title: PED/PEA-15 controls fibroblast motility and wound closure by ERK1/2-dependent mechanisms.
abstract: Cell migration is dependent on the control of signaling events that play significant roles in creating contractile force and in contributing to wound closure. We evaluated wound closure in fibroblasts from mice overexpressing (TgPED) or lacking ped/pea-15 (KO), a gene overexpressed in patients with type 2 diabetes. Cultured skin fibroblasts isolated from TgPED mice showed a significant reduction in the ability to recolonize wounded area during scratch assay, compared to control fibroblasts. This difference was observed both in the absence and in the presence of mytomicin C, an inhibitor of mitosis. In time-lapse experiments, TgPED fibroblasts displayed about twofold lower velocity and diffusion coefficient, as compared to controls. These changes were accompanied by reduced spreading and decreased formation of stress fibers and focal adhesion plaques. At the molecular level, TgPED fibroblasts displayed decreased RhoA activation and increased abundance of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). Inhibition of ERK1/2 activity by PD98059 restored RhoA activation, cytoskeleton organization and cell motility, and almost completely rescued wound closure of TgPED fibroblasts. Interestingly, skin fibroblasts isolated from KO mice displayed an increased wound closure ability. In vivo, healing of dorsal wounds was delayed in TgPED and accelerated in KO mice. Thus, PED/PEA-15 may affect fibroblast motility by a mechanism, at least in part, mediated by ERK1/2.
authors.affiliation: Department of Cellular and Molecular Biology and Pathology, Federico II University of Naples, Naples, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Buonomo
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Giacco
authors.forename: Angela
authors.initials: A
authors.lastname: Vasaturo
authors.forename: Sergio
authors.initials: S
authors.lastname: Caserta
authors.forename: Stefano
authors.initials: S
authors.lastname: Guido
authors.forename: Valentina
authors.initials: V
authors.lastname: Pagliara
authors.forename: Corrado
authors.initials: C
authors.lastname: Garbi
authors.forename: Gelsomina
authors.initials: G
authors.lastname: Mansueto
authors.forename: Angela
authors.initials: A
authors.lastname: Cassese
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Perruolo
authors.forename: Francesco
authors.initials: F
authors.lastname: Oriente
authors.forename: Claudia
authors.initials: C
authors.lastname: Miele
authors.forename: Francesco
authors.initials: F
authors.lastname: Beguinot
authors.forename: Pietro
authors.initials: P
authors.lastname: Formisano
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002448:Cell Adhesion; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D005419:Flavonoids / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D005419:Flavonoids; D015395:Histocompatibility Antigens Class I; C490444:Pea15 protein, mouse; D010750:Phosphoproteins; C032907:Q surface antigens; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020742:rhoA GTP-Binding Protein; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one