Toward drugs for protease-activated receptor 2 (PAR2)

Journal of Medicinal Chemistry

Volumn 56, Issue 19, 2013, Pages 7477-7497

  Yau, Mei Kwan ^a   Liu, Ligong ^a   Fairlie, David P ^a  

^a UNIVERSITY OF QUEENSLAND   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

AGENTS INTERACTING WITH TRANSMITTER, HORMONE OR DRUG RECEPTORS; ENMD 1068; GB 83; GB 88; K 14585; MONOCLONAL ANTIBODY; NORDIHYDROGUAIARETIC ACID; NPS 1557; PEPDUCIN; POLYCLONAL ANTIBODY; PROTEINASE ACTIVATED RECEPTOR 2; PROTEINASE ACTIVATED RECEPTOR 2 ANTIBODY; PROTEINASE ACTIVATED RECEPTOR 2 BLOCKING AGENT; PROTEINASE ACTIVATED RECEPTOR 2 STIMULATING AGENT; RECEPTOR ANTIBODY; SYNTHETIC PEPTIDE; TRIPTOLIDE; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; AMINO ACID SUBSTITUTION; AMINO TERMINAL SEQUENCE; ANTIBODY SPECIFICITY; ANTIINFLAMMATORY ACTIVITY; ARTHRITIS; BLOOD VESSEL INJURY; CALCIUM MOBILIZATION; CANCER CELL; CARBOXY TERMINAL SEQUENCE; CARDIOVASCULAR DISEASE; CHRONIC PAIN; COLITIS; DERMATITIS; DRUG DESIGN; DRUG DETERMINATION; DRUG POTENCY; DRUG RECEPTOR BINDING; ENTERITIS; FETUS DISEASE; FIBROSIS; GASTROINTESTINAL DISEASE; HUMAN; IMMUNOCOMPETENT CELL; INFECTION; INFLAMMATION; LIVER INJURY; METABOLIC DISORDER; MOLECULAR MODEL; NEOPLASM; NEPHRITIS; NEUROLOGIC DISEASE; NONHUMAN; PANCREATITIS; PATENT; PATHOPHYSIOLOGY; PERIODONTITIS; PHENOTYPE; PNEUMONIA; PROTEIN CLEAVAGE; PROTEIN EXPRESSION; PROTEIN STRUCTURE; RESPIRATORY TRACT INFLAMMATION; REVIEW; SIGNAL TRANSDUCTION; SKIN DISEASE; STRUCTURAL HOMOLOGY; STRUCTURE ACTIVITY RELATION;

AMINO ACID SEQUENCE; ANIMALS; ANTIBODIES; GENE KNOCKOUT TECHNIQUES; HUMANS; LIPOPEPTIDES; MOLECULAR SEQUENCE DATA; MOLECULAR TARGETED THERAPY; PROTEIN CONFORMATION; RECEPTOR, PAR-2; SEQUENCE HOMOLOGY, AMINO ACID; SIGNAL TRANSDUCTION;

EID: 84885596692     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm400638v     Document Type: Review

References (205)

1. Steinhoff, M.; Buddenkotte, J.; Shpacovitch, V.; Rattenholl, A.; Moormann, C.; Vergnolle, N.; Luger, T. A.; Hollenberg, M. D. Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response Endocr. Rev. 2005, 26, 1-43
2. Barry, G. D.; Le, G. T.; Fairlie, D. P. Agonists and antagonists of protease activated receptors (PARs) Curr. Med. Chem. 2006, 13, 243-265
3. Adams, M. N.; Ramachandran, R.; Yau, M. K.; Suen, J. Y.; Fairlie, D. P.; Hollenberg, M. D.; Hooper, J. D. Structure, function and pathophysiology of protease activated receptors Pharmacol. Ther. 2011, 130, 248-282
4. Rothmeier, A. S.; Ruf, W. Protease-activated receptor 2 signaling in inflammation Semin. Immunopathol. 2012, 34, 133-149
5. Macfarlane, S. R.; Seatter, M. J.; Kanke, T.; Hunter, G. D.; Plevin, R. Proteinase-activated receptors Pharmacol. Rev. 2001, 53, 245-282
6. Coughlin, S. R.; Camerer, E. PARticipation in inflammation J. Clin. Invest. 2003, 111, 25-27
7. Ramachandran, R.; Noorbakhsh, F.; Defea, K.; Hollenberg, M. D. Targeting proteinase-activated receptors: therapeutic potential and challenges Nat. Rev. Drug Discovery 2012, 11, 69-86
8. Nystedt, S.; Emilsson, K.; Larsson, A. K.; Strombeck, B.; Sundelin, J. Molecular-cloning and functional expression of the gene encoding the human proteinase-activated receptor-2 Eur. J. Biochem. 1995, 232, 84-89
9. Kahn, M. L.; Hammes, S. R.; Botka, C.; Coughlin, S. R. Gene and locus structure and chromosomal localization of the protease-activated receptor gene family J. Biol. Chem. 1998, 273, 23290-23296
10. Ossovskaya, V. S.; Bunnett, N. W. Protease-activated receptors: contribution to physiology and disease Physiol. Rev. 2004, 84, 579-621
11. Suen, J. Y. Regulating Protease Activated Receptor 2. Ph.D. Dissertation, The University of Queensland, Brisbane, Australia, 2009.
12. Lim, J. Links between Inflammation and Obesity. Ph.D. Dissertation, The University of Queensland, Brisbane, Australia, 2013.
13. Lim, J.; Iyer, A.; Liu, L.; Suen, J. Y.; Lohman, R. J.; Seow, V.; Yau, M. K.; Brown, L.; Fairlie, D. P. Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism. Unpublished results.
14. Nystedt, S.; Ramakrishnan, V.; Sundelin, J. The proteinase-activated receptor 2 is induced by inflammatory mediators in human endothelial cells. Comparison with the thrombin receptor J. Biol. Chem. 1996, 271, 14910-14915
15. Freund-Michel, V.; Frossard, N. Inflammatory conditions increase expression of protease-activated receptor-2 by human airway smooth muscle cells in culture Fundam. Clin. Pharmacol. 2006, 20, 351-357
16. Ritchie, E.; Saka, M.; Mackenzie, C.; Drummond, R.; Wheeler-Jones, C.; Kanke, T.; Plevin, R. Cytokine upregulation of proteinase-activated-receptors 2 and 4 expression mediated by p38 MAP kinase and inhibitory kappa B kinase beta in human endothelial cells Br. J. Pharmacol. 2007, 150, 1044-1054
17. Boileau, C.; Amiable, N.; Martel-Pelletier, J.; Fahmi, H.; Duval, N.; Pelletier, J. P. Activation of proteinase-activated receptor 2 in human osteoarthritic cartilage upregulates catabolic and proinflammatory pathways capable of inducing cartilage degradation: a basic science study Arthritis Res. Ther. 2007, 9, R121
18. Kagota, S.; Chia, E.; McGuire, J. J. Preserved arterial vasodilatation via endothelial protease-activated receptor-2 in obese type 2 diabetic mice Br. J. Pharmacol. 2011, 164, 358-371
19. Rallabhandi, P.; Nhu, Q. M.; Toshchakov, V. Y.; Piao, W.; Medvedev, A. E.; Hollenberg, M. D.; Fasano, A.; Vogel, S. N. Analysis of proteinase-activated receptor 2 and TLR4 signal transduction: a novel paradigm for receptor cooperativity J. Biol. Chem. 2008, 283, 24314-24325
20. Nhu, Q. M.; Shirey, K.; Teijaro, J. R.; Farber, D. L.; Netzel-Arnett, S.; Antalis, T. M.; Fasano, A.; Vogel, S. N. Novel signaling interactions between proteinase-activated receptor 2 and Toll-like receptors in vitro and in vivo Mucosal Immunol. 2010, 3, 29-39
21. Nhu, Q. M.; Shirey, K. A.; Pennini, M. E.; Stiltz, J.; Vogel, S. N. Proteinase-activated receptor 2 activation promotes an anti-inflammatory and alternatively activated phenotype in LPS-stimulated murine macrophages Innate Immun. 2012, 18, 193-203
22. Kawabata, A.; Kawao, N. Physiology and pathophysiology of proteinase-activated receptors (PARs): PARs in the respiratory system: cellular signaling and physiological/pathological roles J. Pharmacol. Sci. 2005, 97, 20-24
23. Kaufmann, R.; Hollenberg, M. D. Proteinase-activated receptors (PARs) and calcium signaling in cancer Adv. Exp. Med. Biol. 2012, 740, 979-1000
24. Kawabata, A.; Matsunami, M.; Sekiguchi, F. Gastrointestinal roles for proteinase-activated receptors in health and disease Br. J. Pharmacol. 2008, 153, S230-S240
25. Vesey, D. A.; Hooper, J. D.; Gobe, G. C.; Johnson, D. W. Potential physiological and pathophysiological roles for protease-activated receptor-2 in the kidney Nephrology 2007, 12, 36-43
26. Cocks, T. M.; Moffatt, J. D. Protease-activated receptors: sentries for inflammation? Trends Pharmacol. Sci. 2000, 21, 103-108
