SrGAP3 interacts with lamellipodin at the cell membrane and regulates Rac-dependent cellular protrusions.

SrGAP3/MEGAP is a member of the Slit-Robo GAP (srGAP) family and is implicated in repulsive axon guidance and neuronal migration through Slit-Robo-mediated signal transduction. Here we describe an inhibitory role of srGAP3 on actin dynamics, specifically on lamellipodia formation. We show that the F-BAR domain localizes srGAP3 to the leading edge of cellular protrusions whereas the SH3 domain is important for focal adhesion targeting. We report on a novel srGAP3 interaction partner, lamellipodin, which localizes with srGAP3 at the leading edge. Live-cell analyses revealed that srGAP3 influences lamellipodin-evoked lamellipodial dynamics. Furthermore, we show that mouse embryonic fibroblasts derived from homozygous srGAP3-knockout embryos display an increased cell area and lamellipodia formation that can be blocked by shRNA-mediated knockdown of lamellipodin.