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J. Biol. Chem., Vol. 283, Issue 28, 19561-19569, July 11, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/28/19561    most recent M801194200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Emami, N. Articles by Diamandis, E. P. Search for Related Content PubMed PubMed Citation Articles by Emami, N. Articles by Diamandis, E. P. Social Bookmarking                      What's this?

Major Role of Human KLK14 in Seminal Clot Liquefaction^*

Nashmil Emami, David Deperthes^¶, Johan Malm^||, and Eleftherios P. Diamandis¹

From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada, the Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada, ^¶Med Discovery S.A., Biopôle, Chemin des Criosettes 22, CH-1066 Epalinges, Switzerland, and the ^||Department of Laboratory Medicine, Section for Clinical Chemistry, Lund University, Malmö University Hospital, Malmö SE-205 02, Sweden

Liquefaction of human semen involves proteolytic degradation of the seminal coagulum and release of motile spermatozoa. Several members of human kallikrein-related peptidases (KLKs) have been implicated in semen liquefaction, functioning through highly regulated proteolytic cascades. Among these, KLK3 (also known as prostate-specific antigen) is the main executor enzyme responsible for processing of the primary components of semen coagulum, semenogelins I and II. We have recently identified KLK14 as a potential activator of KLK3 and other KLKs. This study aims to elucidate the cascade-mediated role of KLK14 ex vivo. KLK14 expression was significantly lower (p = 0.0252) in individuals with clinically delayed liquefaction. Concordantly, KLK14 expression was significantly (p = 0.0478) lower in asthenospermic cases. Specific inhibition of KLK14 activity by the synthetic inhibitor ACT_G9 resulted in a significant delay in semen liquefaction, a drop in the "early" (30 min postejaculation) "chymotrypsin-like" and KLK1 activity, and an increase in the "late" (90 min postejaculation) chymotrypsin-like activity. Conversely, the addition of recombinant active KLK14 facilitated the liquefaction process, augmented the early chymotrypsin-like activity, and lowered late chymotrypsin-like activity. Given that the observed chymotrypsin-like activity was almost completely attributed to KLK3 activity, KLK3 seems to be regulated bidirectionally. Accordingly, a higher level of KLK3 fragmentation was observed in KLK14-induced coagula, suggesting an inactivation mechanism via internal cleavage. Finally, semenogelins I and II were directly cleaved by KLK14. Semenogelins were also able to reverse KLK14 inhibition by Zn²⁺, providing a novel regulatory mechanism for KLK14 activity. Our results show that KLK14 exerts a significant and dose-dependent effect in the process of semen liquefaction.

Received for publication, February 13, 2008 , and in revised form, May 13, 2008.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Fig. 1.

¹ To whom correspondence should be addressed: FRCPC, Dept. of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Ave., Toronto M5G 1X5, Ontario, Canada. Tel.: 416-586-8443; Fax: 416-619-5521; E-mail: ediamandis{at}mtsinai.on.ca.

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