Collagen XVII Shedding Suppresses Re-Epithelialization by Directing Keratinocyte Migration and Dampening mTOR Signaling

Joanna Jacków, Stefanie Löffek, Alexander Nyström, Leena Bruckner-Tuderman, Claus Werner Franzke*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1031-1041
Number of pages11
JournalJournal of Investigative Dermatology
Volume136
Issue number5
Early online date28 Jan 2016
DOIs
Publication statusPublished - 1 May 2016

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