Neuronal migration and neurite outgrowth are essential processes for the formation of cortical cytoarchitecture during the development of the central nervous system. Disruption of these biological processes can cause serious defects during brain development in humans. Cdk5 is a critical component of the molecular control regulating these processes. However, its functions are far from being completely understood. Recently a new Cdk5 interacting protein, cables, has been identified to simultaneously bind to Cdk5 and the proto-oncoprotein c-Abl. The latter is implicated in the development of the nervous system and in integrin-mediated cell adhesion events. This project is aimed to probe the regulations of cables by c-Abl and Cdk5 in the context of neurite outgrowth, and to establish c- Abl, cables, and Cdk5 as new components of the integrin signaling pathway pertinent to cortical development. Specifically, the following goals will be achieved: l. To map c-Abl and Cdk5 interaction domains and phosphorylation sites on cables, respectively; To generate interaction and phosphorylation deficient mutants and to analyze the functions of these mutants in neurite outgrowth assay. Dominant negative mutants of cables may be generated in this manner. The overall goal is to dissect the functions of the signaling pathway involving c-Abl, cables, and Cdk5 in neurite outgrowth; 2. To identify other cellular proteins that associate with cables using the yeast two-hybrid system; The functions of such interacting proteins in neurite outgrowth will be examined; 3. To establish c-Abl, cables, and Cdk5 as components of the integrin mediated signaling pathway that is required to regulate neurite outgrowth.
