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J. Biol. Chem., Vol. 282, Issue 6, 3640-3652, February 9, 2007

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A Potential Role for Multiple Tissue Kallikrein Serine Proteases in Epidermal Desquamation^*

Carla A. Borgoño, Iacovos P. Michael, Nahoko Komatsu, Arumugam Jayakumar, Ravi Kapadia, Gary L. Clayman^¶, Georgia Sotiropoulou^||, and Eleftherios P. Diamandis¹

From the Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1X5, Canada, the Department of Head and Neck Surgery and ^¶Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4095, and the ^||Department of Pharmacy, School of Health Sciences, University of Patras, Rion, 26500 Patras, Greece

Desquamation of the stratum corneum is a serine protease-dependent process. Two members of the human tissue kallikrein (KLK) family of (chymo)tryptic-like serine proteases, KLK5 and KLK7, are implicated in desquamation by digestion of (corneo)desmosomes and inhibition by desquamation-related serine protease inhibitors (SPIs). However, the epidermal localization and specificity of additional KLKs also supports a role for these enzymes in desquamation. This study aims to delineate the probable contribution of KLK1, KLK5, KLK6, KLK13, and KLK14 to desquamation by examining their interactions, in vitro, with: 1) colocalized SPI, lympho-epithelial Kazal-type-related inhibitor (LEKTI, four recombinant fragments containing inhibitory domains 1–6 (rLEKTI(1–6)), domains 6–8 and partial domain 9 (rLEKTI(6–9')), domains 9–12 (rLEKTI(9–12)), and domains 12–15 (rLEKTI(12–15)), secretory leukocyte protease inhibitor, and elafin and 2) their ability to digest the (corneo)desmosomal cadherin, desmoglein 1. KLK1 was not inhibited by any SPI tested. KLK5, KLK6, KLK13, and KLK14 were potently inhibited by rLEKTI(1–6), rLEKTI(6–9'), and rLEKTI(9–12) with K_i values in the range of 2.3–28.4 nM, 6.1–221 nM, and 2.7–416 nM for each respective fragment. Only KLK5 was inhibited by rLEKTI(12–15) (K_i = 21.8 nM). No KLK was inhibited by secretory leukocyte protease inhibitor or elafin. Apart from KLK13, all KLKs digested the ectodomain of desmoglein 1 within cadherin repeats, Ca²⁺ binding sites, or in the juxtamembrane region. Our study indicates that multiple KLKs may participate in desquamation through cleavage of desmoglein 1 and regulation by LEKTI. These findings may have clinical implications for the treatment of skin disorders in which KLK activity is elevated.

Received for publication, August 8, 2006 , and in revised form, December 4, 2006.

^* 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: Dept. of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Ave., Toronto, Ontario M5G 1X5, Canada. Tel.: 416-586-8443; Fax: 416-586-8628; E-mail: ediamandis{at}mtsinai.on.ca.

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