From multiple PAR1 receptor/protein interactions to their multiple therapeutic implications

Current Topics in Medicinal Chemistry

Volumn 15, Issue 20, 2015, Pages 2080-2114

  Gutiérrez Rodríguez, Marta ^a   Herranz, Rosario ^a  

^a INSTITUTO DE QUÍMICA MÉDICA   (Spain)

Author keywords

G Protein signaling; Interactome; PAR1; PAR1 modulators; PPIs; Protease activated receptors; Therapeutic target; Thrombin

Indexed keywords

ACTIVATED PROTEIN C; BETA ARRESTIN; BLOOD CLOTTING FACTOR 10A; BLOOD CLOTTING FACTOR 7A; COLLAGENASE 3; ENDOTHELIAL PROTEIN C RECEPTOR; GLYCOGEN SYNTHASE KINASE 3BETA; INTERLEUKIN 1ALPHA; INTERLEUKIN 1BETA; INTERLEUKIN 6; INTERLEUKIN 8; INTERSTITIAL COLLAGENASE; KALLIKREIN 6; LEUKOCYTE ELASTASE; MYELOBLASTIN; NOTCH1 RECEPTOR; PLASMIN; PLASMINOGEN; POTASSIUM CHANNEL KV1.3; PROTEIN P42; PROTEIN P44; PROTEINASE ACTIVATED RECEPTOR 1; PROTEINASE ACTIVATED RECEPTOR 3; PROTEINASE ACTIVATED RECEPTOR 4; SCATTER FACTOR; STREPTOKINASE; THROMBIN; TUMOR NECROSIS FACTOR ALPHA; UNINDEXED DRUG; VASCULOTROPIN; ANTINEOPLASTIC AGENT; GUANINE NUCLEOTIDE BINDING PROTEIN; LIGAND; RETINA S ANTIGEN;

ANGIOGENESIS; CARDIOVASCULAR SYSTEM; ENZYME ACTIVATION; HUMAN; IMMUNE RESPONSE; IMMUNE SYSTEM; INFLAMMATION; NEOPLASM; NERVE CELL PLASTICITY; NERVOUS SYSTEM; NEUROTRANSMITTER RELEASE; NONHUMAN; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; RECEPTOR DOWN REGULATION; REVIEW; SEQUENCE HOMOLOGY; SIGNAL TRANSDUCTION; TRANSACTIVATION; AGONISTS; ANIMAL; ANTAGONISTS AND INHIBITORS; ANTIBODY SPECIFICITY; CHEMISTRY; GENETICS; METABOLISM; NEOPLASMS; PATHOLOGY; PROTEIN ANALYSIS; PROTEIN TRANSPORT; SPECIES DIFFERENCE; SYNTHESIS;

ANIMALS; ANTINEOPLASTIC AGENTS; ARRESTINS; GTP-BINDING PROTEINS; HUMANS; INFLAMMATION; LIGANDS; NEOPLASMS; ORGAN SPECIFICITY; PROTEIN INTERACTION MAPPING; PROTEIN TRANSPORT; PROTEOLYSIS; RECEPTOR, PAR-1; SIGNAL TRANSDUCTION; SPECIES SPECIFICITY; THROMBIN;

EID: 84937114030     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/1568026615666150519103911     Document Type: Review

References (443)

1. [1] Vu, T.K.; Hung, D.T.; Wheaton, V.I.; Coughlin, S.R. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell, 1991, 64, 1057-1068.
2. [2] Rasmussen, U.B.; Vouret-Craviari, V.; Jallat, S.; Schlesinger, Y.; Pagès, G.; Pavirani, A.; Lecocq, J.-P.; Pouysségur, J.; Van Obberghen-Schilling, E. cDNA cloning and expression of a hamster α-thrombin receptor coupled to Ca2+ mobilization. FEBS Lett., 1991, 288, 123-128.
3. [3] Grand, R.J.; Turnell, A.S.; Grabham, P.W. Cellular consequences of thrombin-receptor activation. Biochem. J., 1996, 313, 353-368.
4. [4] Coughlin, S.R. Thrombin signalling and protease-activated receptors. Nature, 2000, 407, 258-264.
5. [5] Macfarlane, S.R.; Seatter, M.J.; Kanke, T.; Hunter, G.D.; Plevin, R. Proteinase-activated receptors. Pharmacol. Rev., 2001, 53, 245-282.
6. [6] Ossovskaya, V.S.; Bunnett, N.W. Protease-activated receptors: contribution to physiology and disease. Physiol. Rev., 2004, 84, 579-621.
7. [7] Steinhoff, M.; Buddenkotte, J.; Shpacovitch, V.; Rattenholl, A.; Moormann, C.; Vergnolle, N.; Luger, T.A.; Hollenberg, M.D. Proteinaseactivated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr. Rev., 2005, 26, 1-43.
8. [8] Ramachandran, R.; Hollenberg, M.D. Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more. Br. J. Pharmacol., 2008, 153, S263-S282.
9. [9] Martorell, L.; Martínez-González, J.; Rodríguez, C.; Gentile, M.; Calvayrac, O.; Badimon, L. Thrombin and protease-activated receptors (PARs) in atherothrombosis. Thromb. Haemostasis, 2008, 99, 305-315.
10. [10] Trejo, J. Regulation of thrombin receptor signaling. In Thrombin: Physiology and Disease. Maragoudakis, M.E.; Tsopanoglou, N.E., Eds.; Springer: New York, 2009, pp 47-61.
11. [11] Shah, R. Protease-activated receptors in cardiovascular health and diseases. Am. Heart J., 2009, 157, 253-262.
12. [12] García-López, M.T.; Gutiérrez-Rodríguez, M.; Herranz, R. Thrombin-Activated Receptors: Promising Targets for Cancer Therapy? Curr. Med. Chem., 2010, 17, 109-128.
13. [13] 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.
14. [14] 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.
15. [15] Gieseler, F.; Ungefroren, H.; Settmacher, U.; Hollenberg, M.D.; Kaufmann, R. Proteinase-activated receptors (PARs)-focus on receptor-receptor-interactions and their physiological and pathophysiological impact. Cell Commun. Signaling, 2013, 11, 86.
16. [16] Blackhart, B.D.; Ruslim-Litrus, L.; Lu, C.C.; Alves, V.L.; Teng, W.; Scarborough, R.M.; Reynolds, E.E.; Oksenberg, D. Extracellular mutations of protease-activated receptor-1 result in differential activation by thrombin and thrombin receptor agonist peptide. Mol. Pharmacol., 2000, 58, 1178-1187.
17. [17] Seeley, S.; Covic, L.; Jacques, S.L.; Sudmeier, J.; Baleja, J.D.; Kuliopulos, A. Structural basis for thrombin activation of a protease-activated receptor: inhibition of intramolecular liganding. Chem. Biol., 2003, 10, 1033-1041.
18. [18] McLaughlin, J.N.; Shen, L.; Holinstat, M.; Brooks, J.D.; Dibenedetto, E.; Hamm, H.E. Functional selectivity of G protein signaling by agonist peptides and thrombin for the proteaseactivated receptor-1. J. Biol. Chem., 2005, 280, 25048-25059.
