Proteinase-activated receptors, targets for kallikrein signaling

Oikonomopoulou, K., Hansen, K. K., Saifeddine, M., Tea, I., Blaber, M., Blaber, S. I., Scarisbrick, I., Andrade-Gordon, P., Cottrell, G. S. ORCID: https://orcid.org/0000-0001-9098-7627, Bunnett, N. W., Diamandis, E. P. and Hollenberg, M. D. (2006) Proteinase-activated receptors, targets for kallikrein signaling. The Journal of Biological Chemistry, 281 (43). pp. 32095-32112. ISSN 1083-351X doi: 10.1074/jbc.M513138200

Abstract/Summary

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 PAR(1) and PAR(4), the endogenous enzymes responsible for activating PAR(2) in settings other than the gastrointestinal system, where trypsin can activate PAR(2), 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 PAR(1), PAR(2), and PAR(4); 2) PAR-dependent calcium signaling responses in cells expressing PAR(1), PAR(2), and PAR(4) and in human platelets; 3) a vascular ring vasorelaxation assay; and 4) a PAR(4)-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 PAR(1), PAR(2), and PAR(4) and to disarm/inhibit PAR(1). Although hK5 and -6 were also able to activate PAR(2), they failed to cause PAR(4)-dependent aggregation of rat and human platelets, although hK14 did. Furthermore, the relative potencies and maximum effects of hK14 and -6 to activate PAR(2)-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 PAR(1), PAR(2), and PAR(4).

Additional Information	Oikonomopoulou, Katerina Hansen, Kristina K Saifeddine, Mahmoud Tea, Illa Blaber, Michael Blaber, Sachiko I Scarisbrick, Isobel Andrade-Gordon, Patricia Cottrell, Graeme S Bunnett, Nigel W Diamandis, Eleftherios P Hollenberg, Morley D DK 39957/DK/NIDDK NIH HHS/ DK 57480/DK/NIDDK NIH HHS/ J Biol Chem. 2006 Oct 27;281(43):32095-112. Epub 2006 Aug 2.
Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/30274
Item Type	Article
Refereed	Yes
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology No Reading authors. Back catalogue items
Uncontrolled Keywords	Amino Acid Sequence Animals Animals, Genetically Modified Aorta, Thoracic/drug effects Baculoviridae/genetics Blood Platelets/metabolism Calcium Signaling/drug effects Cell Line Chromatography, High Pressure Liquid Dose-Response Relationship, Drug Epithelial Cells/drug effects Humans Kallikreins/chemical synthesis/chemistry/classification/*pharmacology Male Mass Spectrometry Mice Mice, Inbred C57BL Mice, Knockout Molecular Sequence Data Muscle Relaxation/drug effects Muscle, Smooth, Vascular/drug effects Platelet Aggregation/drug effects Rats Rats, Sprague-Dawley Receptors, Proteinase-Activated/chemistry/drug effects/genetics/*physiology Recombinant Proteins/chemistry/pharmacology Signal Transduction/*drug effects Swine Thrombin/pharmacology Trypsin/pharmacology
Additional Information	Oikonomopoulou, Katerina Hansen, Kristina K Saifeddine, Mahmoud Tea, Illa Blaber, Michael Blaber, Sachiko I Scarisbrick, Isobel Andrade-Gordon, Patricia Cottrell, Graeme S Bunnett, Nigel W Diamandis, Eleftherios P Hollenberg, Morley D DK 39957/DK/NIDDK NIH HHS/ DK 57480/DK/NIDDK NIH HHS/ J Biol Chem. 2006 Oct 27;281(43):32095-112. Epub 2006 Aug 2.
Publisher	American Society for Biochemistry and Molecular Biology
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