Home Kallikrein-mediated cell signalling: targeting proteinase-activated receptors (PARs)
Article
Licensed
Unlicensed Requires Authentication

Kallikrein-mediated cell signalling: targeting proteinase-activated receptors (PARs)

  • Katerina Oikonomopoulou , Kristina K. Hansen , Mahmoud Saifeddine , Nathalie Vergnolle , Illa Tea , Michael Blaber , Sachiko I. Blaber , Isobel Scarisbrick , Eleftherios P. Diamandis and Morley D. Hollenberg
Published/Copyright: June 26, 2006
Biological Chemistry
From the journal Volume 387 Issue 6

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.

:

Corresponding author

References

al-Ani, B., Saifeddine., M., and Hollenberg, M.D. (1995). Detection of functional receptors for the proteinase-activated-receptor-2-activating polypeptide, SLIGRL-NH2, in rat vascular and gastric smooth muscle. Can. J. Physiol. Pharmacol.73, 1203–1207.10.1139/y95-172Search in Google Scholar

al-Ani, B., Saifeddine, M., Wijesuriya, S.J., and Hollenberg, M.D. (2002). Modified proteinase-activated receptor-1 and -2 derived peptides inhibit proteinase-activated receptor-2 activation by trypsin. J. Pharmacol. Exp. Ther.300, 702–708.10.1124/jpet.300.2.702Search in Google Scholar

Blaber, S.I., Scarisbrick, I.A., Bernett, M.J., Dhanarajan, P., Seavy, M.A., Jin, Y., Schwartz, M.A., Rodriguez, M., and Blaber, M. (2002). Enzymatic properties of rat myelencephalon-specific protease. Biochemistry41, 1165–1173.10.1021/bi015781aSearch in Google Scholar

Borgono, C.A. and Diamandis, E.P. (2004). The emerging roles of human tissue kallikreins in cancer. Nat. Rev. Cancer4, 876–890.10.1038/nrc1474Search in Google Scholar

Borgono, C.A., Grass, L., Soosaipillai, A., Yousef, G.M., Petraki, C.D., Howarth, D.H., Fracchioli, S., Katsaros, D., and Diamandis, E.P. (2003). Human kallikrein 14: a new potential biomarker for ovarian and breast cancer. Cancer Res.63, 9032–9041.Search in Google Scholar

Borgono, C.A., Michael, I.P., and Diamandis, E.P. (2004). Human tissue kallikreins: physiologic roles and applications in cancer. Mol. Cancer Res.2, 257–280.10.1158/1541-7786.257.2.5Search in Google Scholar

Cenac, N., Coelho, A.M., Nguyen, C., Compton, S., Andrade-Gordon, P., MacNaughton, W.K., Wallace, J.L., Hollenberg, M.D., Bunnett, N.W., Garcia-Villar, R., et al. (2002). Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2. Am. J. Pathol.161, 1903–1915.10.1016/S0002-9440(10)64466-5Search in Google Scholar

Choong, P.F. and Nadesapillai, A.P. (2003). Urokinase plasminogen activator system: a multifunctional role in tumor progression and metastasis. Clin. Orthop. Relat. Res.415, S46–58.10.1097/01.blo0000093845.72468.bdSearch in Google Scholar

Compton, S.J., McGuire, J.J., Saifeddine, M., and Hollenberg, M.D. (2002a). Restricted ability of human mast cell tryptase to activate proteinase-activated receptor-2 in rat aorta. Can. J. Physiol. Pharmacol.80, 987–992.10.1139/y02-125Search in Google Scholar PubMed

Compton, S.J., Sandhu, S., Wijesuriya, S.J., and Hollenberg, M.D. (2002b). Glycosylation of human proteinase-activated receptor-2 (hPAR2): role in cell surface expression and signalling. Biochem. J.368, 495–505.10.1042/bj20020706Search in Google Scholar

Corvera, C.U., Dery, O., McConalogue, K., Gamp, P., Thoma, M., al-Ani, B., Caughey, G.H., Hollenberg, M.D., and Bunnett, N.W. (1999). Thrombin and mast cell tryptase regulate guinea-pig myenteric neurons through proteinase-activated receptors-1 and -2. J. Physiol.517, 741–756.10.1111/j.1469-7793.1999.0741s.xSearch in Google Scholar PubMed PubMed Central

Coughlin, S.R. (2000). Thrombin signalling and protease-activated receptors. Nature407, 258–264.10.1038/35025229Search in Google Scholar

