Open AccessTransmembrane Collagen XVII Modulates Integrin Dependent Keratinocyte Migration via PI3K/Rac1 Signaling
Author(s) -
Stefanie Löffek,
Tiina Hurskainen,
J. Jacków,
Florian Christoph Sigloch,
Oliver Schilling,
Kaisa Tasanen,
Leena BrucknerTuderman,
ClausWerner Franzke
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0087263
Subject(s) - lamellipodium , focal adhesion , microbiology and biotechnology , integrin , rac1 , pi3k/akt/mtor pathway , hemidesmosome , cell migration , cell adhesion , keratinocyte , biology , signal transduction , motility , chemistry , cell , cell culture , basement membrane , biochemistry , genetics
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.