27. Molino, M.; Barnathan, E. S.; Numerof, R.; Clark, J.; Dreyer, M.; Cumashi, A.; Hoxie, J. A.; Schechter, N.; Woolkalis, M.; Brass, L. F. Interactions of mast cell tryptase with thrombin receptors and PAR-2 J. Biol. Chem. 1997, 272, 4043-4049
28. Camerer, E.; Huang, W.; Coughlin, S. R. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 5255-5260
29. Lourbakos, A.; Yuan, Y. P.; Jenkins, A. L.; Travis, J.; Andrade-Gordon, P.; Santulli, R.; Potempa, J.; Pike, R. N. Activation of protease-activated receptors by gingipains from Porphyromonas gingivalis leads to platelet aggregation: a new trait in microbial pathogenicity Blood 2001, 97, 3790-3797
30. Oikonomopoulou, K.; Diamandis, E. P.; Hollenberg, M. D. Kallikrein-related peptidases: proteolysis and signaling in cancer, the new frontier Biol. Chem. 2010, 391, 299-310
31. Ramsay, A. J.; Dong, Y.; Hunt, M. L.; Linn, M.; Samaratunga, H.; Clements, J. A.; Hooper, J. D. Kallikrein-related peptidase 4 (KLK4) initiates intracellular signaling via protease-activated receptors (PARs). KLK4 and PAR-2 are co-expressed during prostate cancer progression J. Biol. Chem. 2008, 283, 12293-12304
32. Li, X.; Tai, H. H. Thromboxane A receptor-mediated release of matrix metalloproteinase-1 (MMP-1) induces expression of monocyte chemoattractant protein-1 (MCP-1) by activation of protease-activated receptor 2 (PAR2) in A549 human lung adenocarcinoma cells. Mol. Carcinog. [Online early access]. DOI: 10.1002/mc.22020. Published Online: Mar 8, 2013.
33. Santulli, R. J.; Derian, C. K.; Darrow, A. L.; Tomko, K. A.; Eckardt, A. J.; Seiberg, M.; Scarborough, R. M.; Andrade-Gordon, P. Evidence for the presence of a protease-activated receptor distinct from the thrombin receptor in human keratinocytes Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 9151-9155
34. Dery, O.; Corvera, C. U.; Steinhoff, M.; Bunnett, N. W. Proteinase-activated receptors: novel mechanisms of signaling by serine proteases Am. J. Physiol. 1998, 274, C1429-C1452
35. Maryanoff, B. E.; Santulli, R. J.; McComsey, D. F.; Hoekstra, W. J.; Hoey, K.; Smith, C. E.; Addo, M.; Darrow, A. L.; Andrade-Gordon, P. Protease-activated receptor-2 (PAR-2): structure-function study of receptor activation by diverse peptides related to tethered-ligand epitopes Arch. Biochem. Biophys. 2001, 386, 195-204
36. Shimada, S. G.; Shimada, K. A.; Collins, J. G. Scratching behavior in mice induced by the proteinase-activated receptor-2 agonist, SLIGRL-NH2 Eur. J. Pharmacol. 2006, 530, 281-283
37. Ramachandran, R.; Mihara, K.; Mathur, M.; Rochdi, M. D.; Bouvier, M.; DeFea, K.; Hollenberg, M. D. Agonist-biased signaling via proteinase activated receptor-2: differential activation of calcium and mitogen-activated protein kinase pathways Mol. Pharmacol. 2009, 76, 791-801
38. Matsumoto, T.; Ishida, K.; Taguchi, K.; Kobayashi, T.; Kamata, K. Mechanisms underlying enhanced vasorelaxant response to protease-activated receptor 2-activating peptide in type 2 diabetic Goto-Kakizaki rat mesenteric artery Peptides 2009, 30, 1729-1734
39. Russell, F. A.; Schuelert, N.; Veldhoen, V. E.; Hollenberg, M. D.; McDougall, J. J. Activation of PAR(2) receptors sensitizes primary afferents and causes leukocyte rolling and adherence in the rat knee joint Br. J. Pharmacol. 2012, 167, 1665-1678
40. Hirota, C. L.; Moreau, F.; Iablokov, V.; Dicay, M.; Renaux, B.; Hollenberg, M. D.; MacNaughton, W. K. Epidermal growth factor receptor transactivation is required for proteinase-activated receptor-2-induced COX-2 expression in intestinal epithelial cells Am. J. Physiol.: Gastrointest. Liver Physiol. 2012, 303, G111-119
41. Stenton, G. R.; Nohara, O.; Dery, R. E.; Vliagoftis, H.; Gilchrist, M.; Johri, A.; Wallace, J. L.; Hollenberg, M. D.; Moqbel, R.; Befus, A. D. Proteinase-activated receptor (PAR)-1 and -2 agonists induce mediator release from mast cells by pathways distinct from PAR-1 and PAR-2 J. Pharmacol. Exp. Ther. 2002, 302, 466-474
42. Zhao, A.; Shea-Donohue, T. PAR-2 agonists induce contraction of murine small intestine through neurokinin receptors Am. J. Physiol.: Gastrointest. Liver Physiol. 2003, 285, G696-703
43. Abey, H. T.; Fairlie, D. P.; Moffatt, J. D.; Balzary, R. W.; Cocks, T. M. Protease-activated receptor-2 peptides activate neurokinin-1 receptors in the mouse isolated trachea J. Pharmacol. Exp. Ther. 2006, 317, 598-605
44. Betts, R. J.; Mann, T. S.; Henry, P. J. Inhibitory influence of the hexapeptidic sequence SLIGRL on influenza A virus infection in mice J. Pharmacol. Exp. Ther. 2012, 343, 725-735
45. Gether, U.; Kobilka, B. K. G protein-coupled receptors. II. Mechanism of agonist activation J. Biol. Chem. 1998, 273, 17979-17982
46. Sevigny, L. M.; Zhang, P.; Bohm, A.; Lazarides, K.; Perides, G.; Covic, L.; Kuliopulos, A. Interdicting protease-activated receptor-2-driven inflammation with cell-penetrating pepducins Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 8491-8496
47. Jacob, C.; Cottrell, G. S.; Gehringer, D.; Schmidlin, F.; Grady, E. F.; Bunnett, N. W. c-Cbl mediates ubiquitination, degradation, and down-regulation of human protease-activated receptor 2 J. Biol. Chem. 2005, 280, 16076-16087
48. Adams, M. N.; Christensen, M. E.; He, Y.; Waterhouse, N. J.; Hooper, J. D. The role of palmitoylation in signalling, cellular trafficking and plasma membrane localization of protease-activated receptor-2 PLoS One 2011, 6, e28018
49. Gerszten, R. E.; Chen, J.; Ishii, M.; Ishii, K.; Wang, L.; Nanevicz, T.; Turck, C. W.; Vu, T. K. H.; Coughlin, S. R. Specificity of the thrombin receptor for agonist peptide is defined by its extracellular surface Nature 1994, 368, 648-651
50. Nanevicz, T.; Ishii, M.; Wang, L.; Chen, M.; Chen, J.; Turck, C. W.; Cohen, F. E.; Coughlin, S. R. Mechanisms of thrombin receptor agonist specificity-Chimeric receptors and complementary mutations identify an agonist recognition site J. Biol. Chem. 1995, 270, 21619-21625
51. Nanevicz, T.; Wang, L.; Chen, M.; Ishii, M.; Coughlin, S. R. Thrombin receptor activating mutations-Alteration of an extracellular agonist recognition domain causes constitutive signaling J. Biol. Chem. 1996, 271, 702-706
52. Lerner, D. J.; Chen, M.; Tram, T.; Coughlin, S. R. Agonist recognition by proteinase-activated receptor 2 and thrombin receptor-importance of extracellular loop interactions for receptor function J. Biol. Chem. 1996, 271, 13943-13947
53. Compton, S. J.; Sandhu, S.; Wijesuriya, S. J.; Hollenberg, M. D. Glycosylation of human proteinase-activated receptor-2 (hPAR(2)) role in cell surface expression and signalling Biochem. J. 2002, 368, 495-505
54. Leger, A. J.; Jacques, S. L.; Badar, J.; Kaneider, N. C.; Derian, C. K.; Andrade-Gordon, P.; Covic, L.; Kuliopulos, A. Blocking the protease-activated receptor 1-4 heterodimer in platelet-mediated thrombosis Circulation 2006, 113, 1244-1254
55. Madala, P. K. Computer Aided Drug Design: GPCRs and Proteases. Ph.D. Dissertation, The University of Queensland, Brisbane, Australia, 2008.