Diamandis, E.P., Yousef, G.M., Soosaipillai, A.R., and Bunting, P. (2000). Human kallikrein 6 (zyme/protease M/neurosin): a new serum biomarker of ovarian carcinoma. Clin. Biochem.33, 579–583.10.1016/S0009-9120(00)00182-XSearch in Google Scholar

Frenette, G., Tremblay, R.R., Lazure, C., and Dube, J.Y. (1997). Prostatic kallikrein hK2, but not prostate-specific antigen (hK3), activates single-chain urokinase-type plasminogen activator. Int. J. Cancer71, 897–899.10.1002/(SICI)1097-0215(19970529)71:5<897::AID-IJC31>3.0.CO;2-2Search in Google Scholar

Hollenberg, M.D. and Compton, S.J. (2002). International Union of Pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol. Rev.54, 203–217.Search in Google Scholar

Hollenberg, M.D. and Saifeddine, M. (2001). Proteinase-activated receptor 4 (PAR4): activation and inhibition of rat platelet aggregation by PAR4-derived peptides. Can. J. Physiol. Pharmacol.79, 439–442.10.1139/y01-013Search in Google Scholar

Hollenberg, M.D., Laniyonu, A.A., Saifeddine, M., and Moore, G.J. (1993). Role of the amino- and carboxyl-terminal domains of thrombin receptor-derived polypeptides in biological activity in vascular endothelium and gastric smooth muscle: evidence for receptor subtypes. Mol. Pharmacol.43, 921–930.Search in Google Scholar

Hollenberg, M.D., Saifeddine, M., and al-Ani, B. (1996). Proteinase-activated receptor-2 in rat aorta: structural requirements for agonist activity of receptor-activating peptides. Mol. Pharmacol.49, 229–233.Search in Google Scholar

Hollenberg, M.D., Saifeddine, M., al-Ani, B., and Kawabata, A. (1997). Proteinase-activated receptors: structural requirements for activity, receptor cross-reactivity, and receptor selectivity of receptor-activating peptides. Can. J. Physiol. Pharmacol.75, 832–841.10.1139/y97-110Search in Google Scholar

Hollenberg, M.D., Saifeddine, M., Sandhu, S., Houle, S., and Vergnolle, N. (2004). Proteinase-activated receptor-4: evaluation of tethered ligand-derived peptides as probes for receptor function and as inflammatory agonists in vivo. Br. J. Pharmacol.143, 443–454.10.1038/sj.bjp.0705946Search in Google Scholar

Kawabata, A., Saifeddine, M., al-Ani, B., Leblond, L., and Hollenberg, M.D. (1999). Evaluation of proteinase-activated receptor-1 (PAR1). agonists and antagonists using a cultured cell receptor desensitization assay: activation of PAR2 by PAR1-targeted ligands. J. Pharmacol. Exp. Ther.288, 358–370.Search in Google Scholar

Kim, H., Scorilas, A., Katsaros, D., Yousef, G.M., Massobrio, M., Fracchioli, S., Piccinno, R., Gordini, G., and Diamandis, E.P. (2001). Human kallikrein gene 5 (KLK5) expression is an indicator of poor prognosis in ovarian cancer. Br. J. Cancer84, 643–650.10.1054/bjoc.2000.1649Search in Google Scholar

Kong, W., McConalogue, K., Khitin, L.M., Hollenberg, M.D., Payan, D.G., Bohm, S.K., and Bunnett, N.W. (1997). Luminal trypsin may regulate enterocytes through proteinase-activated receptor 2. Proc. Natl. Acad. Sci. USA94, 8884–8889.10.1073/pnas.94.16.8884Search in Google Scholar

Macfarlane, S.R., Seatter, M.J., Kanke, T., Hunter, G.D., and Plevin, R. (2001). Proteinase-activated receptors. Pharmacol. Rev.53, 245–282.Search in Google Scholar

Mirza, H., Schmidt, V.A., Derian, C.K., Jesty, J., and Bahou, W.F. (1997). Mitogenic responses mediated through the proteinase-activated receptor-2 are induced by expressed forms of mast cell α- or β-tryptases. Blood90, 3914–3922.10.1182/blood.V90.10.3914Search in Google Scholar

Molino, M., Barnathan, E.S., Numerof, R., Clark, J., Dreyer, M., Cumashi, A., Hoxie, J.A., Schechter, N., Woolkalis, M., and Brass, L.F. (1997). Interactions of mast cell tryptase with thrombin receptors and PAR-2. J. Biol. Chem.272, 4043–4049.10.1074/jbc.272.7.4043Search in Google Scholar

