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J. Biol. Chem., Vol. 282, Issue 4, 2405-2422, January 26, 2007

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Expression and Functional Characterization of the Cancer-related Serine Protease, Human Tissue Kallikrein 14^*

Carla A. Borgoño, Iacovos P. Michael, Julie L. V. Shaw, Liu-Ying Luo, Manik C. Ghosh, Antoninus Soosaipillai, Linda Grass, Dionyssios Katsaros, 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 and the Department of Gynecology, Gynecologic Oncology Unit, University of Turin, Turin 10126, Italy

Human tissue kallikrein 14 (KLK14) is a novel extracellular serine protease. Clinical data link KLK14 expression to several diseases, primarily cancer; however, little is known of its (patho)-physiological role. To functionally characterize KLK14, we expressed and purified recombinant KLK14 in mature and proenzyme forms and determined its expression pattern, specificity, regulation, and in vitro substrates. By using our novel immunoassay, the normal and/or diseased skin, breast, prostate, and ovary contained the highest concentration of KLK14. Serum KLK14 levels were significantly elevated in prostate cancer patients compared with healthy males. KLK14 displayed trypsin-like specificity with high selectivity for P1-Arg over Lys. KLK14 activity could be regulated as follows: 1) by autolytic cleavage leading to enzymatic inactivation; 2) by the inhibitory serpins ₁-antitrypsin, ₂-antiplasmin, antithrombin III, and ₁-antichymotrypsin with second order rate constants (k₊₂/K_i) of 49.8, 23.8, 1.48, and 0.224 µM^–1 min^–1, respectively, as well as plasminogen activator inhibitor-1; and 3) by citrate and zinc ions, which exerted stimulatory and inhibitory effects on KLK14 activity, respectively. We also expanded the in vitro target repertoire of KLK14 to include collagens I–IV, fibronectin, laminin, kininogen, fibrinogen, plasminogen, vitronectin, and insulin-like growth factor-binding proteins 2 and 3. Our results indicate that KLK14 may be implicated in several facets of tumor progression, including growth, invasion, and angiogenesis, as well as in arthritic disease via deterioration of cartilage. These findings may have clinical implications for the management of cancer and other disorders in which KLK14 activity is elevated.

Received for publication, August 31, 2006 , and in revised form, November 14, 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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