title: Transmembrane collagen XVII modulates integrin dependent keratinocyte migration via PI3K/Rac1 signaling.
abstract: The hemidesmosomal transmembrane component collagen XVII (ColXVII) plays an important role in the anchorage of the epidermis to the underlying basement membrane. However, this adhesion protein seems to be also involved in the regulation of keratinocyte migration, since its expression in these cells is strongly elevated during reepithelialization of acute wounds and in the invasive front of squamous cell carcinoma, while its absence in ColXVII-deficient keratinocytes leads to altered cell motility. Using a genetic model of murine Col17a1⁻/⁻ keratinocytes we elucidated ColXVII mediated signaling pathways in cell adhesion and migration. Col17a1⁻/⁻ keratinocytes exhibited increased spreading on laminin 332 and accelerated, but less directed cell motility. These effects were accompanied by increased expression of the integrin subunits β4 and β1. The migratory phenotype, as evidenced by formation of multiple unstable lamellipodia, was associated with enhanced phosphoinositide 3-kinase (PI3K) activity. Dissection of the signaling pathway uncovered enhanced phosphorylation of the β4 integrin subunit and the focal adhesion kinase (FAK) as activators of PI3K. This resulted in elevated Rac1 activity as a downstream consequence. These results provide mechanistic evidence that ColXVII coordinates keratinocyte adhesion and directed motility by interfering integrin dependent PI3K activation and by stabilizing lamellipodia at the leading edge of reepithelializing wounds and in invasive squamous cell carcinoma.
authors: Department of Dermatology and Venerology, University Medical Center Freiburg, Freiburg, Germany.
authors: Stefanie
authors: S
authors: Löffek
authors: Department of Dermatology, Oulu Center for Cell-Matrix Research, University of Oulu, and Clinical Research Center, Oulu University Hospital, Oulu, Finland.
authors: Tiina
authors: T
authors: Hurskainen
authors: Department of Dermatology and Venerology, University Medical Center Freiburg, Freiburg, Germany.
authors: Joanna
authors: J
authors: Jackow
authors: Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany ; Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors: Florian Christoph
authors: FC
authors: Sigloch
authors: Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany ; Bioss Centre for Biological Studies, University of Freiburg, Freiburg, Germany.
authors: Oliver
authors: O
authors: Schilling
authors: Department of Dermatology, Oulu Center for Cell-Matrix Research, University of Oulu, and Clinical Research Center, Oulu University Hospital, Oulu, Finland.
authors: Kaisa
authors: K
authors: Tasanen
authors: Department of Dermatology and Venerology, University Medical Center Freiburg, Freiburg, Germany ; Freiburg Institute of Advanced Studies, School of Life Sciences - LifeNet, University of Freiburg, Freiburg, Germany.
authors: Leena
authors: L
authors: Bruckner-Tuderman
authors: Department of Dermatology and Venerology, University Medical Center Freiburg, Freiburg, Germany.
authors: Claus-Werner
authors: CW
authors: Franzke
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D024041:Non-Fibrillar Collagens / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000097794:Kalinin; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D015815:Cell Adhesion Molecules; D051417:Focal Adhesion Kinase 1; D019012:Integrin beta1; D039663:Integrin beta4; D009479:Neuropeptides; D024041:Non-Fibrillar Collagens; D019869:Phosphatidylinositol 3-Kinases; D020830:rac1 GTP-Binding Protein; D000097794:Kalinin; D000097805:Collagen Type XVII; C484602:Rac1 protein, mouse; C496051:Ptk2 protein, mouse