title: Flightless I regulates hemidesmosome formation and integrin-mediated cellular adhesion and migration during wound repair.
abstract: Flightless I (Flii), a highly conserved member of the gelsolin family of actin-remodelling proteins associates with actin structures and is involved in cellular motility and adhesion. Our previous studies have shown that Flii is an important negative regulator of wound repair. Here, we show that Flii affects hemidesmosome formation and integrin-mediated keratinocyte adhesion and migration. Impaired hemidesmosome formation and sparse arrangements of keratin cytoskeleton tonofilaments and actin cytoskeleton anchoring fibrils were observed in Flii(Tg/+) and Flii(Tg/Tg) mice with their skin being significantly more fragile than Flii(+/-) and WT mice. Flii(+/-) primary keratinocytes showed increased adhesion on laminin and collagen I than WT and Flii(Tg/Tg) primary keratinocytes. Decreased expression of CD151 and laminin-binding integrins alpha3, beta1, alpha6 and beta4 were observed in Flii overexpressing wounds, which could contribute to the impaired wound re-epithelialization observed in these mice. Flii interacts with proteins directly linked to the cytoplasmic domain of integrin receptors suggesting that it may be a mechanical link between ligand-bound integrin receptors and the actin cytoskeleton driving adhesion-signaling pathways. Therefore Flii may regulate wound repair through its effect on hemidesmosome formation and integrin-mediated cellular adhesion and migration.
authors.affiliation: Women's and Children's Health Research Institute, North Adelaide, South Australia, Australia.
authors.forename: Zlatko
authors.initials: Z
authors.lastname: Kopecki
authors.forename: Ruth
authors.initials: R
authors.lastname: Arkell
authors.forename: Barry C
authors.initials: BC
authors.lastname: Powell
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Cowin
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D002352:Carrier Proteins; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D022002:Hemidesmosomes / Q000502:physiology*; D039503:Integrin alpha6 / Q000502:physiology; D019012:Integrin beta1 / Q000502:physiology; D039663:Integrin beta4 / Q000502:physiology; D016023:Integrins / Q000502:physiology*; D015603:Keratinocytes / Q000502:physiology; D007797:Laminin / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008840:Microfilament Proteins; D015398:Signal Transduction; D060185:Tetraspanin 24; D015534:Trans-Activators; D014945:Wound Healing / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D002352:Carrier Proteins; C554716:Cd151 protein, mouse; D003598:Cytoskeletal Proteins; C000609263:FlII protein, mouse; D039503:Integrin alpha6; D019012:Integrin beta1; D039663:Integrin beta4; D016023:Integrins; D007797:Laminin; D008840:Microfilament Proteins; D060185:Tetraspanin 24; D015534:Trans-Activators