56. Venkatakrishnan, A. J.; Deupi, X.; Lebon, G.; Tate, C. G.; Schertler, G. F.; Babu, M. M. Molecular signatures of G-protein-coupled receptors Nature 2013, 494, 185-194
57. Thompson, A. A.; Liu, W.; Chun, E.; Katritch, V.; Wu, H.; Vardy, E.; Huang, X. P.; Trapella, C.; Guerrini, R.; Calo, G.; Roth, B. L.; Cherezov, V.; Stevens, R. C. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic Nature 2012, 485, 395-399
58. Wu, B.; Chien, E. Y.; Mol, C. D.; Fenalti, G.; Liu, W.; Katritch, V.; Abagyan, R.; Brooun, A.; Wells, P.; Bi, F. C.; Hamel, D. J.; Kuhn, P.; Handel, T. M.; Cherezov, V.; Stevens, R. C. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists Science 2010, 330, 1066-1071
59. Zhang, C.; Srinivasan, Y.; Arlow, D. H.; Fung, J. J.; Palmer, D.; Zheng, Y.; Green, H. F.; Pandey, A.; Dror, R. O.; Shaw, D. E.; Weis, W. I.; Coughlin, S. R.; Kobilka, B. K. High-resolution crystal structure of human protease-activated receptor 1 Nature 2012, 492, 387-392
60. Fiorucci, S.; Distrutti, E. Role of PAR2 in pain and inflammation Trends Pharmacol. Sci. 2002, 23, 153-155
61. Lindner, J. R.; Kahn, M. L.; Coughlin, S. R.; Sambrano, G. R.; Schauble, E.; Bernstein, D.; Foy, D.; Hafezi-Moghadam, A.; Ley, K. Delayed onset of inflammation in protease-activated receptor-2-deficient mice J. Immunol. 2000, 165, 6504-6510
62. Schmidlin, F.; Amadesi, S.; Dabbagh, K.; Lewis, D. E.; Knott, P.; Bunnett, N. W.; Gater, P. R.; Geppetti, P.; Bertrand, C.; Stevens, M. E. Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway J. Immunol. 2002, 169, 5315-5321
63. Roviezzo, F.; Bucci, M.; Brancaleone, V.; Di Lorenzo, A.; Geppetti, P.; Farneti, S.; Parente, L.; Lungarella, G.; Fiorucci, S.; Cirino, G. Proteinase-activated receptor-2 mediates arterial vasodilation in diabetes Arterioscler., Thromb., Vasc. Biol. 2005, 25, 2349-2354
64. De Cunto, G.; Cardini, S.; Cirino, G.; Geppetti, P.; Lungarella, G.; Lucattelli, M. Pulmonary hypertension in smoking mice over-expressing protease-activated receptor-2 Eur. Respir. J. 2011, 37, 823-834
65. Adams, M. N.; Pagel, C. N.; Mackie, E. J.; Hooper, J. D. Evaluation of antibodies directed against human protease-activated receptor-2 Naunyn Schmiedeberg's Arch. Pharmacol. 2012, 385, 861-873
66. Rohani, M. G.; Beyer, R. P.; Hacker, B. M.; Dommisch, H.; Dale, B. A.; Chung, W. O. Modulation of expression of innate immunity markers CXCL5/ENA-78 and CCL20/MIP3 alpha by protease-activated receptors (PARs) in human gingival epithelial cells Innate Immun. 2010, 16, 104-114
67. Saito, A.; Osuga, Y.; Yoshino, O.; Takamura, M.; Hirata, T.; Hirota, Y.; Koga, K.; Harada, M.; Takemura, Y.; Yano, T.; Taketani, Y. TGF-beta1 induces proteinase-activated receptor 2 (PAR2) expression in endometriotic stromal cells and stimulates PAR2 activation-induced secretion of IL-6 Hum. Reprod. 2011, 26, 1892-1898
68. Zheng, J.; Liu, W.; Fan, Y.; Ye, X.; Xia, W.; Wang, H.; Shi, J.; Xu, G.; Li, H. Suppression of connexin 26 is related to protease-activated receptor 2-mediated pathway in patients with allergic rhinitis Am. J. Rhinol. Allergy 2012, 26, e5-e9
69. Takizawa, T.; Tamiya, M.; Hara, T.; Matsumoto, J.; Saito, N.; Kanke, T.; Kawagoe, J.; Hattori, Y. Abrogation of bronchial eosinophilic inflammation and attenuated eotaxin content in protease-activated receptor 2-deficient mice J. Pharmacol. Sci. 2005, 98, 99-102
70. Shichijo, M.; Kondo, S.; Ishimori, M.; Watanabe, S.; Helin, H.; Yamasaki, T.; Stevens, M. E.; Gantner, F.; Bacon, K. B. PAR-2 deficient CD4+ T cells exhibit downregulation of IL-4 and upregulation of IFN-gamma after antigen challenge in mice Allergol. Int. 2006, 55, 271-278
71. Day, S. B.; Zhou, P.; Ledford, J. R.; Page, K. German cockroach frass proteases modulate the innate immune response via activation of protease-activated receptor-2 J. Innate Immun. 2010, 2, 495-504
72. Page, K.; Ledford, J. R.; Zhou, P.; Dienger, K.; Wills-Karp, M. Mucosal sensitization to German cockroach involves protease-activated receptor-2 Respir. Res. 2010, 11, 62
73. Lee, H. J.; Yang, Y. M.; Kim, K.; Shin, D. M.; Yoon, J. H.; Cho, H. J.; Choi, J. Y. Protease-activated receptor 2 mediates mucus secretion in the airway submucosal gland PLoS One 2012, 7, e43188
74. Liang, G.; Barker, T.; Xie, Z.; Charles, N.; Rivera, J.; Druey, K. M. Naive T cells sense the cysteine protease allergen papain through protease-activated receptor 2 and propel TH2 immunity J. Allergy Clin. Immunol. 2012, 129, 1377-1386 e13
75. Ferrell, W. R.; Lockhart, J. C.; Kelso, E. B.; Dunning, L.; Plevin, R.; Meek, S. E.; Smith, A. J.; Hunter, G. D.; McLean, J. S.; McGarry, F.; Ramage, R.; Jiang, L.; Kanke, T.; Kawagoe, J. Essential role for proteinase-activated receptor-2 in arthritis J. Clin. Invest. 2003, 111, 35-41
76. Kelso, E. B.; Lockhart, J. C.; Hembrough, T.; Dunning, L.; Plevin, R.; Hollenberg, M. D.; Sommerhoff, C. P.; McLean, J. S.; Ferrell, W. R. Therapeutic promise of proteinase-activated receptor-2 antagonism in joint inflammation J. Pharmacol. Exp. Ther. 2006, 316, 1017-1024
77. Yang, Y. H.; Hall, P.; Little, C. B.; Fosang, A. J.; Milenkovski, G.; Santos, L.; Xue, J.; Tipping, P.; Morand, E. F. Reduction of arthritis severity in protease-activated receptor-deficient mice Arthritis Rheum. 2005, 52, 1325-1332
78. Busso, N.; Frasnelli, M.; Feifel, R.; Cenni, B.; Steinhoff, M.; Hamilton, J.; So, A. Evaluation of protease-activated receptor 2 in murine models of arthritis Arthritis Rheum. 2007, 56, 101-107
79. Paszcuk, A. F.; Quintao, N. L.; Fernandes, E. S.; Juliano, L.; Chapman, K.; Andrade-Gordon, P.; Campos, M. M.; Vergnolle, N.; Calixto, J. B. Mechanisms underlying the nociceptive and inflammatory responses induced by trypsin in the mouse paw Eur. J. Pharmacol. 2008, 581, 204-215
80. Busso, N.; Chobaz-Peclat, V.; Hamilton, J.; Spee, P.; Wagtmann, N.; So, A. Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation Arthritis Res. Ther. 2008, 10, R42
81. Ferrell, W. R.; Kelso, E. B.; Lockhart, J. C.; Plevin, R.; McInnes, I. B. Protease-activated receptor 2: a novel pathogenic pathway in a murine model of osteoarthritis Ann. Rheum. Dis. 2010, 69, 2051-2054
