title: Cdc42 and p190RhoGAP activation by CCN2 regulates cell spreading and polarity and induces actin disassembly in migrating keratinocytes.
abstract: Cell migration requires spatiotemporal integration of signals that regulate cytoskeletal dynamics. In response to a migration-promoting agent, cells begin to polarise and extend protrusions in the direction of migration. These cytoskeletal rearrangements are orchestrated by a variety of proteins, including focal adhesion kinase (FAK) and the Rho family of GTPases. CCN2, also known as connective tissue growth factor, has emerged as a regulator of cell migration but the mechanism by which CCN2 regulates keratinocyte function is not well understood. In this article, we sought to elucidate the basic mechanism of CCN2-induced cell migration in human keratinocytes. Immunohistochemical staining was used to demonstrate that treatment with CCN2 induces a migratory phenotype through actin disassembly, spreading of lamellipodia and re-orientation of the Golgi. In vitro assays were used to show that CCN2-induced cell migration is dependent on FAK, RhoA and Cdc42, but independent of Rac1. CCN2-treated keratinocytes displayed increased Cdc42 activity and decreased RhoA activity up to 12 hours post-treatment, with upregulation of p190RhoGAP. An improved understanding of how CCN2 regulates cell migration may establish the foundation for future therapeutics in fibrotic and neoplastic diseases.
authors.affiliation: Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Department of Surgical Sciences, Plastic Surgery Unit, Uppsala University, Uppsala, Sweden.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kiwanuka
authors.affiliation: Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Cameron Cy
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Hackl
authors.affiliation: Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Caterson
authors.affiliation: Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Johan Pe
authors.initials: JP
authors.lastname: Junker
authors.affiliation: Department of Surgical Sciences, Plastic Surgery Unit, Uppsala University, Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Gerdin
authors.affiliation: Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Elof
authors.initials: E
authors.lastname: Eriksson
mesh_terms: D000199:Actins; D002465:Cell Movement; D016764:Cell Polarity; D055513:Connective Tissue Growth Factor; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D015603:Keratinocytes; D012097:Repressor Proteins; D020764:cdc42 GTP-Binding Protein
chemical_list: C074560:ARHGAP35 protein, human; D000199:Actins; C526317:CCN2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D012097:Repressor Proteins; D055513:Connective Tissue Growth Factor; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020764:cdc42 GTP-Binding Protein
keywords: Actin cytoskeleton; CCN2; CTGF; Cell polarity; Cell spreading; Keratinocytes