title: AP-1-controlled hepatocyte growth factor activation promotes keratinocyte migration via CEACAM1 and urokinase plasminogen activator/urokinase plasminogen receptor.
abstract: Keratinocyte migration is essential for the rapid closure of the epidermis in the process of wound healing. Mesenchymal cell-derived hepatocyte growth factor (HGF) is a central regulator of this process. However, the molecular mechanisms and relevant genes that facilitate this cellular response are still poorly defined. We used heterologous cocultures combining primary human keratinocytes and genetically modified murine fibroblasts to identify key factors mediating HGF-induced epidermal cell migration. The absence of c-Jun activity in fibroblasts completely abolished the expression of HGF in these cells and consequently altered the behavior of keratinocytes. Time-resolved expression series of keratinocytes stimulated with HGF disclosed target genes regulating HGF-dependent motility. In addition to well-established HGF-dependent wound healing-associated genes, carcinoembryogenic antigen-related cell adhesion molecule (CEACAM)-1 and the urokinase plasminogen activator (uPA)/uPA-receptor (uPAR) pathway were identified as possible mediators in HGF-induced keratinocyte migration. The functional relevance of CEACAM-1 and uPA/uPAR on epidermal cell motility was demonstrated using the HaCaT cell culture model. In conclusion, the distinct spatiotemporal regulation of genes by HGF is essential for proper epidermal cell migration in cutaneous wound healing.
authors.affiliation: Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schnickmann
authors.forename: David
authors.initials: D
authors.lastname: Camacho-Trullio
authors.forename: Michaela
authors.initials: M
authors.lastname: Bissinger
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Peter
authors.initials: P
authors.lastname: Angel
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Axel
authors.initials: A
authors.lastname: Szabowski
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D018920:Coculture Techniques; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D016755:Proto-Oncogene Proteins c-jun; D055293:Receptors, Urokinase Plasminogen Activator; D018808:Transcription Factor AP-1; D017228:Hepatocyte Growth Factor