82. Xue, M.; Chan, Y. K.; Shen, K.; Dervish, S.; March, L.; Sambrook, P. N.; Jackson, C. J. Protease-activated receptor 2, rather than protease-activated receptor 1, contributes to the aggressive properties of synovial fibroblasts in rheumatoid arthritis Arthritis Rheum. 2012, 64, 88-98
83. Rattenholl, A.; Seeliger, S.; Buddenkotte, J.; Schon, M.; Schon, M. P.; Stander, S.; Vergnolle, N.; Steinhoff, M. Proteinase-activated receptor-2 (PAR2): a tumor suppressor in skin carcinogenesis J. Invest. Dermatol. 2007, 127, 2245-2252
84. Versteeg, H. H.; Schaffner, F.; Kerver, M.; Ellies, L. G.; Andrade-Gordon, P.; Mueller, B. M.; Ruf, W. Protease-activated receptor (PAR) 2, but not PAR1, signaling promotes the development of mammary adenocarcinoma in polyoma middle T mice Cancer Res. 2008, 68, 7219-7227
85. Ryden, L.; Grabau, D.; Schaffner, F.; Jonsson, P. E.; Ruf, W.; Belting, M. Evidence for tissue factor phosphorylation and its correlation with protease-activated receptor expression and the prognosis of primary breast cancer Int. J. Cancer 2010, 126, 2330-2340
86. Schaffner, F.; Versteeg, H. H.; Schillert, A.; Yokota, N.; Petersen, L. C.; Mueller, B. M.; Ruf, W. Cooperation of tissue factor cytoplasmic domain and PAR2 signaling in breast cancer development Blood 2010, 116, 6106-6113
87. Lam, D. K.; Dang, D.; Zhang, J.; Dolan, J. C.; Schmidt, B. L. Novel animal models of acute and chronic cancer pain: a pivotal role for PAR2 J. Neurosci. 2012, 32, 14178-14183
88. Matej, R.; Zadinova, M.; Pouckova, P.; Kukal, J.; Olejar, T. PAR2 knock-out C57Bl6 mice as a model for evaluating metastases of cancer cells: pilot in vivo study of the metastatic potential of B16 melanoma in knock-out (PAR2-/-) animals Folia Biol. (Prague, Czech Republic) 2012, 58, 81-86
89. Damiano, B. P.; Cheung, W. M.; Santulli, R. J.; Fung-Leung, W. P.; Ngo, K.; Ye, R. D.; Darrow, A. L.; Derian, C. K.; de Garavilla, L.; Andrade-Gordon, P. Cardiovascular responses mediated by protease-activated receptor-2 (PAR-2) and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2 or PAR-1 J. Pharmacol. Exp. Ther. 1999, 288, 671-678
90. Uusitalo-Jarvinen, H.; Kurokawa, T.; Mueller, B. M.; Andrade-Gordon, P.; Friedlander, M.; Ruf, W. Role of protease activated receptor 1 and 2 signaling in hypoxia-induced angiogenesis Arterioscler., Thromb., Vasc. Biol. 2007, 27, 1456-1462
91. McGuire, J. J.; Van Vliet, B. N.; Halfyard, S. J. Blood pressures, heart rate and locomotor activity during salt loading and angiotensin II infusion in protease-activated receptor 2 (PAR2) knockout mice BMC Physiol. 2008, 8, 20
92. Antoniak, S.; Rojas, M.; Spring, D.; Bullard, T. A.; Verrier, E. D.; Blaxall, B. C.; Mackman, N.; Pawlinski, R. Protease-activated receptor 2 deficiency reduces cardiac ischemia/reperfusion injury Arterioscler., Thromb., Vasc. Biol. 2010, 30, 2136-2142
93. Chia, E.; Kagota, S.; Wijekoon, E. P.; McGuire, J. J. Protection of protease-activated receptor 2 mediated vasodilatation against angiotensin II-induced vascular dysfunction in mice BMC Pharmacol. 2011, 11, 10
94. 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.; Wallace, J. L. Proteinase-activated receptor-2 and hyperalgesia: a novel pain pathway Nat. Med. 2001, 7, 821-826
95. Liu, Q.; Weng, H. J.; Patel, K. N.; Tang, Z.; Bai, H.; Steinhoff, M.; Dong, X. The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia Sci. Signaling 2011, 4, ra45
96. Lam, D. K.; Schmidt, B. L. Serine proteases and protease-activated receptor 2-dependent allodynia: a novel cancer pain pathway Pain 2010, 149, 263-272
97. 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.; Bueno, L.; Vergnolle, N. Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2 Am. J. Pathol. 2002, 161, 1903-1915
98. Hansen, K. K.; Sherman, P. M.; Cellars, L.; Andrade-Gordon, P.; Pan, Z.; Baruch, A.; Wallace, J. L.; Hollenberg, M. D.; Vergnolle, N. A major role for proteolytic activity and proteinase-activated receptor-2 in the pathogenesis of infectious colitis Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 8363-8368
99. Kawabata, A.; Kawao, N.; Kitano, T.; Matsunami, M.; Satoh, R.; Ishiki, T.; Masuko, T.; Kanke, T.; Saito, N. Colonic hyperalgesia triggered by proteinase-activated receptor-2 in mice: involvement of endogenous bradykinin Neurosci. Lett. 2006, 402, 167-172
100. Cenac, N.; Andrews, C. N.; Holzhausen, M.; Chapman, K.; Cottrell, G.; Andrade-Gordon, P.; Steinhoff, M.; Barbara, G.; Beck, P.; Bunnett, N. W.; Sharkey, K. A.; Ferraz, J. G. P.; Shaffer, E.; Vergnolle, N. Role for protease activity in visceral pain in irritable bowel syndrome J. Clin. Invest. 2007, 117, 636-647
101. Cottrell, G. S.; Amadesi, S.; Pikios, S.; Camerer, E.; Willardsen, J. A.; Murphy, B. R.; Caughey, G. H.; Wolters, P. J.; Coughlin, S. R.; Peterson, A.; Knecht, W.; Pothoulakis, C.; Bunnett, N. W.; Grady, E. F. Protease-activated receptor 2, dipeptidyl peptidase I, and proteases mediate Clostridium difficile toxin A enteritis Gastroenterology 2007, 132, 2422-2437
102. Hyun, E.; Andrade-Gordon, P.; Steinhoff, M.; Beck, P. L.; Vergnolle, N. Contribution of bone marrow-derived cells to the pro-inflammatory effects of protease-activated receptor-2 in colitis Inflammation Res. 2010, 59, 699-709
103. Cattaruzza, F.; Lyo, V.; Jones, E.; Pham, D.; Hawkins, J.; Kirkwood, K.; Valdez-Morales, E.; Ibeakanma, C.; Vanner, S. J.; Bogyo, M.; Bunnett, N. W. Cathepsin S is activated during colitis and causes visceral hyperalgesia by a PAR2-dependent mechanism in mice Gastroenterology 2011, 141, 1864-1874
104. Kawagoe, J.; Takizawa, T.; Matsumoto, J.; Tamiya, M.; Meek, S. E.; Smith, A. J.; Hunter, G. D.; Plevin, R.; Saito, N.; Kanke, T.; Fujii, M.; Wada, Y. Effect of protease-activated receptor-2 deficiency on allergic dermatitis in the mouse ear Jpn. J. Pharmacol. 2002, 88, 77-84
