title: srGAP1 regulates lamellipodial dynamics and cell migratory behavior by modulating Rac1 activity.
abstract: 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 Slit-Robo GAP 1 (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, 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.
authors.affiliation: Division of Membrane Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan Laboratory of Lipid Biochemistry, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamazaki
authors.forename: Toshiki
authors.initials: T
authors.lastname: Itoh
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miki
authors.forename: Tadaomi
authors.initials: T
authors.lastname: Takenawa
mesh_terms: D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002522:Chlorocebus aethiops; D031541:Fluorescence Resonance Energy Transfer; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D018613:Microscopy, Confocal; D009154:Mutation; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D059008:Time-Lapse Imaging / Q000379:methods; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; C107953:RAC1 protein, human; C582067:SRGAP1 protein, human; C066737:RHOA protein, human; D000205:Actomyosin; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein