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J. Biol. Chem., Vol. 281, Issue 44, 32941-32945, November 3, 2006

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Evidence for a Matriptase-Prostasin Proteolytic Cascade Regulating Terminal Epidermal Differentiation^*

Sarah Netzel-Arnett¹, Brooke M. Currie¹, Roman Szabo, Chen-Yong Lin^¶, Li-Mei Chen^||, Karl X. Chai^||, Toni M. Antalis, Thomas H. Bugge², and Karin List

From the Center for Vascular and Inflammatory Diseases and Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, the Proteases and Tissue Remodeling Unit, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, the ^¶Lombardi Cancer Center, Georgetown University Medical Center, Washington, D. C. 20007, and the ^||Department of Molecular Biology and Microbiology, University of Central Florida, Orlando, Florida 32816-2364

Recent gene ablation studies in mice have shown that matriptase, a type II transmembrane serine protease, and prostasin, a glycosylphosphatidylinositol-anchored membrane serine protease, are both required for processing of the epidermis-specific polyprotein, profilaggrin, stratum corneum formation, and acquisition of epidermal barrier function. Here we present evidence that matriptase acts upstream of prostasin in a zymogen activation cascade that regulates terminal epidermal differentiation and is required for prostasin zymogen activation. Enzymatic gene trapping of matriptase combined with prostasin immunohistochemistry revealed that matriptase was co-localized with prostasin in transitional layer cells of the epidermis and that the developmental onset of expression of the two membrane proteases was coordinated and correlated with acquisition of epidermal barrier function. Purified soluble matriptase efficiently converted soluble prostasin zymogen to an active two-chain form that formed SDS-stable complexes with the serpin protease nexin-1. Whereas two forms of prostasin with molecular weights corresponding to the prostasin zymogen and active prostasin were present in wild type epidermis, prostasin was exclusively found in the zymogen form in matriptase-deficient epidermis. These data suggest that matriptase, an autoactivating protease, acts upstream from prostasin to initiate a zymogen cascade that is essential for epidermal differentiation.

Received for publication, August 4, 2006 , and in revised form, September 11, 2006.

^* This work was supported by the National Institutes of Health (NIH) Intramural program and by Grant DAMD-17-02-1-0693 from the Department of Defense (DOD) (to T. H. B.), by National Institutes of Health Grant CA098369 and the Lance Armstrong Foundation (to T. M. A.), NIH Grant HL07698 (to S. N.-A.), DOD Grant DAMD17-02-1-0338 (to K. X. C.), NIH Grant HD 40241 (to L-M. C.), and by NIH Grants R01-CA-104944 and R01-CA-096851 (to C.-Y. L.). 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. We dedicate this paper to the memory of our friend Robert B. Dickson who passed away June 24, 2006.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Proteases and Tissue Remodeling Unit, NIDCR, NIH, 30 Convent Dr., Rm. 211, Bethesda, MD 20892. Tel.: 301-435-1840; Fax: 301-402-0823; E-mail: thomas.bugge{at}nih.gov.

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