19. [19] Ramachandran, R.; El-Daly, M.; Saifeddine, M.; Hollenberg, M.D. Thrombin: To PAR or not to PAR, and the regulation of inflamation. In Thrombin: Physiology and Disease. Maragoudakis, M.E.; Tsopanoglou, N.E., Eds.; Springer: New York, 2009, pp 19-46.
20. [20] Derian, C.K.; Maryanoff, B.E.; Zhang, H.-C.; Andrade-Gordon, P. Therapeutic potential of protease-activated receptor-1 antagonists. Expert Opin. Investig. Drugs, 2003, 12, 209-221.
21. [21] Chen, C.; Maryanoff, B.E.; Andrade-Gordon, P. Thrombin receptor modulators: Medicinal chemistry, biological evaluation, and clinical applications. In Thrombin: Physiology and Disease. Maragoudakis, M.E.; Tsopanoglou, N.E., Eds.; Springer: New York, 2009, pp 205-236.
22. [22] Kataoka, H.; Hamilton, J.R.; McKemy, D.D.; Camerer, E.; Zheng, Y.-W.; Cheng, A.; Griffin, C.; Coughlin, S.R. Protease-activated receptors 1 and 4 mediate thrombin signaling in endothelial cells. Blood, 2003, 102, 3224-3231.
23. [23] Gudmundsdóttir, I.J.; Megson, I.L.; Kell, J.S.; Ludlam, C.A.; Fox, K.A.A.; Webb, D.J.; Newby, D.E. Direct vascular effects of protease-activated receptor type 1 agonism in vivo in humans. Circulation, 2006, 114, 1625-1632.
24. [24] Sokolova, E.; Reiser, G. Prothrombin/thrombin and the thrombin receptors PAR-1 and PAR-4 in the brain: localization, expression and participation in neurodegenerative diseases. Thromb. Haemost., 2008, 100, 576-581.
25. [25] Luo, W.; Wang, Y.; Reiser, G. The role of thrombin and thrombin receptors in the brain. In Thrombin: Physiology and Disease. Maragoudakis, M.E.; Tsopanoglou, N.E., Eds.; Springer: New York, 2009, pp 133-159.
26. [26] Ishii, K.; Hein, L.; Kobilka, B.; Coughlin, S.R. Kinetics of thrombin receptor cleavage on intact cells. Relation to signaling. J. Biol. Chem., 1993, 268, 9780-9786.
27. [27] De Candia, E.; Hall, S.W.; Rutella, S.; Landolfi, R.; Andrews, R.K.; De Cristofaro, R. Binding of thrombin to glycoprotein Ib accelerates the hydrolysis of Par-1 on intact platelets. J. Biol. Chem., 2001, 276, 4692-4698.
28. [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., 2000, 97, 5255-5260.
29. [29] Schaffner, F.; Ruf, W. Tissue factor and protease-activated receptor signaling in cancer. Semin. Thromb. Hemost., 2008, 34, 147-153.
30. [30] Riewald, M.; Ruf, W. Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor. Proc. Natl. Acad. Sci., 2001, 98, 7742-7747.
31. [31] Riewald, M.; Kravchenko, V.V.; Petrovan, R.J.; O'Brien, P.J.; Brass, L.F.; Ulevitch, R.J.; Ruf, W. Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1. Blood, 2001, 97, 3109-3116.
32. [32] Borensztajn, K.; Peppelenbosch, M.P.; Spek, C.A. Factor Xa: at the crossroads between coagulation and signaling in physiology and disease. Trends Mol. Med., 14, 429-440.
33. [33] Rana, S.; Yang, L.; Hassanian, S.M.; Rezaie, A.R. Determinants of the specificity of protease-activated receptors 1 and 2 signaling by factor Xa and thrombin. J. Cell. Biochem., 2012, 113, 977-984.
34. [34] Jobi, K.; Rauch, B.H.; Dangwal, S.; Freidel, K.; Doller, A.; Eberhardt, W.; Fischer, J.W.; Schroer, K.; Rosenkranz, A.C. Redox regulation of human protease-activated receptor-2 by activated factor X. Free Radical Biol. Med., 2011, 51, 1758-1764.
35. [35] Scotton, C.J.; Krupiczojc, M.A.; Konigshoff, M.; Mercer, P.F.; Lee, Y.C.G.; Kaminski, N.; Morser, J.; Post, J.M.; Maher, T.M.; Nicholson, A.G.; Moffatt, J.D.; Laurent, G.J.; Derian, C.K.; Eickelberg, O.; Chambers, R.C. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. J. Clin. Invest., 2009, 119, 2550-2563.
36. [36] Bukowska, A.; Zacharias, I.; Weinert, S.; Skopp, K.; Hartmann, C.; Huth, C.; Goette, A. Coagulation factor Xa induces an inflammatory signalling by activation of protease-activated receptors in human atrial tissue. Eur. J. Pharmacol., 2013, 718, 114-123.
37. [37] Riewald, M. Thrombin and activated protein C: Integrated to regulate vascular physiology. In Thrombin: Physiology and Disease. Maragoudakis, M.E.; Tsopanoglou, N.E., Eds.; Springer: New York, 2009, pp 63-80.
38. [38] Riewald, M.; Petrovan, R.J.; Donner, A.; Mueller, B.M.; Ruf, W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science, 2002, 296, 1880-1882.
39. [39] Cheng, T.; Liu, D.; Griffin, J.H.; Fernandez, J.A.; Castellino, F.; Rosen, E.D.; Fukudome, K.; Zlokovic, B.V. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat. Med., 2003, 9, 338-342.
40. [40] Mosnier, L.O.; Sinha, R.K.; Burnier, L.; Bouwens, E.A.; Griffin, J.H. Biased agonism of protease-activated receptor 1 by activated protein C caused by noncanonical cleavage at Arg46. Blood, 2012, 120, 5237-5246.
41. [41] Schuepbach, R.A.; Madon, J.; Ender, M.; Galli, P.; Riewald, M. Protease-activated receptor-1 cleaved at R46 mediates cytoprotective effects. J. Thromb. Haemost., 2012, 10, 1675-1684.
42. [42] Kuliopulos, A.; Covic, L.; Seeley, S.K.; Sheridan, P.J.; Helin, J.; Costello, C.E. Plasmin desensitization of the PAR1 thrombin receptor: Kinetics, sites of truncation, and implications for thrombolytic therapy. Biochemistry, 1999, 38, 4572-4585.
43. [43] Mannaioni, G.; Orr, A.G.; Hamill, C.E.; Yuan, H.; Pedone, K.H.; McCoy, K.L.; Palmini, R.B.; Junge, C.E.; Lee, C.J.; Yepes, M.; Hepler, J.R.; Traynelis, S.F. Plasmin potentiates synaptic NMethyl-D-aspartate receptor function in hippocampal neurons through activation of protease-activated receptor-1. J. Biol. Chem., 2008, 283, 20600-20611.
