title: Collagen XVII Shedding Suppresses Re-Epithelialization by Directing Keratinocyte Migration and Dampening mTOR Signaling.
abstract: Transmembrane collagen XVII is traditionally viewed as an important hemidesmosomal attachment component that promotes stable dermal-epidermal adhesion in the skin. However, its expression is highly elevated at the leading edges of cutaneous wounds or invasive carcinomas, suggesting alternative functions in cell migration. The collagenous ectodomain of collagen XVII is constitutively shed from the cell surface by a disintegrin and metalloproteinases, and this shedding is strongly induced during wound healing. Recently, we investigated the physiological relevance of collagen XVII shedding by generating knock-in mice, which exclusively express a functional non-sheddable collagen XVII mutant. Prevention of ectodomain shedding in these mice caused no spontaneous phenotype in resting skin, but accelerated re-epithelialization on skin wounding. Here, we investigated the mechanistic function of shedding during wound healing. Using the non-shedding collagen XVII mice as a model, we uncovered ectodomain shedding as a highly dynamic modulator of in vivo proliferation and motility of activated keratinocytes through tight coordination of α6β4 integrin-laminin-332 interactions and dampening of mechanistic target of rapamycin signaling at the wound edges. Thus, our studies identify ectodomain shedding of collagen XVII as an interactive platform that translates shedding into a signal for directed cell growth and motility during skin regeneration.
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Germany. Electronic address: joanna.jackow@inserm.fr.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jacków
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Löffek
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nyström
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Germany.
authors.forename: Leena
authors.initials: L
authors.lastname: Bruckner-Tuderman
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Germany. Electronic address: claus-werner.franzke@uniklinik-freiburg.de.
authors.forename: Claus-Werner
authors.initials: CW
authors.lastname: Franzke
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024041:Non-Fibrillar Collagens / Q000378:metabolism*; D011897:Random Allocation; D062326:Re-Epithelialization / Q000235:genetics*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D014947:Wounds and Injuries / Q000235:genetics / Q000473:pathology; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D024041:Non-Fibrillar Collagens; D058570:TOR Serine-Threonine Kinases; D000097805:Collagen Type XVII; C546843:mTOR protein, mouse