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J. Biol. Chem., Vol. 283, Issue 18, 12293-12304, May 2, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/18/12293    most recent M709493200v1 Alert me when this article is cited 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 Google Scholar Articles by Ramsay, A. J. Articles by Hooper, J. D. PubMed PubMed Citation Articles by Ramsay, A. J. Articles by Hooper, J. D. Social Bookmarking                      What's this?

Kallikrein-related Peptidase 4 (KLK4) Initiates Intracellular Signaling via Protease-activated Receptors (PARs)

KLK4 AND PAR-2 ARE CO-EXPRESSED DURING PROSTATE CANCER PROGRESSION^*

Andrew J. Ramsay, Ying Dong, Melanie L. Hunt, MayLa Linn, Hemamali Samaratunga, Judith A. Clements, and John D. Hooper¹

From the Institute of Health and Biomedical Innovation and School of Life Sciences, Queensland University of Technology, Corner Musk Ave. and Blamey St., Kelvin Grove, Queensland 4059, Australia and the Department of Anatomical Pathology, Sullivan Nicolaides Pathology, Taringa, Queensland 4068, Australia

Kallikrein-related peptidase 4 (KLK4) is one of the 15 members of the human KLK family and a trypsin-like, prostate cancer-associated serine protease. Signaling initiated by trypsin-like serine proteases are transduced across the plasma membrane primarily by members of the protease-activated receptor (PAR) family of G protein-coupled receptors. Here we show, using Ca²⁺ flux assays, that KLK4 signals via both PAR-1 and PAR-2 but not via PAR-4. Dose-response analysis over the enzyme concentration range 0.1–1000 nM indicated that KLK4-induced Ca²⁺ mobilization via PAR-1 is more potent than via PAR-2, whereas KLK4 displayed greater efficacy via the latter PAR. We confirmed the specificity of KLK4 signaling via PAR-2 using in vitro protease cleavage assays and anti-phospho-ERK1/2/total ERK1/2 Western blot analysis of PAR-2-overexpressing and small interfering RNA-mediated receptor knockdown cell lines. Consistently, confocal microscopy analyses indicated that KLK4 initiates loss of PAR-2 from the cell surface and receptor internalization. Immunohistochemical analysis indicated the co-expression of agonist and PAR-2 in primary prostate cancer and bone metastases, suggesting that KLK4 signaling via this receptor will have pathological relevance. These data provide insight into KLK4-mediated cell signaling and suggest that signals induced by this enzyme via PARs may be important in prostate cancer.

Received for publication, November 19, 2007 , and in revised form, February 15, 2008.

^* This work was supported by National Health and Medical Research Council of Australia Fellowship 390125 (to J. A. C.) and Fellowship 339732 (to J. D. H.), a Queensland Cancer Fund scholarship (to A. J. R.), and the Ramaciotti Foundation. 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. Tel.: 61-7-3138-6197; Fax: 61-7-3138-6030; E-mail: jd.hooper{at}qut.edu.au.

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