Transmembrane Collagen XVII Modulates Integrin Dependent Keratinocyte Migration via PI3K/Rac1 Signaling
Authors
Stefanie Loffek, Tiina Hurskainen, Joanna Jackow, Florian Christoph Sigloch, Oliver Schilling, Kaisa Tasanen, Leena Bruckner-Tuderman, Claus-Werner Franzke
Institution
Uni Freiburg
Country
Germany
Year
2014
Journal
PLOS
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 Col17a12/2 keratinocytes we elucidated ColXVII mediated
signaling pathways in cell adhesion and migration. Col17a12/2 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 b4 and b1. 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 b4 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.