105. Seeliger, S.; Derian, C. K.; Vergnolle, N.; Bunnett, N. W.; Nawroth, R.; Schmelz, M.; Von Der Weid, P. Y.; Buddenkotte, J.; Sunderkotter, C.; Metze, D.; Andrade-Gordon, P.; Harms, E.; Vestweber, D.; Luger, T. A.; Steinhoff, M. Proinflammatory role of proteinase-activated receptor-2 in humans and mice during cutaneous inflammation in vivo FASEB J. 2003, 17, 1871-1885
106. Briot, A.; Deraison, C.; Lacroix, M.; Bonnart, C.; Robin, A.; Besson, C.; Dubus, P.; Hovnanian, A. Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome J. Exp. Med. 2009, 206, 1135-1147
107. Briot, A.; Lacroix, M.; Robin, A.; Steinhoff, M.; Deraison, C.; Hovnanian, A. Par2 inactivation inhibits early production of TSLP, but not cutaneous inflammation, in Netherton syndrome adult mouse model J. Invest. Dermatol. 2010, 130, 2736-2742
108. Frateschi, S.; Camerer, E.; Crisante, G.; Rieser, S.; Membrez, M.; Charles, R. P.; Beermann, F.; Stehle, J. C.; Breiden, B.; Sandhoff, K.; Rotman, S.; Haftek, M.; Wilson, A.; Ryser, S.; Steinhoff, M.; Coughlin, S. R.; Hummler, E. PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin Nat. Commun. 2011, 2, 161
109. Redecha, P.; Franzke, C. W.; Ruf, W.; Mackman, N.; Girardi, G. Neutrophil activation by the tissue factor/factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome J. Clin. Invest. 2008, 118, 3453-3461
110. Knight, V.; Tchongue, J.; Lourensz, D.; Tipping, P.; Sievert, W. Protease-activated receptor 2 promotes experimental liver fibrosis in mice and activates human hepatic stellate cells Hepatology 2012, 55, 879-887
111. Khoufache, K.; LeBouder, F.; Morello, E.; Laurent, F.; Riffault, S.; Andrade-Gordon, P.; Boullier, S.; Rousset, P.; Vergnolle, N.; Riteau, B. Protective role for protease-activated receptor-2 against influenza virus pathogenesis via an IFN-gamma-dependent pathway J. Immunol. 2009, 182, 7795-7802
112. Velin, D.; Narayan, S.; Bernasconi, E.; Busso, N.; Ramelli, G.; Maillard, M. H.; Bachmann, D.; Pythoud, C.; Bouzourene, H.; Michetti, P.; So, A. PAR2 promotes vaccine-induced protection against Helicobacter infection in mice Gastroenterology 2011, 141, 1273-1282
113. Park, M. K.; Cho, M. K.; Kang, S. A.; Park, H. K.; Kim, Y. S.; Kim, K. U.; Ahn, S. C.; Kim, D. H.; Yu, H. S. Protease-activated receptor 2 is involved in Th2 responses against Trichinella spiralis infection Korean J. Parasitol. 2011, 49, 235-243
114. Ikawa, K.; Nishioka, T.; Yu, Z.; Sugawara, Y.; Kawagoe, J.; Takizawa, T.; Primo, V.; Nikolic, B.; Kuroishi, T.; Sasano, T.; Shimauchi, H.; Takada, H.; Endo, Y.; Sugawara, S. Involvement of neutrophil recruitment and protease-activated receptor 2 activation in the induction of IL-18 in mice J. Leukocyte Biol. 2005, 78, 1118-1126
115. Su, X.; Camerer, E.; Hamilton, J. R.; Coughlin, S. R.; Matthay, M. A. Protease-activated receptor-2 activation induces acute lung inflammation by neuropeptide-dependent mechanisms J. Immunol. 2005, 175, 2598-2605
116. Moraes, T. J.; Martin, R.; Plumb, J. D.; Vachon, E.; Cameron, C. M.; Danesh, A.; Kelvin, D. J.; Ruf, W.; Downey, G. P. Role of PAR2 in murine pulmonary pseudomonal infection Am. J. Physiol.: Lung Cell. Mol. Physiol. 2008, 294, L368-377
117. Jin, G.; Hayashi, T.; Kawagoe, J.; Takizawa, T.; Nagata, T.; Nagano, I.; Syoji, M.; Abe, K. Deficiency of PAR-2 gene increases acute focal ischemic brain injury J. Cereb. Blood Flow Metab. 2005, 25, 302-313
118. Noorbakhsh, F.; Tsutsui, S.; Vergnolle, N.; Boven, L. A.; Shariat, N.; Vodjgani, M.; Warren, K. G.; Andrade-Gordon, P.; Hollenberg, M. D.; Power, C. Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis J. Exp. Med. 2006, 203, 425-435
119. Afkhami-Goli, A.; Noorbakhsh, F.; Keller, A. J.; Vergnolle, N.; Westaway, D.; Jhamandas, J. H.; Andrade-Gordon, P.; Hollenberg, M. D.; Arab, H.; Dyck, R. H.; Power, C. Proteinase-activated receptor-2 exerts protective and pathogenic cell type-specific effects in Alzheimer's disease J. Immunol. 2007, 179, 5493-5503
120. Knecht, W.; Cottrell, G. S.; Amadesi, S.; Mohlin, J.; Skaregarde, A.; Gedda, K.; Peterson, A.; Chapman, K.; Hollenberg, M. D.; Vergnolle, N.; Bunnett, N. W. Trypsin IV or mesotrypsin and p23 cleave protease-activated receptors 1 and 2 to induce inflammation and hyperalgesia J. Biol. Chem. 2007, 282, 26089-26100
121. Matej, R.; Olejar, T.; Janouskova, O.; Holada, K. Deletion of protease-activated receptor 2 prolongs survival of scrapie-inoculated mice J. Gen. Virol. 2012, 93, 2057-2061
122. Noorbakhsh, F.; Vergnolle, N.; McArthur, J. C.; Silva, C.; Vodjgani, M.; Andrade-Gordon, P.; Hollenberg, M. D.; Power, C. Proteinase-activated receptor-2 induction by neuroinflammation prevents neuronal death during HIV infection J. Immunol. 2005, 174, 7320-7329
123. Alier, K. A.; Endicott, J. A.; Stemkowski, P. L.; Cenac, N.; Cellars, L.; Chapman, K.; Andrade-Gordon, P.; Vergnolle, N.; Smith, P. A. Intrathecal administration of proteinase-activated receptor-2 agonists produces hyperalgesia by exciting the cell bodies of primary sensory neurons J. Pharmacol. Exp. Ther. 2008, 324, 224-233
124. Yuan, H. B.; Zhu, X. L.; Zhou, S. Q.; Chen, Q. B.; Zhu, X. X.; Ma, X.; He, X. Y.; Tian, M. L.; Shi, X. Y. Role of mast cell activation in inducing microglial cells to release neurotrophin J. Neurosci. Res. 2010, 88, 1348-1354
125. Regard, J. B.; Kataoka, H.; Cano, D. A.; Camerer, E.; Yin, L.; Zheng, Y. W.; Scanlan, T. S.; Hebrok, M.; Coughlin, S. R. Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion J. Clin. Invest. 2007, 117, 4034-4043
126. Badeanlou, L.; Furlan-Freguia, C.; Yang, G.; Ruf, W.; Samad, F. Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation Nat. Med. 2011, 17, 1490-U1200
127. Sharma, A.; Tao, X.; Gopal, A.; Ligon, B.; Andrade-Gordon, P.; Steer, M. L.; Perides, G. Protection against acute pancreatitis by activation of protease-activated receptor-2 Am. J. Physiol.: Gastrointest. Liver Physiol. 2005, 288, G388-395
128. Sharma, A.; Tao, X.; Gopal, A.; Ligon, B.; Steer, M. L.; Perides, G. Calcium dependence of proteinase-activated receptor 2 and cholecystokinin- mediated amylase secretion from pancreatic acini Am. J. Physiol.: Gastrointest. Liver Physiol. 2005, 289, G686-695