44. [44] Suidan, H.S.; Bouvier, J.; Schaerer, E.; Stone, S.R.; Monard, D.; Tschopp, J. Granzyme A released upon stimulation of cytotoxic T lymphocytes activates the thrombin receptor on neuronal cells and astrocytes. Proc. Natl. Acad. Sci. USA, 1994, 91, 8112-8116.
45. [45] Wang, T.; Lee, M.-H.; Choi, E.; Pardo-Villamizar, C.A.; Lee, S.B.; Yang, I.H.; Calabresi, P.A.; Nath, A. Granzyme B induced neurotoxicity is mediated via activation of PAR-1 receptor and Kv1.3 channel. PLoS One, 2012, 7, e43950.
46. [46] Cooper, D.M.; Petchkovsky, D.V.; Hackett, T.L.; Knight, D.A.; Granville, D.J. Granzyme K activates protease-activated receptor-1. PLoS One, 2011, 6, e21484.
47. [47] Hollenberg, M.D.; Oikonomopoulou, K.; Hansen, K.K.; Saifeddine, M.; Ramachandran, R.; Diamandis, E.P. Kallikreins and proteinase-mediated signaling: proteinase-activated receptors (PARs) and the pathophysiology of inflammatory diseases and cancer. Biol. Chem., 2008, 389, 643-651.
48. [48] 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.
49. [49] Gratio, V.; Beaufort, N.; Seiz, L.; Maier, J.; Virca, G.D.; Debela, M.; Grebenchtchikov, N.; Magdolen, V.; Darmoul, D. Kallikreinrelated peptidase 4: a new activator of the aberrantly expressed protease-activated receptor 1 in colon cancer cells. Am. J. Pathol., 2010, 176, 1452-1461.
50. [50] Boire, A.; Covic, L.; Agarwal, A.; Jacques, S.; Sherifi, S.; Kuliopulos, A. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell, 2005, 120, 303-313.
51. [51] Austin, K.M.; Covic, L.; Kuliopulos, A. Matrix metalloproteases and PAR1 activation. Blood, 2013, 121, 431-439.
52. [52] Blackburn, J.S.; Liu, I.; Coon, C.I.; Brinckerhoff, C.E. A matrix metalloproteinase-1/protease activated receptor-1 signaling axis promotes melanoma invasion and metastasis. Oncogene, 2009, 28, 4237-4248.
53. [53] Blackburn, J.S.; Brinckerhoff, C.E. Matrix metalloproteinase-1 and thrombin differentially activate gene expression in endothelial cells via PAR-1 and promote angiogenesis. Am. J. Pathol., 2008, 173, 1736-1746.
54. [54] Pei, D. Matrix metalloproteinases target protease-activated receptors on the tumor cell surface. Cancer Cell, 7, 207-208.
55. [55] Trivedi, V.; Boire, A.; Tchernychev, B.; Kaneider, N.C.; Leger, A.J.; O'Callaghan, K.; Covic, L.; Kuliopulos, A. Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site. Cell, 2009, 137, 332-343.
56. [56] Austin, K.M.; Nguyen, N.; Javid, G.; Covic, L.; Kuliopulos, A. Noncanonical matrix metalloprotease-1-protease-activated receptor-1 signaling triggers vascular smooth muscle cell dedifferentiation and arterial stenosis. J. Biol. Chem., 2013, 288, 23105-23115.
57. [57] Jaffré, F.; Friedman, A.E.; Hu, Z.; Mackman, N.; Blaxall, B.C. β-Adrenergic receptor stimulation transactivates protease-activated receptor 1 via matrix metalloproteinase 13 in cardiac cells. Circulation, 2012, 125, 2993-3003.
58. [58] Mao, Y.; Jin, J.; Kunapuli, S.P. Characterization of a new peptide agonist of the protease-activated receptor-1. Biochem. Pharmacol., 2008, 75, 438-447.
59. [59] Hollenberg, M.D.; Saifeddine, M.; Al-Ani, B.; Kawabata, A. Proteinase-activated receptors: structural requirements for activity, receptor cross-reactivity, and receptor selectivity of receptoractivating peptides. Can. J. Physiol. Pharmacol., 1997, 75, 832-841.
60. [60] Rasmussen, U.B.; Gachet, C.; Schlesinger, Y.; Hanau, D.; Ohlmann, P.; Van Obberghen-Schilling, E.; Pouysségur, J.; Cazenave, J.P.; Pavirani, A. A peptide ligand of the human thrombin receptor antagonizes alpha-thrombin and partially activates platelets. J. Biol. Chem., 1993, 268, 14322-14328.
61. [61] Mihara, K.; Ramachandran, R.; Renaux, B.; Saifeddine, M.; Hollenberg, M.D. Neutrophil elastase and proteinase-3 trigger G protein-biased signaling through proteinase-activated receptor-1 (PAR1). J. Biol. Chem., 2013, 288, 32979-32990.
62. [62] Tull, S.P.; Bevins, A.; Kuravi, S.J.; Satchell, S.C.; Al-Ani, B.; Young, S.P.; Harper, L.; Williams, J.M.; Rainger, G.E.; Savage, C.O. PR3 and elastase alter PAR1 signaling and trigger vWF release via a calcium-independent mechanism from glomerular endothelial cells. PLoS One, 2012, 7, e43916.
63. [63] Lourbakos, A.; Yuan, Y.; 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.
64. [64] Lourbakos, A.; Potempa, J.; Travis, J.; D'Andrea, M.R.; Andrade-Gordon, P.; Santulli, R.; Mackie, E.J.; Pike, R.N. Arginine-specific protease from Porphyromonas gingivalis activates proteaseactivated receptors on human oral epithelial cells and induces interleukin-6 secretion. Infect. Immun., 2001, 69, 5121-5130.
65. [65] Giacaman, R.A.; Asrani, A.C.; Ross, K.F.; Herzberg, M.C. Cleavage of protease-activated receptors on an immortalized oral epithelial cell line by Porphyromonas gingivalis gingipains. Microbiology, 2009, 155, 3238-3246.
66. [66] Uehara, A.; Muramoto, K.; Imamura, T.; Nakayama, K.; Potempa, J.; Travis, J.; Sugawara, S.; Takada, H. Arginine-specific gingipains from Porphyromonas gingivalis stimulate production of hepatocyte growth factor (Scatter factor) through protease-activated receptors in human gingival fibroblasts in culture. J. Immunol., 2005, 175, 6076-6084.
67. [67] Uehara, A.; Imamura, T.; Potempa, J.; Travis, J.; Takada, H. Gingipains from Porphyromonas gingivalis synergistically induce the production of proinflammatory cytokines through proteaseactivated receptors with Toll-like receptor and NOD1/2 ligands in human monocytic cells. Cell. Microbiol., 2008, 10, 1181-1189.
68. [68] McRedmond, J.P.; Harriott, P.; Walker, B.; Fitzgerald, D.J. Streptokinase-induced platelet activation involves antistreptokinase antibodies and cleavage of protease-activated receptor-1. Blood, 2000, 95, 1301-1308.
