Actin remodeling at the plasma membrane is required for cell migration. The Ena/VASP family of actin regulatory proteins are key regulators of filopodia and lamellipodia dynamics, both environment sensing protrusions involved in migration. These proteins are potential convergent points for second messenger pathways. Lamellipodin (Lpd) is an Ena/VASP ligand recently identified in the Gertler laboratory. Lamellipodin (Lpd) is discretely targeted to the leading edge of lamellipodia and the tips of filopodia. Knockdown of Lpd expression causes defects in lamellipodia formation and alters F-actin geometry and content with the cell. Lpd contains a RAS-association (RA) domain. RA domains mediate binding to specific members of the RAS subfamily of small GTPases. RAS signaling can induce changes in cell polarity and motility and drive oncogenic transformation. We hypothesize that Lpd couples signaling by RAS proteins to cytoskeletal dynamics. The goal of this proposal is to elucidate the underlying molecular mechanisms for Lpd function by addressing the general hypothesis that Lpd transduces signals from the RAS family proteins to regulate cell migration by regulating actin dynamics, in part via Ena/VASP proteins.
