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Proteinase-activated receptors, targets for kallikrein signaling.
J Biol Chem. 2006 Oct 27; 281(43):32095-112.JB

Abstract

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).

Authors+Show Affiliations

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16885167

Citation

Oikonomopoulou, Katerina, et al. "Proteinase-activated Receptors, Targets for Kallikrein Signaling." The Journal of Biological Chemistry, vol. 281, no. 43, 2006, pp. 32095-112.
Oikonomopoulou K, Hansen KK, Saifeddine M, et al. Proteinase-activated receptors, targets for kallikrein signaling. J Biol Chem. 2006;281(43):32095-112.
Oikonomopoulou, K., Hansen, K. K., Saifeddine, M., Tea, I., Blaber, M., Blaber, S. I., Scarisbrick, I., Andrade-Gordon, P., Cottrell, G. S., Bunnett, N. W., Diamandis, E. P., & Hollenberg, M. D. (2006). Proteinase-activated receptors, targets for kallikrein signaling. The Journal of Biological Chemistry, 281(43), 32095-112.
Oikonomopoulou K, et al. Proteinase-activated Receptors, Targets for Kallikrein Signaling. J Biol Chem. 2006 Oct 27;281(43):32095-112. PubMed PMID: 16885167.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Proteinase-activated receptors, targets for kallikrein signaling. AU - Oikonomopoulou,Katerina, AU - Hansen,Kristina K, AU - Saifeddine,Mahmoud, AU - Tea,Illa, AU - Blaber,Michael, AU - Blaber,Sachiko I, AU - Scarisbrick,Isobel, AU - Andrade-Gordon,Patricia, AU - Cottrell,Graeme S, AU - Bunnett,Nigel W, AU - Diamandis,Eleftherios P, AU - Hollenberg,Morley D, Y1 - 2006/08/02/ PY - 2006/8/4/pubmed PY - 2006/12/9/medline PY - 2006/8/4/entrez SP - 32095 EP - 112 JF - The Journal of biological chemistry JO - J Biol Chem VL - 281 IS - 43 N2 - 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). SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/16885167/Proteinase_activated_receptors_targets_for_kallikrein_signaling_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)86784-2 DB - PRIME DP - Unbound Medicine ER -