69. [69] van den Biggelaar, M.; Hernández-Fernaud, J.R.; van den Eshof, B.L.; Neilson, L.J.; Meijer, A.B.; Mertens, K.; Zanivan, S. Quantitative phosphoproteomics unveils temporal dynamics of thrombin signaling in human endothelial cells. Blood, 2014, 123, e22-e36.
70. [70] Swift, S.; Sheridan, P.J.; Covic, L.; Kuliopulos, A. PAR1 Thrombin Receptor-G Protein Interactions: Separation of binding and coupling determinants in the Gα subunit. J. Biol. Chem., 2000, 275, 2627-2635.
71. [71] McCoy, K.L.; Traynelis, S.F.; Hepler, J.R. PAR1 and PAR2 couple to overlapping and distinct sets of G proteins and linked signaling pathways to differentially regulate cell physiology. Mol. Pharmacol., 2010, 77, 1005-1015.
72. [72] Hains, M.D.; Wing, M.R.; Maddileti, S.; Siderovski, D.P.; Harden, T.K. Gα12/13-and Rho-dependent activation of phospholipase C-ϵ by lysophosphatidic acid and thrombin receptors. Mol. Pharmacol., 2006, 69, 2068-2075.
73. [73] Deng, X.; Mercer, P.F.; Scotton, C.J.; Gilchrist, A.; Chambers, R.C. Thrombin induces fibroblast CCL2/JE production and release via coupling of PAR1 to Gαq and cooperation between ERK1/2 and Rho kinase signaling pathways. Mol. Biol. Cell, 2008, 19, 2520-2533.
74. [74] Voss, B.; McLaughlin, J.N.; Holinstat, M.; Zent, R.; Hamm, H.E. PAR1, but Not PAR4, activates human platelets through a Gi/o/phosphoinositide-3 kinase signaling axis. Mol. Pharmacol., 2007, 71, 1399-1406.
75. [75] Nakanishi, K.; Toyoda, H.; Tanaka, S.; Yamamoto, H.; Komada, Y.; Gabazza, E.C.; Hayashi, T.; Suzuki, K.; Ido, M. Phosphoinositide 3-kinase induced activation and cytoskeletal translocation of protein kinase CK2 in protease activated receptor 1-stimulated platelets. Thromb. Res., 2010, 126, 511-516.
76. [76] Hatziapostolou, M.; Koukos, G.; Polytarchou, C.; Kottakis, F.; Serebrennikova, O.; Kuliopulos, A.; Tsichlis, P.N. Tumor progression locus 2 mediates signal-induced increases in cytoplasmic calcium and cell migration. Sci. Signal., 2011, 4, ra55.
77. [77] Nguyen, Q.D.; Faivre, S.; Bruyneel, E.; Rivat, C.; Seto, M.; Endo, T.; Mareel, M.; Emami, S.; Gespach, C. RhoA-and RhoDdependent regulatory switch of Galpha subunit signaling by PAR-1 receptors in cellular invasion. FASEB J., 2002, 16, 565-576.
78. [78] Gavard, J.; Gutkind, J.S. Protein kinase C-related kinase and ROCK are required for thrombin-induced endothelial cell permeability downstream from Galpha12/13 and Galpha11/q. J. Biol. Chem., 2008, 283, 29888-29896.
79. [79] De Vries, L.; Palmier, C.; Finana, F.; Le Grand, B.; Perez, M.; Cussac, D. Pharmacological characterization of protease activated receptor-1 by a serum responsive element-dependent reporter gene assay: major role of calmodulin. Biochem. Pharmacol., 2006, 71, 1449-1458.
80. [80] Klages, B.; Brandt, U.; Simon, M.I.; Schultz, G.; Offermanns, S. Activation of G12/G13 results in shape change and Rho/Rhokinase-mediated myosin light chain phosphorylation in mouse platelets. J. Cell Biol., 1999, 144, 745-754.
81. [81] Huang, J.-S.; Dong, L.; Kozasa, T.; Breton, G.C. Signaling through Gα13 Switch Region I Is Essential for Protease-activated Receptor 1-mediated Human Platelet Shape Change, Aggregation, and Secretion. J. Biol. Chem., 2007, 282, 10210-10222.
82. [82] Vouret-Craviari, V.; Boquet, P.; Pouyssegur, J.; Van Obberghen-Schilling, E. Regulation of the actin cytoskeleton by thrombin in human endothelial cells: role of Rho proteins in endothelial barrier function. Mol. Biol. Cell, 1998, 9, 2639-2653.
83. [83] Offermanns, S.; Mancino, V.; Revel, J.-P.; Simon, M.I. Vascular system defects and impaired cell chemokinesis as a result of Gα13 deficiency. Science, 1997, 275, 533-536.
84. [84] Otani, H.; Yoshioka, K.; Nishikawa, H.; Inagaki, C.; Nakamura, T. Involvement of protein kinase C and RhoA in protease-activated receptor 1-mediated F-actin reorganization and cell growth in rat cardiomyocytes. J. Pharmacol. Sci. , 2011, 115, 135-143.
85. [85] Nguyen, Q.D.; De Wever, O.; Bruyneel, E.; Hendrix, A.; Xie, W.Z.; Lombet, A.; Leibl, M.; Mareel, M.; Gieseler, F.; Bracke, M.; Gespach, C. Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho-Rho kinase axis and tumor microenvironment. Oncogene, 2005, 24, 8240-8251.
86. [86] Hatziapostolou, M.; Polytarchou, C.; Panutsopulos, D.; Covic, L.; Tsichlis, P.N. Proteinase-activated receptor-1-triggered activation of tumor progression locus-2 promotes actin cytoskeleton reorganization and cell migration. Cancer Res., 2008, 68, 1851-1861.
87. [87] Watts, V.L.; Motley, E.D. Role of protease-activated receptor-1 in endothelial nitric oxide synthase-Thr495 phosphorylation. Exp. Biol. Med, 2009, 234, 132-139.
88. [88] Turm, H.; Maoz, M.; Katz, V.; Yin, Y.-J.; Offermanns, S.; Bar-Shavit, R. Protease-activated receptor-1 (PAR1) acts via a novel Gα13-Dishevelled axis to stabilize β-catenin levels. J. Biol. Chem., 2010, 285, 15137-15148.
89. [89] Furuhashi, I.; Abe, K.; Sato, T.; Inoue, H. Thrombin-stimulated proliferation of cultured human synovial fibroblasts through proteolytic activation of proteinase-activated receptor-1. J. Pharmacol. Sci., 2008, 108, 104-111.
90. [90] Palma-Nicolas, J.P.; López, E.; López-Colomé, A.M. PKC isoenzymes differentially modulate the effect of thrombin on MAPKdependent RPE proliferation. Biosci. Rep., 2008, 28, 307-317.
91. [91] Chiu, Y.C.; Fong, Y.C.; Lai, C.H.; Hung, C.H.; Hsu, H.C.; Lee, T.S.; Yang, R.S.; Fu, W.M.; Tang, C.H. Thrombin-induced IL-6 production in human synovial fibroblasts is mediated by PAR1, phospholipase C, protein kinase C alpha, c-Src, NF-kappa B and p300 pathway. Mol. Immunol., 2008, 45, 1587-1599.
