srGAP1 regulates lamellipodial dynamics and cell migratory behavior by modulating Rac1 activity.

Molecular biology of the cell

PubMedID: 24006490

Yamazaki D, Itoh T, Miki H, Takenawa T. srGAP1 regulates lamellipodial dynamics and cell migratory behavior by modulating Rac1 activity. Mol Biol Cell. 2013;.
The distinct levels of Rac activity differentially regulate the pattern of intrinsic cell migration. However, it remains unknown how Rac activity is modulated and how the level of Rac activity controls cell migratory behavior. Here we show that srGAP1 is a modulator of Rac activity in locomotive cells. srGAP1 possesses a GAP activity specific to Rac1 and is recruited to lamellipodia in a Rac1-dependent manner. srGAP1 limits Rac1 activity and allows concomitant activation of Rac1 and RhoA, which are mutually inhibitory. When both GTPases are activated, the protrusive structures caused by Rac1-dependent actin reorganization are spatially restricted and periodically destabilized, causing ruffling by RhoA-induced actomyosin contractility. Depletion of srGAP1 overactivates Rac1 and inactivates RhoA, thereby resulting in continuous spatiotemporal spreading of lamellipodia and a modal shift of intrinsic cell motility from random to directionally persistent. Thus, srGAP1 is a key determinant of lamellipodial dynamics and cell migratory behavior.