title: Kallikrein-mediated cell signalling: targeting proteinase-activated receptors (PARs).
abstract: We tested the hypothesis that human tissue kallikreins (hKs) may regulate signal transduction by cleaving and activating proteinase-activated receptors (PARs). We found that hK5, 6 and 14 cleaved PAR N-terminal peptide sequences representing the cleavage/activation motifs of human PAR1 and PAR2 to yield receptor-activating peptides. hK5, 6 and 14 activated calcium signalling in rat PAR2-expressing (but not background) KNRK cells. Calcium signalling in HEK cells co-expressing human PAR1 and PAR2 was also triggered by hK14 (via PAR1 and PAR2) and hK6 (via PAR2). In isolated rat platelets that do not express PAR1, but signal via PAR4, hK14 also activated PAR-dependent calcium signalling responses and triggered aggregation. The aggregation response elicited by hK14 was in contrast to the lack of aggregation triggered by hK5 and 6. hK14 also caused vasorelaxation in a phenylephrine-preconstricted rat aorta ring assay and triggered oedema in an in vivo model of murine paw inflammation. We propose that, like thrombin and trypsin, the kallikreins must now be considered as important 'hormonal' regulators of tissue function, very likely acting in part via PARs.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto and Mount Sinai Hospital, Toronto M5G 1X5, ON, Canada.
authors.forename: Katerina
authors.initials: K
authors.lastname: Oikonomopoulou
authors.forename: Kristina K
authors.initials: KK
authors.lastname: Hansen
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Saifeddine
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vergnolle
authors.forename: Illa
authors.initials: I
authors.lastname: Tea
authors.forename: Michael
authors.initials: M
authors.lastname: Blaber
authors.forename: Sachiko I
authors.initials: SI
authors.lastname: Blaber
authors.forename: Isobel
authors.initials: I
authors.lastname: Scarisbrick
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Diamandis
authors.forename: Morley D
authors.initials: MD
authors.lastname: Hollenberg
mesh_terms: D000818:Animals; D002460:Cell Line; D004487:Edema / Q000139:chemically induced; D006801:Humans; D007610:Kallikreins / Q000494:pharmacology*; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D044463:Receptor, PAR-1 / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism; D018179:Receptors, Thrombin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; C425336:KLK14 protein, human; C400147:KLK5 protein, human; C103551:KLK6 protein, human; D007610:Kallikreins