92. [92] Huang, Y.L.; Shi, G.Y.; Lee, H.; Jiang, M.J.; Huang, B.M.; Wu, H.L.; Yang, H.Y. Thrombin induces nestin expression via the transactivation of EGFR signalings in rat vascular smooth muscle cells. Cell. Signal., 2009, 21, 954-968.
93. [93] Arora, P.; Cuevas, B.D.; Russo, A.; Johnson, G.L.; Trejo, J. Persistent transactivation of EGFR and ErbB2/HER2 by proteaseactivated receptor-1 promotes breast carcinoma cell invasion. Oncogene, 2008, 27, 4434-4445.
94. [94] Chandrasekharan, U.M.; Waitkus, M.; Kinney, C.M.; Walters-Stewart, A.; DiCorleto, P.E. Synergistic induction of mitogenactivated protein kinase phosphatase-1 by thrombin and epidermal growth factor requires vascular endothelial growth factor receptor-2. Arterioscler., Thromb., Vasc. Biol., 2010, 30, 1983-1989.
95. [95] Hashimotodani, Y.; Ohno-Shosaku, T.; Yamazaki, M.; Sakimura, K.; Kano, M. Neuronal protease-activated receptor 1 drives synaptic retrograde signaling mediated by the endocannabinoid 2-arachidonoylglycerol. J. Neurosci., 2011, 31, 3104-3109.
96. [96] Faivre, S.; Régnauld, K.; Bruyneel, E.; Nguyen, Q.-D.; Mareel, M.; Emami, S.; Gespach, C. Suppression of cellular invasion by activated G-protein subunits Gαo, Gαi1, Gαi2, and Gαi3 and sequestration of Gβγ. Mol. Pharmacol., 2001, 60, 363-372.
97. [97] Wang, H.; Ubl, J.J.; Stricker, R.; Reiser, G. Thrombin (PAR-1)-induced proliferation in astrocytes via MAPK involves multiple signaling pathways. Am. J. Physiol. Cell Physiol., 2002, 283, C1351-C1364.
98. [98] Hollenberg, M.D.; Mihara, K.; Polley, D.; Suen, J.Y.; Han, A.; Fairlie, D.P.; Ramachandran, R. Biased signalling and proteinaseactivated receptors (PARs): targeting inflammatory disease. Brit. J. Pharmacol., 2014, 171, 1180-1194.
99. [99] Russo, A.; Soh, U.J.K.; Paing, M.M.; Arora, P.; Trejo, J. Caveolae are required for protease-selective signaling by protease-activated receptor–1. Proc. Natl. Acad. Sci., 2009, 106, 6393-6397.
100. [100] Dowal, L.; Sim, D.S.; Dilks, J.R.; Blair, P.; Beaudry, S.; Denker, B.M.; Koukos, G.; Kuliopulos, A.; Flaumenhaft, R. Identification of an antithrombotic allosteric modulator that acts through helix 8 of PAR1. Proc. Natl. Acad. Sci. U. S. A., 2011, 108, 2951-2956.
101. [101] Dockendorff, C.; Aisiku, O.; VerPlank, L.; Dilks, J.R.; Smith, D.A.; Gunnink, S.F.; Dowal, L.; Negri, J.; Palmer, M.; MacPherson, L.; Schreiber, S.L.; Flaumenhaft, R. Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor. ACS Med. Chem. Lett., 2012, 3, 232-237.
102. [102] Asteriti, S.; Daniele, S.; Porchia, F.; Dell' Anno, M.T.; Fazzini, A.; Pugliesi, I.; Trincavelli, M.L.; Taliani, S.; Martini, C.; Mazzoni, M.R.; Gilchrist, A. Modulation of PAR1 signalling by benzimidazole compounds. Brit. J. Pharmacol., 2012, 167, 80-94.
103. [103] Ayoub, M.A.; Trinquet, E.; Pfleger, K.D.G.; Pin, J.-P. Differential association modes of the thrombin receptor PAR1 with Gαi1, Gα12, and β-arrestin 1. FASEB J., 2010, 24, 3522-3535.
104. [104] Verrall, S.; Ishii, M.; Chen, M.; Wang, L.; Tram, T.; Coughlin, S.R. The thrombin receptor second cytoplasmic loop confers coupling to Gq-like G proteins in chimeric receptors: Additional evidence for a common transmembrane signaling and G ptotein coupling mechanism in G protein-coupled receptors. J. Biol. Chem., 1997, 272, 6898-6902.
105. [105] Covic, L.; Gresser, A.L.; Talavera, J.; Swift, S.; Kuliopulos, A. Activation and inhibition of G protein-coupled receptors by cellpenetrating membrane-tethered peptides. Proc. Natl. Acad. Sci., 2002, 99, 643-648.
106. [106] Swift, S.; Leger, A.J.; Talavera, J.; Zhang, L.; Bohm, A.; Kuliopulos, A. Role of the PAR1 Receptor 8th Helix in Signaling: The 7-8-1 receptor activation mechanism. J. Biol. Chem., 2006, 281, 4109-4116.
107. [107] McCoy, K.L.; Gyoneva, S.; Vellano, C.P.; Smrcka, A.V.; Traynelis, S.F.; Hepler, J.R. Protease-activated receptor 1 (PAR1) coupling to G(q/11) but not to G(i/o) or G(12/13) is mediated by discrete amino acids within the receptor second intracellular loop. Cell. Signal., 2012, 24, 1351-1360.
108. [108] Luttrell, L.M.; Lefkowitz, R.J. The role of β-arrestins in the termination and transduction of G-protein-coupled receptor signals. J. Cell Sci., 2002, 115, 455-465.
109. [109] DeFea, K. β-arrestins and heterotrimeric G-proteins: collaborators and competitors in signal transduction. Brit. J. Pharmacol., 2008, 153, S298-S309.
110. [110] Goel, R.; Phillips-Mason, P.J.; Raben, D.M.; Baldassare, J.J. α-Thrombin induces rapid and sustained Akt phosphorylation by β-arrestin1-dependent and-independent mechanisms, and only the sustained Akt phosphorylation Is essential for G1 phase progression. J. Biol. Chem., 2002, 277, 18640-18648.
111. [111] Goel, R.; Baldassare, J.J. β-Arrestin 1 couples thrombin to the rapid activation of the Akt pathway. Ann. N. Y. Acad. Sci., 2002, 973, 138-141.
112. [112] Kuo, F.-T.; Lu, T.-L.; Fu, H.-W. Opposing effects of β-arrestin1 and β-arrestin2 on activation and degradation of Src induced by protease-activated receptor 1. Cell. Signal., 2006, 18, 1914-1923.
113. [113] Soh, U.J.K.; Trejo, J. Activated protein C promotes proteaseactivated receptor-1 cytoprotective signaling through β-arrestin and dishevelled-2 scaffolds. Proc. Natl. Acad. Sci., 2011, 108, E1372-E1380.
114. [114] Little, P.J.; Burch, M.L.; Al-Aryahi, S.; Zheng, W. The paradigm of G protein receptor transactivation: a mechanistic definition and novel example. TheScientificWorldJournal, 2011, 11, 709-714.
