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J. Biol. Chem., Vol. 282, Issue 18, 13610-13616, May 4, 2007

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Protein C Is an Autocrine Growth Factor for Human Skin Keratinocytes^*

From the Sutton Research Laboratories, The University of Sydney at Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia

The protein C (PC) pathway plays an important role in coagulation and inflammation. Many components of the PC pathway have been identified in epidermal keratinocytes, including endothelial protein C receptor (EPCR), which is the specific receptor for PC/activated PC (APC), but the core member of this pathway, PC, and its function in keratinocytes has not been defined. In this study, we reveal that PC is strongly expressed by human keratinocytes at both gene and protein levels. When endogenous PC was blocked by siRNA the proliferation of keratinocytes was significantly decreased. This inhibitory effect was restored by the addition of recombinant APC. PC siRNA treatment also increased cell apoptosis by 3-fold and inhibited cell migration by more than 20%. When keratinocytes were pretreated with RCR252, an EPCR-blocking antibody, or PD153035, an epidermal growth factor receptor (EGFR) inhibitor, cell proliferation was hindered by more than 30%. These inhibitors also completely abolished recombinant APC (10 µg/ml)-stimulated proliferation. Blocking PC expression or inhibiting its binding to EPCR/EGFR decreased the phosphorylation of ERK1/2 but increased p38 activation. Furthermore, inhibition of ERK decreased cell proliferation by 30% and completely abolished the stimulatory effect of APC on proliferation. Taken together, these results indicate that keratinocyte-derived PC promotes cell survival, growth, and migration in an autocrine manner via EPCR, EGFR, and activation of ERK1/2. Our results highlight a novel role for the PC pathway in normal skin physiology and wound healing.

Received for publication, November 20, 2006 , and in revised form, January 30, 2007.

^* This work was supported by a University of Sydney postdoctoral fellowship, The Lincoln Centre, Rebecca Cooper Foundation, a grant from Northern Sydney Area Health (to M. X.) and the Sutton Arthritis Research Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Level One, Block Four, Sutton Research Labs, The University of Sydney at Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia. Tel.: 612-99266045; Fax: 612-99266269; E-mail: mlxue{at}med.usyd.edu.au.

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