Cell migration is essential to a variety of physiological and pathological processes. The long-term objective of this research is to elucidate the molecular mechanisms whereby the Abl tyrosine kinases and associated adaptor proteins regulate cytoskeletal dynamics and cell migration. Genetic studies in Drosophila over the past 10 years have shown that Abl plays a role in the regulation of axonal outgrowth and fasciculation. Recently, we have shown that c-Abl plays a functional role in the reorganization of the actin cytoskeleton in response to growth factors in mammalian cells. We discovered that c-Abl is activated in response to growth factor stimulation, and that reorganization of the cytoskeleton by growth factors requires an active Abl tyrosine kinase. Studies in our laboratory have uncovered several Abl target proteins that are implicated in regulation of the actin cytoskeleton. Among these are the WASP/WAVE protein family, the PAK serine kinase, and the Abi adaptor proteins. The Abi proteins have been recently implicated in the transduction of signals from Ras to Rac. Moreover, like c-Abl, the Abi proteins are required for reorganization of the cytoskeleton in response to growth factors.
The specific aims of this proposal are: 1) to elucidate the role of the Abl tyrosine kinases in cell adhesion, spreading and migration and to define the Abl-dependent pathway that links activated tyrosine kinases to reorganization of the cytoskeleton; 2) to determine whether the Abl kinases regulate actin polymerization and depolymerization via the WASP/WAVE protein family and the PAK protein kinases, respectively; and 3) to determine whether the Abi adaptor proteins regulate cytoskeletal processes in response to extracellular stimuli, and whether they are required for cell migration in vitro and in vivo through the use of mice with targeted deletions of abi-l and abi-2 generated in our laboratory. Results from the aims proposed here will provide a mechanistic understanding of the role of Abl tyrosine kinases and associated proteins in the regulation of actin cytoskeleton dynamics and cell migration. With these findings we will gain a better understanding of the role of Abl kinases and their targets during mammalian development, and will obtain greater insights into the intracellular pathways that are altered as a consequence of deregulated Abl tyrosine kinase activity in human cancers.