115. [115] Narita, M.; Usui, A.; Narita, M.; Niikura, K.; Nozaki, H.; Khotib, J.; Nagumo, Y.; Yajima, Y.; Suzuki, T. Protease-activated receptor-1 and platelet-derived growth factor in spinal cord neurons are implicated in neuropathic pain after nerve injury. J. Neurosci., 2005, 25, 10000-10009.
116. [116] Du, J.; Sperling, L.S.; Marrero, M.B.; Phillips, L.; Delafontaine, P. G-protein and tyrosine kinase receptor cross-talk in rat aortic smooth muscle cells: thrombin-and angiotensin II-induced tyrosine phosphorylation of insulin receptor substrate-1 and insulin-like growth factor 1 receptor. Biochem. Biophys. Res. Commun., 1996, 218, 934-939.
117. [117] Delafontaine, P.; Anwar, A.; Lou, H.; Ku, L. G-protein coupled and tyrosine kinase receptors: evidence that activation of the insulinlike growth factor I receptor is required for thrombin-induced mitogenesis of rat aortic smooth muscle cells. J. Clin. Invest., 1996, 97, 139-145.
118. [118] Chan, B.; Sukhatme, V.P. Receptor tyrosine kinase EphA2 mediates thrombin-induced upregulation of ICAM-1 in endothelial cells in vitro. Thromb. Res., 2009, 123, 745-752.
119. [119] Burch, M.L.; Ballinger, M.L.; Yang, S.N.Y.; Getachew, R.; Itman, C.; Loveland, K.; Osman, N.; Little, P.J. Thrombin stimulation of proteoglycan synthesis in vascular smooth muscle is mediated by protease-activated receptor-1 transactivation of the transforming growth factor β type I receptor. J. Biol. Chem., 2010, 285, 26798-26805.
120. [120] Jenkins, R.G.; Su, X.; Su, G.; Scotton, C.J.; Camerer, E.; Laurent, G.J.; Davis, G.E.; Chambers, R.C.; Matthay, M.A.; Sheppard, D. Ligation of protease-activated receptor 1 enhances αvβ6 integrindependent TGF-β activation and promotes acute lung injury. J. Clin. Invest., 2006, 116, 1606-1614.
121. [121] Kaneider, N.C.; Leger, A.J.; Agarwal, A.; Nguyen, N.; Perides, G.; Derian, C.; Covic, L.; Kuliopulos, A. 'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage. Nat. Immunol., 2007, 8, 1303-1312.
122. [122] O'Brien, P.J.; Prevost, N.; Molino, M.; Hollinger, M.K.; Woolkalis, M.J.; Woulfe, D.S.; Brass, L.F. Thrombin responses in human endothelial cells. Contributions from receptors other than PAR1 include the transactivation of PAR2 by thrombin-cleaved PAR1. J. Biol. Chem., 2000, 275, 13502-13509.
123. [123] 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.
124. [124] McEachron, T.A.; Pawlinski, R.; Richards, K.L.; Church, F.C.; Mackman, N. Protease-activated receptors mediate crosstalk between coagulation and fibrinolysis. Blood, 2010, 116, 5037-5044.
125. [125] Lin, H.; Trejo, J. Transactivation of the PAR1-PAR2 heterodimer by thrombin elicits β-arrestin-mediated endosomal signaling. J. Biol. Chem., 2013, 288, 11203-11215.
126. [126] 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.
127. [127] Kaufmann, R.; Patt, S.; Zieger, M.; Kraft, R.; Tausch, S.; Henklein, P.; Nowak, G. The two-receptor system PAR-1/PAR-4 mediates α-thrombin-induced [Ca2+]i mobilization in human astrocytoma cells. J. Cancer Res. Clin. Oncol., 2000, 126, 91-94.
128. [128] Kaufmann, R.; Rahn, S.; Pollrich, K.; Hertel, J.; Dittmar, Y.; Hommann, M.; Henklein, P.; Biskup, C.; Westermann, M.; Hollenberg, M.D.; Settmacher, U. Thrombin-mediated hepatocellular carcinoma cell migration: cooperative action via proteinase-activated receptors 1 and 4. J. Cell Physiol., 2007, 211, 699-707.
129. [129] Feistritzer, C.; Riewald, M. Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood, 2005, 105, 3178-3184.
130. [130] Niessen, F.; Schaffner, F.; Furlan-Freguia, C.; Pawlinski, R.; Bhattacharjee, G.; Chun, J.; Derian, C.K.; Andrade-Gordon, P.; Rosen, H.; Ruf, W. Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation. Nature, 2008, 452, 654-658.
131. [131] Guo, H.; Zhao, Z.; Yang, Q.; Wang, M.; Bell, R.D.; Wang, S.; Chow, N.; Davis, T.P.; Griffin, J.H.; Goldman, S.A.; Zlokovic, B.V. An activated protein C analog stimulates neuronal production by human neural progenitor cells via a PAR1-PAR3-S1PR1-Akt pathway. J. Neurosci., 2013, 33, 6181-6190.
132. [132] Nagai, T.; Ito, M.; Nakamichi, N.; Mizoguchi, H.; Kamei, H.; Fukakusa, A.; Nabeshima, T.; Takuma, K.; Yamada, K. The rewards of nicotine: regulation by tissue plasminogen activator-plasmin system through protease activated receptor-1. J. Neurosci., 2006, 26, 12374-12383.
133. [133] Hamill, C.E.; Mannaioni, G.; Lyuboslavsky, P.; Sastre, A.A.; Traynelis, S.F. Protease-activated receptor 1-dependent neuronal damage involves NMDA receptor function. Exp. Neurol., 2009, 217, 136-146.
134. [134] Gingrich, M.B.; Junge, C.E.; Lyuboslavsky, P.; Traynelis, S.F. Potentiation of NMDA receptor function by the serine protease thrombin. J. Neurosci., 2000, 20, 4582-4595.
135. [135] Lee, C.J.; Mannaioni, G.; Yuan, H.; Woo, D.H.; Gingrich, M.B.; Traynelis, S.F. Astrocytic control of synaptic NMDA receptors. J. Physiol. , 2006, 581, 1057-1081.
136. [136] Vellani, V.; Kinsey, A.M.; Prandini, M.; Hechtfischer, S.C.; Reeh, P.; Magherini, P.C.; Giacomoni, C.; McNaughton, P.A. Protease activated receptors 1 and 4 sensitize TRPV1 in nociceptive neurones. Mol. Pain, 2010, 6, 61.
137. [137] Schuepbach, R.A.; Feistritzer, C.; Brass, L.F.; Riewald, M. Activated protein C-cleaved protease activated receptor-1 is retained on the endothelial cell surface even in the presence of thrombin. Blood, 2008, 111, 2667-2673.
138. [138] Ishii, K.; Chen, J.; Ishii, M.; Koch, W.J.; Freedman, N.J.; Lefkowitz, R.J.; Coughlin, S.R. Inhibition of thrombin receptor signaling by a G-protein coupled receptor kinase. Functional specificity among G-protein coupled receptor kinases. J. Biol. Chem., 1994, 269, 1125-1130.