129. Kawabata, A.; Matsunami, M.; Tsutsumi, M.; Ishiki, T.; Fukushima, O.; Sekiguchi, F.; Kawao, N.; Minami, T.; Kanke, T.; Saito, N. Suppression of pancreatitis-related allodynia/hyperalgesia by proteinase-activated receptor-2 in mice Br. J. Pharmacol. 2006, 148, 54-60
130. Laukkarinen, J. M.; Weiss, E. R.; van Acker, G. J.; Steer, M. L.; Perides, G. Protease-activated receptor-2 exerts contrasting model-specific effects on acute experimental pancreatitis J. Biol. Chem. 2008, 283, 20703-20712
131. Komatsu, H.; Shimose, A.; Shimizu, T.; Mukai, Y.; Kobayashi, J.; Ohama, T.; Sato, K. Trypsin inhibits lipopolysaccharide signaling in macrophages via toll-like receptor 4 accessory molecules Life Sci. 2012, 91, 143-150
132. Holzhausen, M.; Spolidorio, L. C.; Ellen, R. P.; Jobin, M. C.; Steinhoff, M.; Andrade-Gordon, P.; Vergnolle, N. Protease-activated receptor-2 activation: a major role in the pathogenesis of Porphyromonas gingivalis infection Am. J. Pathol. 2006, 168, 1189-1199
133. Wong, D. M.; Tam, V.; Lam, R.; Walsh, K. A.; Tatarczuch, L.; Pagel, C. N.; Reynolds, E. C.; O'Brien-Simpson, N. M.; Mackie, E. J.; Pike, R. N. Protease-activated receptor 2 has pivotal roles in cellular mechanisms involved in experimental periodontitis Infect. Immun. 2010, 78, 629-638
134. Moussa, L.; Apostolopoulos, J.; Davenport, P.; Tchongue, J.; Tipping, P. G. Protease-activated receptor-2 augments experimental crescentic glomerulonephritis Am. J. Pathol. 2007, 171, 800-808
135. Sevigny, L. M.; Austin, K. M.; Zhang, P.; Kasuda, S.; Koukos, G.; Sharifi, S.; Covic, L.; Kuliopulos, A. Protease-activated receptor-2 modulates protease-activated receptor-1-driven neointimal hyperplasia Arterioscler., Thromb., Vasc. Biol. 2011, 31, e100-106
136. Camerer, E.; Kataoka, H.; Kahn, M.; Lease, K.; Coughlin, S. R. Genetic evidence that protease-activated receptors mediate factor Xa signaling in endothelial cells J. Biol. Chem. 2002, 277, 16081-16087
137. Fields, R. C.; Schoenecker, J. G.; Hart, J. P.; Hoffman, M. R.; Pizzo, S. V.; Lawson, J. H. Protease-activated receptor-2 signaling triggers dendritic cell development Am. J. Pathol. 2003, 162, 1817-1822
138. Ramelli, G.; Fuertes, S.; Narayan, S.; Busso, N.; Acha-Orbea, H.; So, A. Protease-activated receptor 2 signalling promotes dendritic cell antigen transport and T-cell activation in vivo Immunology 2010, 129, 20-27
139. Georgy, S. R.; Pagel, C. N.; Wong, D. M.; Sivagurunathan, S.; Loh, L. H.; Myers, D. E.; Hollenberg, M. D.; Pike, R. N.; Mackie, E. J. Proteinase-activated receptor-2 (PAR2) and mouse osteoblasts: regulation of cell function and lack of specificity of PAR2-activating peptides Clin. Exp. Pharmacol. Physiol. 2010, 37, 328-336
140. Seok, J.; Warren, H. S.; Cuenca, A. G.; Mindrinos, M. N.; Baker, H. V.; Xu, W.; Richards, D. R.; McDonald-Smith, G. P.; Gao, H.; Hennessy, L.; Finnerty, C. C.; Lopez, C. M.; Honari, S.; Moore, E. E.; Minei, J. P.; Cuschieri, J.; Bankey, P. E.; Johnson, J. L.; Sperry, J.; Nathens, A. B.; Billiar, T. R.; West, M. A.; Jeschke, M. G.; Klein, M. B.; Gamelli, R. L.; Gibran, N. S.; Brownstein, B. H.; Miller-Graziano, C.; Calvano, S. E.; Mason, P. H.; Cobb, J. P.; Rahme, L. G.; Lowry, S. F.; Maier, R. V.; Moldawer, L. L.; Herndon, D. N.; Davis, R. W.; Xiao, W.; Tompkins, R. G. Genomic responses in mouse models poorly mimic human inflammatory diseases Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 3507-3512
141. Cocks, T. M.; Fong, B.; Chow, J. M.; Anderson, G. P.; Frauman, A. G.; Goldie, R. G.; Henry, P. J.; Carr, M. J.; Hamilton, J. R.; Moffatt, J. D. A protective role for protease-activated receptors in the airways Nature 1999, 398, 156-160
142. Cocks, T. M.; Moffatt, J. D. Protease-activated receptor-2 (PAR2) in the airways Pulm. Pharmacol. Ther. 2001, 14, 183-191
143. Moffatt, J. D.; Jeffrey, K. L.; Cocks, T. M. Protease-activated receptor-2 activating peptide SLIGRL inhibits bacterial lipopolysaccharide- induced recruitment of polymorphonuclear leukocytes into the airways of mice Am. J. Respir. Cell Mol. Biol. 2002, 26, 680-684
144. Vliagoftis, H.; Befus, A. D.; Hollenberg, M. D.; Moqbel, R. Airway epithelial cells release eosinophil survival-promoting factors (GM-CSF) after stimulation of proteinase-activated receptor 2 J. Allergy Clin. Immunol. 2001, 107, 679-685
145. Johansson, U.; Lawson, C.; Dabare, M.; Syndercombe-Court, D.; Newland, A. C.; Howells, G. L.; Macey, M. G. Human peripheral blood monocytes express protease receptor-2 and respond to receptor activation by production of IL-6, IL-8, and IL-1{beta} J. Leukocyte Biol. 2005, 78, 967-975
146. Suen, J. Y.; Gardiner, B.; Grimmond, S.; Fairlie, D. P. Profiling gene expression induced by protease-activated receptor 2 (PAR2) activation in human kidney cells PLoS One 2010, 5, e13809
147. Vesey, D. A.; Suen, J. Y.; Seow, V.; Lohman, R. J.; Liu, L.; Gobe, G. C.; Johnson, D. W.; Fairlie, D. P. PAR2-induced inflammatory responses in human kidney tubular epithelial cells Am. J. Physiol.: Renal Physiol. 2013, 304, F737-750
148. Wilson, S.; Greer, B.; Hooper, J.; Zijlstra, A.; Walker, B.; Quigley, J.; Hawthorne, S. The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells Biochem. J. 2005, 388, 967-972
149. Darmoul, D.; Gratio, V.; Devaud, H.; Laburthe, M. Protease-activated receptor 2 in colon cancer-Trypsin-induced MAPK phosphorylation and cell proliferation are mediated by epidermal growth factor receptor transactivation J. Biol. Chem. 2004, 279, 20927-20934
150. Chung, H.; Hamza, M.; Oikonomopoulou, K.; Gratio, V.; Saifeddine, M.; Virca, G. D.; Diamandis, E. P.; Hollenberg, M. D.; Darmoul, D. Kallikrein-related peptidase signaling in colon carcinoma cells: targeting proteinase-activated receptors Biol. Chem. 2012, 393, 413-420
151. Guo, D.; Zhou, H.; Wu, Y.; Zhou, F.; Xu, G.; Wen, H.; Zhang, X. Involvement of ERK1/2/NF-kappaB signal transduction pathway in TF/FVIIa/PAR2-induced proliferation and migration of colon cancer cell SW620 Tumor Biol. 2011, 32, 921-930
