Protein tyrosine kinases (PTK's) are of immense importance in growth regulation, differentiation and development. We have recently characterized a c-abl related PTK, designated arg. Arg is widely expressed, located at chromosome position 1q23-25 and encodes a 145 kD protein with tyrosine kinase activity. Arg and c-abl are strikingly similar with regard to overall structure, including distinctive C- terminal domains which distinguish them from all other PTK's. Our elucidation of the arg coding sequences defines the Abelson subfamily of nonreceptor PTK's, and our studies suggest that arg is the only close relative of c-abl. In addition to its important role in Chronic Myelogenous Leukemia, particularly interesting features of p140c-abl are that it is the only known PTK with sequence specific DNA binding activity, and that its binding activity is influences by differential phosphorylation during the cell cycle. cdc2 kinase phosphorylation sites, a proline rich DNA binding site and a nuclear targeting sequence are located in the distinct p140c-abl C-terminal domain. The close structural relationship between p145arg and p140c-abl, including the presence in p145arg of a possible nuclear targeting sequence and a proline rich region at positions analogous to those of p140c-abl, raises the interesting possibility that p145arg might also have DNA binding activity and play a role in the cell cycle. The experiments described in this proposal will employ molecular genetic and cell biological techniques to explore the normal role of arg in cell physiology, including an examination of its possible cell cycle and DNA binding functions. The arg signalling pathways will be defined by identifying the p145arg protein substrates and the mechanism of mitogenic coupling by p145arg will be explored by a structure function analysis that is based on our observation that arg and c-abl have different biochemical and transforming properties. Finally, the role of arg in human cancer will be examined by a focused analysis of human tumors, using the arg chromosomal location as a guide.