139. [139] Tiruppathi, C.; Yan, W.; Sandoval, R.; Naqvi, T.; Pronin, A.N.; Benovic, J.L.; Malik, A.B. G protein-coupled receptor kinase-5 regulates thrombin-activated signaling in endothelial cells. Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 7440-7445.
140. [140] Paing, M.M.; Stutts, A.B.; Kohout, T.A.; Lefkowitz, R.J.; Trejo, J. β-Arrestins regulate protease-activated receptor-1 desensitization but not internalization or down-regulation. J. Biol. Chem., 2002, 277, 1292-1300.
141. [141] Chen, C.-H.; Paing, M.M.; Trejo, J. Termination of proteaseactivated receptor-1 signaling by β-arrestins is independent of receptor phosphorylation. J. Biol. Chem., 2004, 279, 10020-10031.
142. [142] Ghil, S.; McCoy, K.L.; Hepler, J.R. Regulator of G protein signaling 2 (RGS2) and RGS4 form distinct G protein-dependent complexes with protease activated-receptor 1 (PAR1) in live cells. PLoS One, 2014, 9, e95355.
143. [143] Chen, B.; Siderovski, D.P.; Neubig, R.R.; Lawson, M.A.; Trejo, J. Regulation of protease-activated receptor 1 signaling by the adaptor protein complex 2 and R4 subfamily of regulator of G protein signaling proteins. J. Biol. Chem., 2014, 289, 1580-1591.
144. [144] Wolfe, B.L.; Marchese, A.; Trejo, J. Ubiquitination differentially regulates clathrin-dependent internalization of protease-activated receptor-1. J. Cell Biol., 2007, 177, 905-916.
145. [145] Chen, B.; Dores, M.R.; Grimsey, N.; Canto, I.; Barker, B.L.; Trejo, J. Adaptor protein complex-2 (AP-2) and epsin-1 mediate proteaseactivated receptor-1 internalization via phosphorylation-and ubiquitination-dependent sorting signals. J. Biol. Chem., 2011, 286, 40760-40770.
146. [146] Swift, S.; Xu, J.; Trivedi, V.; Austin, K.M.; Tressel, S.L.; Zhang, L.; Covic, L.; Kuliopulos, A. A novel protease-activated receptor-1 interactor, bicaudal D1, regulates G protein signaling and internalization. J. Biol. Chem., 2010, 285, 11402-11410.
147. [147] Wang, Y.; Zhou, Y.; Szabo, K.; Haft, C.R.; Trejo, J. Downregulation of protease-activated receptor-1 is regulated by sorting nexin 1. Mol. Biol. Cell, 2002, 13, 1965-1976.
148. [148] Gullapalli, A.; Wolfe, B.L.; Griffin, C.T.; Magnuson, T.; Trejo, J. An essential role for SNX1 in lysosomal sorting of proteaseactivated receptor-1: evidence for Retromer-, Hrs-, and Tsg101-independent functions of sorting nexins. Mol. Biol. Cell, 2006, 17, 1228-1238.
149. [149] Wang, Y.-J.; Guo, X.-L.; Li, S.-A.; Zhao, Y.-Q.; Liu, Z.-C.; Lee, W.-H.; Xiang, Y.; Zhang, Y. Prohibitin is involved in the activated internalization and degradation of protease-activated receptor 1. Biochim. Biophys. Acta, 2014, 1843, 1393-1401.
150. [150] Kuliopulos, A.; Covic, L.; Seeley, S.K.; Sheridan, P.J.; Helin, J.; Costello, C.E. Plasmin desensitization of the PAR1 thrombin receptor: Kinetics, sites of truncation, and implications for thrombolytic therapy. Biochemistry, 1999, 38, 4572-4585.
151. [151] Renesto, P.; Si-Tahar, M.; Moniatte, M.; Balloy, V.; Van Dorsselaer, A.; Pidard, D.; Chignard, M. Specific inhibition of thrombininduced cell activation by the neutrophil proteinases elastase, cathepsin G, and proteinase 3: evidence for distinct cleavage sites within the amino terminal domain of the thrombin receptor. Blood, 1997, 89, 1944-1953.
152. [152] Xiao, Y.P.; Morice, A.H.; Compton, S.J.; Sadofsky, L. N-Linked glycosylation regulates human proteinase-activated receptor-1 cell surface expression and disarming via neutrophil proteinases and thermolysin. J. Biol. Chem., 2011, 286, 22991-23002.
153. [153] Nakayama, T.; Hirano, K.; Shintani, Y.; Nishimura, J.; Nakatsuka, A.; Kuga, H.; Takahashi, S.; Kanaide, H. Unproductive cleavage and the inactivation of protease-activated receptor-1 by trypsin in vascular endothelial cells. Br. J. Pharmacol., 2003, 138, 121-130.
154. [154] Schechter, N.M.; Brass, L.F.; Lavker, R.M.; Iensen, P.J. Reaction of mast cell proteases tryptase and chymase with protease activated receptors (PARs) on keratinocytes and fibroblasts. J. Cell. Physiol., 1998, 176, 365-373.
155. [155] Molino, M.; Blanchard, N.; Belmonte, E.; Tarver, A.P.; Abrams, C.; Hoxie, J.A.; Cerletti, C.; Brass, L.F. Proteolysis of the human platelet and endothelial cell thrombin receptor by neutrophilderived cathepsin G. J. Biol. Chem., 1995, 270, 11168-11175.
156. [156] Paing, M.M.; Johnston, C.A.; Siderovski, D.P.; Trejo, J. Clathrin adaptor AP2 regulates thrombin receptor constitutive internalization and endothelial cell resensitization. Mol. Cell. Biol., 2006, 26, 3231-3242.
157. [157] Alberelli, M.A.; De Candia, E. Functional role of protease activated receptors in vascular biology. Vascul. Pharmacol., 2014.
158. [158] Lee, H.; Hamilton, J.R. Physiology, pharmacology, and therapeutic potential of protease-activated receptors in vascular disease. Pharmacol. Ther., 2012, 134, 246-259.
159. [159] Shpacovitch, V.; Feld, M.; Bunnett, N.W.; Steinhoff, M. Proteaseactivated receptors: novel PARtners in innate immunity. Trends Immunol., 2007, 28, 541-550.
160. [160] Zlokovic, B.V.; Griffin, J.H. Cytoprotective protein C pathways and implications for stroke and neurological disorders. Trends Neurosci., 2011, 34, 198-209.
161. [161] Maggio, N.; Cavaliere, C.; Papa, M.; Blatt, I.; Chapman, J.; Segal, M. Thrombin regulation of synaptic transmission: Implications for seizure onset. Neurobiol. Dis., 2013, 50, 171-178.
162. [162] Landis, R.C. Protease activated receptors: clinical relevance to hemostasis and inflammation. Hematol. Oncol. Clin. North Am., 2007, 21, 103-113.
163. [163] Sokolova, E.; Reiser, G. A novel therapeutic target in various lung diseases: Airway proteases and protease-activated receptors. Pharmacol. Ther., 2007, 115, 70-83.
