Journal
JOURNAL OF CELL SCIENCE
Volume 121, Issue 23, Pages 3922-3932Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.037549
Keywords
EGF-receptor; Laminin-5; Keratinocytes; uPAR; Wound healing
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Funding
- AICR (Association for International Cancer Research)
- AIRC (Italian Association for Cancer Research)
- Italian Ministry of Health
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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.
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