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J. Biol. Chem., Vol. 281, Issue 43, 32095-32112, October 27, 2006

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Proteinase-activated Receptors, Targets for Kallikrein Signaling^*

Katerina Oikonomopoulou, Kristina K. Hansen^¶1, Mahmoud Saifeddine^¶, Illa Tea^¶, Michael Blaber^||, Sachiko I. Blaber^||, Isobel Scarisbrick^**, Patricia Andrade-Gordon, Graeme S. Cottrell, Nigel W. Bunnett, Eleftherios P. Diamandis, and Morley D. Hollenberg^¶2

From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada, ^¶Proteinases and Inflammation Network, Mucosal Inflammation Research Group, Department of Pharmacology and Therapeutics and Department of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada, ^||Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306-4380, ^**Program for Molecular Neuroscience, Departments of Neurology and Physical Medicine and Rehabilitation, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, and Departments of Surgery and Physiology, University of California, San Francisco, California 94143-0660

Serine proteinases like thrombin can signal to cells by the cleavage/activation of proteinase-activated receptors (PARs). Although thrombin is a recognized physiological activator of PAR₁ and PAR₄, the endogenous enzymes responsible for activating PAR₂ in settings other than the gastrointestinal system, where trypsin can activate PAR₂, are unknown. We tested the hypothesis that the human tissue kallikrein (hK) family of proteinases regulates PAR signaling by using the following: 1) a high pressure liquid chromatography (HPLC)-mass spectral analysis of the cleavage products yielded upon incubation of hK5, -6, and -14 with synthetic PAR N-terminal peptide sequences representing the cleavage/activation motifs of PAR₁, PAR₂, and PAR₄; 2) PAR-dependent calcium signaling responses in cells expressing PAR₁, PAR₂, and PAR₄ and in human platelets; 3) a vascular ring vasorelaxation assay; and 4) a PAR₄-dependent rat and human platelet aggregation assay. We found that hK5, -6, and -14 all yielded PAR peptide cleavage sequences consistent with either receptor activation or inactivation/disarming. Furthermore, hK14 was able to activate PAR₁, PAR₂, and PAR₄ and to disarm/inhibit PAR₁. Although hK5 and -6 were also able to activate PAR₂, they failed to cause PAR₄-dependent aggregation of rat and human platelets, although hK14 did. Furthermore, the relative potencies and maximum effects of hK14 and -6 to activate PAR₂-mediated calcium signaling differed. Our data indicate that in physiological settings, hKs may represent important endogenous regulators of the PARs and that different hKs can have differential actions on PAR₁, PAR₂, and PAR₄.

Received for publication, December 8, 2005 , and in revised form, June 28, 2006.

^* This work was supported in part by a Canadian Institutes of Health Research Proteinases and Inflammation Network Group grant (to M. D. H.), in conjunction with operating grants from the Canadian Institutes of Health Research (to M. D. H.), and a Servier International Alliance Project grant. Work in the Diamandis laboratory was supported by a University-Industry Grant from the Natural Sciences and Engineering Research Council of Canada (IBEX Technologies, Montreal, Canada). Work in the Bunnett laboratory was supported by National Institutes of Health Grants DK57480 and DK39957. The preparation of hK6 for this study was supported by Grant RG3406-A-2 (to M. B.) and RG3367B-4-01 (to I. S.) from the National Multiple Sclerosis Society. 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 a supplemental table.

¹ Supported by a postdoctoral fellowship from the Alberta Heritage Foundation for Medical Research.

² To whom correspondence and reprints should be addressed: Dept. of Pharmacology and Therapeutics, University of Calgary Faculty of Medicine, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. Tel.: 1-403-220-6931; Fax: 1-403-270-0979; E-mail: mhollenb{at}ucalgary.ca.

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