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First published online 11 November 2008
doi: 10.1242/jcs.037549

Journal of Cell Science 121, 3922-3932 (2008)
Published by The Company of Biologists 2008
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Research Article

uPAR-deficient mouse keratinocytes fail to produce EGFR-dependent laminin-5, affecting migration in vivo and in vitro

Silvia D'Alessio1, Laura Gerasi1 and Francesco Blasi2,*

1 Università Vita Salute San Raffaele and Istituto Scientifico H San Raffaele, via Olgettina 60, 20132 Milano, Italy
2 IFOM (Fondazione Istituto FIRC di Oncologia Molecolare), via Adamello 16, 20139 Milano, Italy

* Author for correspondence (e-mail: blasi.francesco{at}hsr.it)

Accepted 11 September 2008

The urokinase receptor (uPAR) is involved in a series of pathological processes, from inflammation to cancer. We have analyzed in detail the role of uPAR and the mechanisms involved in keratinocyte behavior during wound healing by exploiting uPAR-knockout (KO) mice. In vivo, uPAR-KO mice showed delayed wound healing, with abnormal keratinocyte migration and proliferation. In vitro, unlike wild-type cells, primary uPAR-KO keratinocytes did not proliferate in response to epidermal growth factor (EGF), their growth and migration were not inhibited by EGF-receptor (EGFR) inhibitors, and they did not adhere to uncoated surfaces. Whereas EGFR levels in uPAR-KO keratinocytes were normal, there was no tyrosine phosphorylation upon addition of EGF, and its downstream targets, extracellular-signal-regulated kinases 1 and 2 (ERK1/2), were not activated. Re-introduction of mouse uPAR rescued all phenotypes. In vitro adhesion and migration defects were associated with the failure of uPAR-KO keratinocytes to normally produce and secrete laminin-5 (LN5), an event that requires EGFR signaling. These results were confirmed in vivo, with LN5 being upregulated during wound healing in wild-type but not in uPAR-KO epidermis.

Key words: EGF-receptor, Laminin-5, Keratinocytes, uPAR, Wound healing






© The Company of Biologists Ltd 2008