152. Wu, B.; Zhou, H.; Hu, L.; Mu, Y.; Wu, Y. Involvement of PKCalpha activation in TF/VIIa/PAR2-induced proliferation, migration, and survival of colon cancer cell SW620 Tumor Biol. 2013, 34, 837-846
153. Morris, D. R.; Ding, Y.; Ricks, T. K.; Gullapalli, A.; Wolfe, B. L.; Trejo, J. Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration, and invasion of breast cancer cells Cancer Res. 2006, 66, 307-314
154. Ge, L.; Shenoy, S. K.; Lefkowitz, R. J.; DeFea, K. Constitutive protease-activated receptor-2-mediated migration of MDA MB-231 breast cancer cells requires both beta-arrestin-1 and -2 J. Biol. Chem. 2004, 279, 55419-55424
155. Parisis, N.; Metodieva, G.; Metodiev, M. V. Pseudopodial and beta-arrestin-interacting proteomes from migrating breast cancer cells upon PAR2 activation J. Proteomics 2013, 80C, 91-106
156. DeFea, K. A.; Zalevsky, J.; Thoma, M. S.; Dery, O.; Mullins, R. D.; Bunnett, N. W. beta-Arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2 J. Cell Biol. 2000, 148, 1267-1281
157. Ge, L.; Ly, Y.; Hollenberg, M.; DeFea, K. A beta-arrestin-dependent scaffold is associated with prolonged MAPK activation in pseudopodia during protease-activated receptor-2-induced chemotaxis J. Biol. Chem. 2003, 278, 34418-34426
158. Soh, U. J. K.; Dores, M. R.; Chen, B.; Trejo, J. Signal transduction by protease-activated receptors Br. J. Pharmacol. 2010, 160, 191-203
159. Amadesi, S.; Cottrell, G. S.; Divino, L.; Chapman, K.; Grady, E. F.; Bautista, F.; Karanjia, R.; Barajas-Lopez, C.; Vanner, S.; Vergnolle, N.; Bunnett, N. W. Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice J. Physiol. 2006, 575, 555-571
160. Tanaka, Y.; Sekiguchi, F.; Hong, H.; Kawabata, A. PAR2 triggers IL-8 release via MEK/ERK and PI3-kinase/Akt pathways in GI epithelial cells Biochem. Biophys. Res. Commun. 2008, 377, 622-626
161. Wang, H.; Moreau, F.; Hirota, C. L.; MacNaughton, W. K. Proteinase-activated receptors induce interleukin-8 expression by intestinal epithelial cells through ERK/RSK90 activation and histone acetylation FASEB J. 2010, 24, 1971-1980
162. Rudack, C.; Steinhoff, M.; Mooren, F.; Buddenkotte, J.; Becker, K.; von Eiff, C.; Sachse, F. PAR-2 activation regulates IL-8 and GRO-alpha synthesis by NF-kappaB, but not RANTES, IL-6, eotaxin or TARC expression in nasal epithelium Clin. Exp. Allergy 2007, 37, 1009-1022
163. Han, P. Profiling the Regulation of Protease-Activated Receptor 2 (PAR2). Honours Thesis, The University of Queensland, Brisbane, Australia, 2008.
164. Hollenberg, M. D.; Mihara, K.; Polley, D.; Suen, J. Y.; Han, A.; Fairlie, D. P.; Ramachandran, R. Biased signaling and proteinase-activated receptors (PARs): targeting inflammatory disease. Unpublished review.
165. Suen, J. Y.; Cotterell, A.; Lohman, R. J.; Han, A.; Lim, J.; Yau, M. K.; Liu, L.; Vesey, D. A.; Cooper, M. A.; Fairlie, D. P. A biased PAR2 antagonist is anti-inflammatory by selectively inhibiting Gq/11 signaling. Unpublished results.
166. Kenakin, T. Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors Trends Pharmacol. Sci. 2007, 28, 407-415
167. Kenakin, T. Functional selectivity and biased receptor signaling J. Pharmacol. Exp. Ther. 2011, 336, 296-302
168. Kenakin, T. P. Biased signalling and allosteric machines: new vistas and challenges for drug discovery Br. J. Pharmacol. 2012, 165, 1659-1669
169. Kawabata, A.; Saifeddine, M.; Al-Ani, B.; Leblond, L.; Hollenberg, M. D. 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. 1999, 288, 358-370
170. Shi, X.; Gangadharan, B.; Brass, L. F.; Ruf, W.; Mueller, B. M. Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis Mol. Cancer Res. 2004, 2, 395-402
171. Barry, G. D.; Suen, J. Y.; Le, G. T.; Cotterell, A.; Reid, R. C.; Fairlie, D. P. Novel agonists and antagonists for human protease activated receptor 2 J. Med. Chem. 2010, 53, 7428-7440
172. Lim, S. Y.; Wainwright, C. L.; Kennedy, S.; Kane, K. A. Activation of protease activated receptor-2 induces delayed cardioprotection in anesthetized mice Cardiovasc. Drugs Ther. 2009, 23, 519-520
173. Flynn, A. N.; Hoffman, J.; Tillu, D. V.; Sherwood, C. L.; Zhang, Z.; Patek, R.; Asiedu, M. N.; Vagner, J.; Price, T. J.; Boitano, S. Development of highly potent protease-activated receptor 2 agonists via synthetic lipid tethering FASEB J. 2013, 27, 1498-1510
174. Kanke, T.; Ishiwata, H.; Kabeya, M.; Saka, M.; Doi, T.; Hattori, Y.; Kawabata, A.; Plevin, R. Binding of a highly potent protease-activated receptor-2 (PAR2) activating peptide, [3H]2-furoyl-LIGRL-NH2, to human PAR2 Br. J. Pharmacol. 2005, 145, 255-263
175. Hollenberg, M. D.; Renaux, B.; Hyun, E.; Houle, S.; Vergnolle, N.; Saifeddine, M.; Ramachandran, R. Derivatized 2-furoyl-LIGRLO-amide, a versatile and selective probe for proteinase-activated receptor 2: binding and visualization J. Pharmacol. Exp. Ther. 2008, 326, 453-462
176. Hoffman, J.; Flynn, A. N.; Tillu, D. V.; Zhang, Z.; Patek, R.; Price, T. J.; Vagner, J.; Boitano, S. Lanthanide labeling of a potent protease activated receptor-2 agonist for time-resolved fluorescence analysis Bioconjugate Chem. 2012, 23, 2098-2104
177. Hollenberg, M. D.; Saifeddine, M.; al-Ani, B. Proteinase-activated receptor-2 in rat aorta: structural requirements for agonist activity of receptor-activating peptides Mol. Pharmacol. 1996, 49, 229-233
178. Hollenberg, M. D.; Saifeddine, M.; al-Ani, B.; Kawabata, A. Proteinase-activated receptors: structural requirements for activity, receptor cross-reactivity, and receptor selectivity of receptor-activating peptides Can. J. Physiol. Pharmacol. 1997, 75, 832-841
179. Kawabata, A.; Nishikawa, H.; Kuroda, R.; Kawai, K.; Hollenberg, M. D. Proteinase-activated receptor-2 (PAR-2): regulation of salivary and pancreatic exocrine secretion in vivo in rats and mice Br. J. Pharmacol. 2000, 129, 1808-1814
180. McGuire, J. J.; Saifeddine, M.; Triggle, C. R.; Sun, K.; Hollenberg, M. D. 2-Furoyl-LIGRLO-amide: a potent and selective proteinase-activated receptor 2 agonist J. Pharmacol. Exp. Ther. 2004, 309, 1124-1131
