title: Desmoglein 3-Dependent Signaling Regulates Keratinocyte Migration and Wound Healing.
abstract: The desmosomal transmembrane adhesion molecules desmoglein 3 (Dsg3) and desmocollin 3 (Dsc3) are required for strong keratinocyte cohesion. Recently, we have shown that Dsg3 associates with p38 mitogen-activated protein kinase (p38MAPK) and suppresses its activity. Here, we further investigated the role of Dsg3-dependent control of p38MAPK function. Dsg3-deficient mice display recurrent spontaneously healing skin erosions. In lesional and perilesional biopsies, p38MAPK activation was detectable compared with control animals. This led us to speculate that Dsg3 regulates wound repair in a p38MAPK-dependent manner. Indeed, scratch-wounded keratinocyte monolayers exhibited p38MAPK activation and loss of Dsg3 in cells lining the wound edge. Human keratinocytes after silencing of Dsg3 as well as primary cells isolated from Dsg3 knockout animals exhibited accelerated migration, which was further corroborated in an ex vivo skin outgrowth assay. Importantly, migration was efficiently blocked by inhibition of p38MAPK, indicating that p38MAPK mediates the effects observed upon loss of Dsg3. In line with this, we show that levels of active p38MAPK associated with Dsc3 are increased in Dsg3-deficient cells. These data indicate that Dsg3 controls a switch from an adhesive to a migratory keratinocyte phenotype via p38MAPK inhibition. Thus, loss of Dsg3 adhesion may foster wound closure by allowing p38MAPK-dependent migration.
authors.affiliation: Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Rötzer
authors.affiliation: Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Hartlieb
authors.affiliation: Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Winkler
authors.affiliation: Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Elias
authors.initials: E
authors.lastname: Walter
authors.affiliation: Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Schlipp
authors.affiliation: Department of Dermatology and Allergology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Miklós
authors.initials: M
authors.lastname: Sardy
authors.affiliation: Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität München, Munich, Germany. Electronic address: volker.spindler@med.uni-muenchen.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Spindler
authors.affiliation: Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität München, Munich, Germany. Electronic address: jens.waschke@med.uni-muenchen.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Waschke
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D051184:Desmoglein 3 / Q000172:deficiency / Q000378:metabolism*; D003896:Desmosomes / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014945:Wound Healing / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051184:Desmoglein 3; C495300:Dsg3 protein, mouse; D034741:RNA, Small Interfering; D048051:p38 Mitogen-Activated Protein Kinases