Nguyen, C., Coelho, A.M., Grady, E., Compton, S.J., Wallace, J.L., Hollenberg, M.D., Cenac, N., Garcia-Villar, R., Bueno, L., Steinhoff, M., et al. (2003). Colitis induced by proteinase-activated receptor-2 agonists is mediated by a neurogenic mechanism. Can. J. Physiol. Pharmacol.81, 920–927.10.1139/y03-080Search in Google Scholar

Noorbakhsh, F., Vergnolle, N., Hollenberg, M.D., and Power, C. (2003). Proteinase-activated receptors in the nervous system. Nat. Rev. Neurosci.4, 981–990.10.1038/nrn1255Search in Google Scholar

Noorbakhsh, F., Vergnolle, N., McArthur, J.C., Silva, C., Vodjgani, M., Andrade-Gordon, P., Hollenberg, M.D., and Power, C. (2005). Proteinase-activated receptor-2 induction by neuroinflammation prevents neuronal death during HIV infection. J. Immunol.174, 7320–7329.10.4049/jimmunol.174.11.7320Search in Google Scholar

Nystedt, S., Emilsson, K., Wahlestedt, C., and Sundelin, J. (1994). Molecular cloning of a potential proteinase activated receptor. Proc. Natl. Acad. Sci. USA91, 9208–9212.10.1073/pnas.91.20.9208Search in Google Scholar

Ossovskaya, V.S. and Bunnett, N.W. (2004). Protease-activated receptors: contribution to physiology and disease. Physiol. Rev.84, 579–621.10.1152/physrev.00028.2003Search in Google Scholar

Rasmussen, U.B., Vouret-Craviari, V., Jallat, S., Schlesinger, Y., Pages, G., Pavirani, A., Lecocq, J.P., Pouyssegur, J., and Van Obberghen-Schilling, E. (1991). cDNA cloning and expression of a hamster alpha-thrombin receptor coupled to Ca2+ mobilization. FEBS Lett.288, 123–128.10.1016/0014-5793(91)81017-3Search in Google Scholar

Ruf, W., Dorfleutner, A., and Riewald, M. (2003). Specificity of coagulation factor signaling. J. Thromb. Haemost.1, 1495–1503.10.1046/j.1538-7836.2003.00300.xSearch in Google Scholar PubMed

Saifeddine, M., al-Ani, B., Cheng, C.H., Wang, L., and Hollenberg, M.D. (1996). Rat proteinase-activated receptor-2 (PAR-2): cDNA sequence and activity of receptor-derived peptides in gastric and vascular tissue. Br. J. Pharmacol.118, 521–530.10.1111/j.1476-5381.1996.tb15433.xSearch in Google Scholar PubMed PubMed Central

Scarisbrick, I.A., Blaber, S.I., Lucchinetti, C.F., Genain, C.P., Blaber, M., and Rodriguez, M. (2002). Activity of a newly identified serine protease in CNS demyelination. Brain125, 1283–1296.10.1093/brain/awf142Search in Google Scholar PubMed

Steinhoff, M., Buddenkotte, J., Shpacovitch, V., Rattenholl, A., Moormann, C., Vergnolle, N., Luger, T.A., and Hollenberg, M.D. (2005). Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr. Rev.26, 1–43.10.1210/er.2003-0025Search in Google Scholar PubMed

Takayama, T.K., McMullen, B.A., Nelson, P.S., Matsumura, M., and Fujikawa, K. (2001). Characterization of hK4 (prostase), a prostate-specific serine protease: activation of the precursor of prostate specific antigen (pro-PSA) and single-chain urokinase-type plasminogen activator and degradation of prostatic acid phosphatase. Biochemistry40, 15341–15348.10.1021/bi015775eSearch in Google Scholar

Tanimoto, H., Underwood, L.J., Shigemasa, K., Parmley, T.H., and O'Brien, T.J. (2001). Increased expression of protease M in ovarian tumors. Tumour Biol.22, 11–18.10.1159/000030150Search in Google Scholar

Vergnolle, N. (2004). Modulation of visceral pain and inflammation by protease-activated receptors. Br. J. Pharmacol.141, 1264–1274.10.1038/sj.bjp.0705750Search in Google Scholar

Vergnolle, N. (2005). Clinical relevance of proteinase activated receptors (PARs) in the gut. Gut54, 867–874.10.1136/gut.2004.048876Search in Google Scholar

