Arg is one of the two mammalian members of the Abl family of PTKs. Although Arg shares a common topology with c-Abl, the cytoplasmic subcellular localization of Arg indicates that its function in the cell is distinct from that of c-Abl, which is localized predominantly in the nucleus. Arg and c-Abl have several domains, including SH2 and SH3 domains, as well as large C-terminal domains that distinguish them from other nonreceptor PTKs. The Arg and c-Abl C-terminal domains are largely dissimilar and confer distinct biological activities, but have in common several SH3 binding sites, through which they select some substrates. Using the Arg SH3 bindings sites as bait, we have isolated two novel Arg interacting proteins, designated ArgBP1 and ArgBP2. ArgBP1 has an SH3 domain and a proline motif that specifically bind to the Xenopus gene whose restricted embryonic expression pattern indicates a role in CNS development. In addition, ArgBP1 can bind to a component of the stress response pathway, an association that suggests participation in signaling cascades that may relate to the known activity of c-Abl in mediating signals arising from DNA damage. In addition, ArgBP1 potentially links Arg to developmental pathways suggested by the known involvement of Drosophila Abl, the common homologue of Arg and c-Abl, in CNS axonogenesis. ArgBP2 is a multiple SH3 domain containing protein that is localized in stress fibers, focal adhesions and the nucleus. These observations suggest that ArgBP2 is an adapter protein that may participate in the formation of signaling complexes associated with the actin cytoskeleton, and that it may link Arg, and possibly c-Abl, to cytoskeletal modeling. This proposal contains molecular, cellular biological and genetic experiments designed to explore the involvement of Arg in stress response and developmental signaling pathways, and to define the roles of ArgBP1 in these pathways. In addition, they will define the role of ArgBP2 in cytoskeletal modeling and determine its role in mediating ignals arising from Arg. Finally they will identify additional Arg substrates, and utilize the Drosophila genetic model to gain insights into the functions of ArgBP1 and ArgBP2.
