apoptotic response to oxidative stress.