title: Regulation of focal adhesions by flightless i involves inhibition of paxillin phosphorylation via a Rac1-dependent pathway.
abstract: Flightless I (Flii) is an actin-remodeling protein that influences diverse processes including cell migration and gene transcription and links signal transduction with cytoskeletal regulation. Here, we show that Flii modulation of focal adhesions and filamentous actin stress fibers is Rac1-dependent. Using primary skin fibroblasts from Flii overexpressing (Flii(Tg/Tg)), wild-type, and Flii deficient (Flii(+/-)) mice, we show that elevated expression of Flii increases stress fiber formation by impaired focal adhesion turnover and enhanced formation of fibrillar adhesions. Conversely, Flii knockdown increases the percentage of focal complex positive cells. We further show that a functional effect of Flii at both the cellular level and in in vivo mouse wounds is through inhibiting paxillin tyrosine phosphorylation and suppression of signaling proteins Src and p130Cas, both of which regulate adhesion signaling pathways. Flii is upregulated in response to wounding, and overexpression of Flii inhibits paxillin activity and reduces adhesion signaling by modulating the activity of the Rho family GTPases. Overexpression of constitutively active Rac1 GTPase restores the spreading ability of Flii(Tg/Tg) fibroblasts and may explain the reduced adhesion, migration, and proliferation observed in Flii(Tg/Tg) mice and their impaired wound healing, a process dependent on effective cellular motility and adhesion.
authors: Wound Healing Laboratory, Women's and Children's Health Research Institute, University of Adelaide, North Adelaide, South Australia, Australia.
authors: Zlatko
authors: Z
authors: Kopecki
authors: Geraldine M
authors: GM
authors: O'Neill
authors: Ruth M
authors: RM
authors: Arkell
authors: Allison J
authors: AJ
authors: Cowin
mesh_terms: D000199:Actins / Q000737:chemistry; D000818:Animals; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins / Q000502:physiology*; D022001:Focal Adhesions; D051379:Mice; D008807:Mice, Inbred BALB C; D008840:Microfilament Proteins; D009479:Neuropeptides / Q000502:physiology*; D051419:Paxillin / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D015534:Trans-Activators; D014947:Wounds and Injuries / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000502:physiology*; D020830:rac1 GTP-Binding Protein
chemical_list: D000199:Actins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C000609263:FlII protein, mouse; D008840:Microfilament Proteins; D009479:Neuropeptides; D051419:Paxillin; C484602:Rac1 protein, mouse; D015534:Trans-Activators; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein