Abstract
Filopodia are thin, actin-enriched structure of membrane protrusions. Filopodia play instrumental roles in pathogen detection, cell migration, wound healing, and during development. During neurogenesis, filopodium formation precedes the formation of dendrites and spines. The insulin receptor substrate protein of 53 kDa (IRSp53) has been shown to regulate the formation of filopodia. Our preliminary results suggest that overexpressing an adaptor protein SH2B1β enhances neurite outgrowth of hippocampal neurons. Thus, I hypothesize that IRSp53 and SH2B1β may act together to regulate actin cytoskeleton remodeling and thus filopodium formation. In this thesis, I show that overexpression of either IRSp53 or SH2B1β induces the filopodium formation of 293T cells. In addition, SH2B1β interacts with IRSp53 to enhance filopodium formation and highly branched filopodia. Furthermore, IMD and SH3 domains of IRSp53 as well as N-terminal proline-rich domains of SH2B1β are required for the enhancement of filopodium formation. One mechanism for this enhancement of filopodia is that IRSp53 recruits SH2B1β to the plasma membrane. Finally, I demonstrate that IRSp53 and SH2B1β synergistically enhance neurite branching of hippocampal neurons. Taken together, this study provides novel findings that SH2B1β interacts with IRSp53-containing complexes to promote filopodium formation and thus neurite outgrowth.