Vergnolle, N., Hollenberg, M.D., and Wallace, J.L. (1999a). Pro- and anti-inflammatory actions of thrombin: a distinct role for proteinase-activated receptor-1 (PAR1). Br. J. Pharmacol.126, 1262–1268.10.1038/sj.bjp.0702408Search in Google Scholar

Vergnolle, N., Hollenberg, M.D., Sharkey, K.A., and Wallace, J.L. (1999b). Characterization of the inflammatory response to proteinase-activated receptor-2 (PAR2)-activating peptides in the rat paw. Br. J. Pharmacol.127, 1083–1090.10.1038/sj.bjp.0702634Search in Google Scholar

Vergnolle, N., Bunnett, N.W., Sharkey, K.A., Brussee, V., Compton, S.J., Grady, E.F., Cirino, G., Gerard, N., Basbaum, A.I., Andrade-Gordon, P., Hollenberg, M.D., and Wallace, J.L. (2001a). Proteinase-activated receptor-2 and hyperalgesia: a novel pain pathway. Nat. Med.7, 821–826.10.1038/89945Search in Google Scholar

Vergnolle, N., Wallace, J.L., Bunnett, N.W., and Hollenberg, M.D. (2001b). Protease-activated receptors in inflammation, neuronal signaling and pain. Trends. Pharmacol. Sci.22, 146–152.10.1016/S0165-6147(00)01634-5Search in Google Scholar

Vu, T.K., Hung, D.T., Wheaton, V.I., and Coughlin, S.R. (1991). Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell64, 1057–1068.10.1016/0092-8674(91)90261-VSearch in Google Scholar

Yousef, G.M., Polymeris, M.E., Grass, L., Soosaipillai, A., Chan, P.C., Scorilas, A., Borgono, C., Harbeck, N., Schmalfeldt, B., Dorn, J., et al. (2003). Human kallikrein 5, a potential novel serum biomarker for breast and ovarian cancer. Cancer Res.63, 3958–3965.Search in Google Scholar

Published Online: 2006-06-26
Published in Print: 2006-06-01

©2006 by Walter de Gruyter Berlin New York

Articles in the same Issue

  1. The First International Symposium on Kallikreins
  2. A comprehensive nomenclature for serine proteases with homology to tissue kallikreins
  3. The kallikrein world: an update on the human tissue kallikreins
  4. Cellular distribution of human tissue kallikreins: immunohistochemical localization
  5. The tissue kallikrein-kinin system protects against cardiovascular and renal diseases and ischemic stroke independently of blood pressure reduction
  6. Proteinase-mediated cell signalling: targeting proteinase-activated receptors (PARs) by kallikreins and more
  7. Recombinant kallikrein expression: site-specific integration for hK6 production in human cells
  8. Kallikrein-related peptidase (KLK) family mRNA variants and protein isoforms in hormone-related cancers: do they have a function?
  9. The role of kallikrein-related peptidases in prostate cancer: potential involvement in an epithelial to mesenchymal transition
  10. Human kallikrein 10, a predictive marker for breast cancer
  11. Activation and enzymatic characterization of recombinant human kallikrein 8
  12. Human tissue kallikrein 9: production of recombinant proteins and specific antibodies
  13. The human kallikrein 10 promoter contains a functional retinoid response element
  14. Human kallikrein 4: enzymatic activity, inhibition, and degradation of extracellular matrix proteins
  15. Kallikrein-related peptidase 14 may be a major contributor to trypsin-like proteolytic activity in human stratum corneum
  16. A sensitive proximity ligation assay for active PSA
  17. Multiple mechanisms underlie the aberrant expression of the human kallikrein 6 gene in breast cancer
  18. Expression of the human kallikrein genes 10 (KLK10) and 11 (KLK11) in cancerous and non-cancerous lung tissues
  19. mRNA expression analysis of human kallikrein 11 (KLK11) may be useful in the discrimination of benign prostatic hyperplasia from prostate cancer after needle prostate biopsy
  20. The epigenetic basis for the aberrant expression of kallikreins in human cancers
  21. Improved prostate cancer detection with a human kallikrein 11 and percentage free PSA-based artificial neural network
  22. Overexpression of the human tissue kallikrein genes KLK4, 5, 6, and 7 increases the malignant phenotype of ovarian cancer cells
  23. Inhibition profiles of human tissue kallikreins by serine protease inhibitors
  24. Kallikrein-mediated cell signalling: targeting proteinase-activated receptors (PARs)
Downloaded on 22.10.2025 from https://www.degruyterbrill.com/document/doi/10.1515/BC.2006.104/html?lang=en
Scroll to top button