181. Boitano, S.; Flynn, A. N.; Schulz, S. M.; Hoffman, J.; Price, T. J.; Vagner, J. Potent agonists of the protease activated receptor 2 (PAR(2)) J. Med. Chem. 2011, 54, 1308-1313
182. Barry, G. D.; Suen, J. Y.; Low, H. B.; Pfeiffer, B.; Flanagan, B.; Halili, M.; Le, G. T.; Fairlie, D. P. A refined agonist pharmacophore for protease activated receptor 2 Bioorg. Med. Chem. Lett. 2007, 17, 5552-5557
183. Devlin, M. G.; Pfeiffer, B.; Flanagan, B.; Beyer, R. L.; Cocks, T. M.; Fairlie, D. P. Hepta and octapeptide agonists of protease-activated receptor 2 J. Pept. Sci. 2007, 13, 856-861
184. Seitzberg, J. G.; Knapp, A. E.; Lund, B. W.; Bertozzi, S. M.; Currier, E. A.; Ma, J. N.; Sherbukhin, V.; Burstein, E. S.; Olsson, R. Discovery of potent and selective small-molecule PAR-2 agonists J. Med. Chem. 2008, 51, 5490-5493
185. Gardell, L. R.; Ma, J. N.; Seitzberg, J. G.; Knapp, A. E.; Schiffer, H. H.; Tabatabaei, A.; Davis, C. N.; Owens, M.; Clemons, B.; Wong, K. K.; Lund, B.; Nash, N. R.; Gao, Y.; Lameh, J.; Schmelzer, K.; Olsson, R.; Burstein, E. S. Identification and characterization of novel small-molecule protease-activated receptor 2 agonists J. Pharmacol. Exp. Ther. 2008, 327, 799-808
186. Lohman, R. J.; Cotterell, A. J.; Suen, J.; Liu, L.; Do, A. T.; Vesey, D. A.; Fairlie, D. P. Antagonism of protease-activated receptor 2 protects against experimental colitis J. Pharmacol. Exp. Ther. 2012, 340, 256-265
187. Suen, J. Y.; Barry, G. D.; Lohman, R. J.; Halili, M. A.; Cotterell, A. J.; Le, G. T.; Fairlie, D. P. Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110) Br. J. Pharmacol. 2012, 165, 1413-1423
188. Lohman, R. J.; Cotterell, A. J.; Barry, G. D.; Liu, L.; Suen, J. Y.; Vesey, D. A.; Fairlie, D. P. An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats FASEB J. 2012, 26, 2877-2887
189. Lohman, R. J.; Jones, N. C.; O'Brien, T. J.; Cocks, T. M. A regulatory role for protease-activated receptor-2 in motivational learning in rats Neurobiol. Learn. Mem. 2009, 92, 301-309
190. Lohman, R. J.; O'Brien, T. J.; Cocks, T. M. Protease-activated receptor-2 regulates trypsin expression in the brain and protects against seizures and epileptogenesis Neurobiol. Dis. 2008, 30, 84-93
191. Flynn, A. N.; Tillu, D. V.; Asiedu, M. N.; Hoffman, J.; Vagner, J.; Price, T. J.; Boitano, S. The protease-activated receptor-2-specific agonists 2-aminothiazol-4-yl-LIGRL-NH2 and 6-aminonicotinyl-LIGRL-NH2 stimulate multiple signaling pathways to induce physiological responses in vitro and in vivo J. Biol. Chem. 2011, 286, 19076-19088
192. Al-Ani, B.; Saifeddine, M.; Wijesuriya, S. J.; Hollenberg, M. D. Modified proteinase-activated receptor-1 and -2 derived peptides inhibit proteinase-activated receptor-2 activation by trypsin J. Pharmacol. Exp. Ther. 2002, 300, 702-708
193. Kanke, T.; Kabeya, M.; Kubo, S.; Kondo, S.; Yasuoka, K.; Tagashira, J.; Ishiwata, H.; Saka, M.; Furuyama, T.; Nishiyama, T.; Doi, T.; Hattori, Y.; Kawabata, A.; Cunningham, M. R.; Plevin, R. Novel antagonists for proteinase-activated receptor 2: inhibition of cellular and vascular responses in vitro and in vivo Br. J. Pharmacol. 2009, 158, 361-371
194. Goh, F. G.; Ng, P. Y.; Nilsson, M.; Kanke, T.; Plevin, R. Dual effect of the novel peptide antagonist K-14585 on proteinase-activated receptor-2-mediated signalling Br. J. Pharmacol. 2009, 158, 1695-1704
195. Hoyle, G. W.; Hoyle, C. I.; Chen, J.; Chang, W.; Williams, R. W.; Rando, R. J. Identification of triptolide, a natural diterpenoid compound, as an inhibitor of lung inflammation Am. J. Physiol.: Lung Cell. Mol. Physiol. 2010, 298, L830-836
196. Shao, F.; Wang, G.; Xie, H.; Zhu, X.; Sun, J.; A, J. Pharmacokinetic study of triptolide, a constituent of immunosuppressive chinese herb medicine, in rats Biol. Pharm. Bull. 2007, 30, 702-707
197. Kim, H. Y.; Goo, J. H.; Joo, Y. A.; Lee, H. Y.; Lee, S. M.; Oh, C. T.; Ahn, S. M.; Kim, N. H.; Hwang, J. S. Impact on inflammation and recovery of skin barrier by nordihydroguaiaretic acid as a protease-activated receptor 2 antagonist Biomol. Ther. 2012, 20, 463-469
198. Leong, S.; Lee, D.; Kim, H.; Jeon, J.; Bae, J.; Gwak, H.; Yun, J.; Lee, H.; Lee, S.; Lee, S. Anti-inflammatory activity of NPS-1577, PAR-2 specific antagonist, on oxazolone-induced chronic dermatitis animal model J. Invest. Dermatol. 2011, 131, S9-S9
199. Moniaga, C. S.; Jeong, S. K.; Egawa, G.; Nakajima, S.; Hara-Chikuma, M.; Jeon, J. E.; Lee, S. H.; Hibino, T.; Miyachi, Y.; Kabashima, K. Protease activity enhances production of thymic stromal lymphopoietin and basophil accumulation in flaky tail mice Am. J. Pathol. 2013, 182, 841-851
200. Yau, M. K. Novel Agonists and Antagonists for Protease-Activated Receptor 2 and C3a Receptor. Ph.D. Dissertation, The University of Queensland, Brisbane, Australia, 2013.
201. O'Callaghan, K.; Kuliopulos, A.; Covic, L. Turning receptors on and off with intracellular pepducins: new insights into G-protein-coupled receptor drug development J. Biol. Chem. 2012, 287, 12787-12796
202. Covic, L.; Gresser, A. L.; Talavera, J.; Swift, S.; Kuliopulos, A. Activation and inhibition of G protein-coupled receptors by cell-penetrating membrane-tethered peptides Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 643-648
203. Michael, E. S.; Kuliopulos, A.; Covic, L.; Steer, M. L.; Perides, G. Pharmacological inhibition of PAR2 with the pepducin P2pal-18S protects mice against acute experimental biliary pancreatitis Am. J. Physiol.: Gastrointest. Liver Physiol. 2013, 304, G516-G526
204. Crilly, A.; Palmer, H.; Nickdel, M. B.; Dunning, L.; Lockhart, J. C.; Plevin, R.; McInnes, I. B.; Ferrell, W. R. Immunomodulatory role of proteinase-activated receptor-2 Ann. Rheum. Dis. 2012, 71, 1559-1566
205. Giblin, P.; Boxhammer, R.; Desai, S.; Kroe-Barrett, R.; Hansen, G.; Ksiazek, J.; Panzenbeck, M.; Ralph, K.; Schwartz, R.; Zimmitti, C.; Pracht, C.; Miller, S.; Magram, J.; Litzenburger, T. Fully human antibodies against the protease-activated receptor-2 (PAR-2) with anti-inflammatory activity Hum. Antibodies 2011, 20, 83-94