164. [164] Chambers, R.C. Procoagulant signalling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention? Br. J. Pharmacol., 2008, 153, S367-S378.
165. [165] Kobrinsky, B.; Karpatkin, S. The role of thrombin in tumor biology. In Thrombin: Physiology and Disease. Maragoudakis, M.E.; Tsopanoglou, N.E., Eds.; Springer: New York, 2009, pp 161-172.
166. [166] Salah, Z.; Grisaru-Granovsky, S.; Maoz, M.; Uziely, B.; Cohen, I.; Turn, H.; Perezt, T.; Bar-Shavit, R. The role of thrombin and its receptors in epithelial malignancies: Lessons from a transgenic mouse model and transcriptional regulation. In Thrombin: Physiology and Disease. Maragoudakis, M.E.; Tsopanoglou, N.E., Eds.; Springer: New York, 2009, pp 173-188.
167. [167] Gudmundsdóttir, I.J.; Lang, N.N.; Boon, N.A.; Ludlam, C.A.; Webb, D.J.; Fox, K.A.; Newby, D.E. Role of the endothelium in the vascular effects of the thrombin receptor (protease-activated receptor type 1) in humans. J. Am. Coll. Cardiol., 2008, 51, 1749-1756.
168. [168] Kahn, M.L.; Zheng, Y.W.; Huang, W.; Bigornia, V.; Zeng, D.; Moff, S.; Farese, R.V., Jr.; Tam, C.; Coughlin, S.R. A dual thrombin receptor system for platelet activation. Nature, 1998, 394, 690-694.
169. [169] Covic, L.; Gresser, A.L.; Kuliopulos, A. Biphasic kinetics of activation and signaling for PAR1 and PAR4 thrombin receptors in platelets. Biochemistry, 2000, 39, 5458-5467.
170. [170] White, H.D. Oral antiplatelet therapy for atherothrombotic disease: Current evidence and new directions. Am. Heart J., 2011, 161, 450-461.
171. [171] Van de Werf, F. Thrombin receptor antagonists may become an important antiplatelet therapy for coronary artery disease. Eur. Heart J., 2010, 31, 2575-2576.
172. [172] Bassand, J.-P. Current antithrombotic agents for acute coronary syndromes: focus on bleeding risk. Int. J. Cardiol., 2013, 163, 5-18.
173. [173] Costopoulos, C.; Niespialowska-Steuden, M.; Kukreja, N.; Gorog, D.A. Novel oral anticoagulants in acute coronary syndrome. Int. J. Cardiol., 2013, 167, 2449-2455.
174. [174] Mizuno, O.; Hirano, K.; Nishimura, J.; Kubo, C.; Kanaide, H. Mechanism of endothelium-dependent relaxation induced by thrombin in the pig coronary artery. Eur. J. Pharmacol., 1998, 351, 67-77.
175. [175] Hamilton, J.R.; Nguyen, P.B.; Cocks, T.M. Atypical proteaseactivated receptor mediates endothelium-dependent relaxation of human coronary arteries. Circ. Res., 1998, 82, 1306-1311.
176. [176] Derkach, D.N.; Ihara, E.; Hirano, K.; Nishimura, J.; Takahashi, S.; Kanaide, H. Thrombin causes endothelium-dependent biphasic regulation of vascular tone in the porcine renal interlobar artery. Br. J. Pharmacol., 2000, 131, 1635-1642.
177. [177] Malik, A.B.; Fenton, J.W., 2nd Thrombin-mediated increase in vascular endothelial permeability. Semin. Thromb. Hemost., 1992, 18, 193-199.
178. [178] Nobe, K.; Sone, T.; Paul, R.J.; Honda, K. Thrombin-induced force development in vascular endothelial cells: Contribution to alteration of permeability mediated by calcium-dependent and-independent pathways. J. Pharmacol. Sci, 2005, 99, 252-263.
179. [179] Garcia, J.G.N.; Patterson, C.; Bahler, C.; Aschner, J.; Hart, C.M.; English, D. Thrombin receptor activating peptides induce calcium mobilization, barrier dysfunction, prostaglandin synthesis, and platelet-derived growth factor mRNA expression in cultured endothelium. J. Cell. Physiol., 1993, 156, 541-549.
180. [180] Coughlin, S.R. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemost., 2005, 3, 1800-1814.
181. [181] Cleator, J.H.; Zhu, W.Q.; Vaughan, D.E.; Hamm, H.E. Differential regulation of endothelial exocytosis of P-selectin and von Willebrand factor by protease-activated receptors and cAMP. Blood, 2006, 107, 2736-2744.
182. [182] Hirano, K. The roles of proteinase-activated receptors in the vascular physiology and pathophysiology. Arterioscler. Thromb. Vasc. Biol., 2007, 27, 27-36.
183. [183] De Garavilla, L.; Vergnolle, N.; Young, S.H.; Ennes, H.; Steinhoff, M.; Ossovskaya, V.S.; D'Andrea, M.R.; Mayer, E.A.; Wallace, J.L.; Hollenberg, M.D.; Andrade-Gordon, P.; Bunnett, N.W. Agonists of proteinase-activated receptor 1 induce plasma extravasation by a neurogenic mechanism. Br. J. Pharmacol., 2001, 133, 975-987.
184. [184] Sugama, Y.; Malik, A.B. Thrombin receptor 14-amino acid peptide mediates endothelial hyperadhesivity and neutrophil adhesion by Pselectin-dependent mechanism. Circ. Res., 1992, 71, 1015-1019.
185. [185] Minami, T.; Miura, M.; Aird, W.C.; Kodama, T. Thrombin-induced autoinhibitory factor, Down Syndrome critical region-1, attenuates NFAT-dependent vascular cell adhesion molecule-1 expression and inflammation in the endothelium. J. Biol. Chem., 2006, 281, 20503-20520.
186. [186] Connolly, A.J.; Ishihara, H.; Kahn, M.L.; Farese, R.V., Jr.; Coughlin, S.R. Role of the thrombin receptor in development and evidence for a second receptor. Nature, 1996, 381, 516-519.
187. [187] Griffin, C.T.; Srinivasan, Y.; Zheng, Y.-W.; Huang, W.; Coughlin, S.R. A role for thrombin receptor signaling in endothelial cells during embryonic development. Science, 2001, 293, 1666-1670.
188. [188] Moser, M.; Patterson, C. The role of thrombin in vascular development. In Thrombin: Physiology and Disease. Maragoudakis, M.E.; Tsopanoglou, N.E., Eds.; Springer: New York, 2009, pp 81-92.
189. [189] Smadja, D.M.; Laurendeau, I.; Avignon, C.; Vidaud, M.; Aiach, M.; Gaussem, P. The angiopoietin pathway is modulated by PAR-1 activation on human endothelial progenitor cells. J. Thromb. Haemost., 2006, 4, 2051-2058.
190. [190] Tsopanoglou, N.E.; Pipili-Synetos, E.; Maragoudakis, M.E. Thrombin promotes angiogenesis by a mechanism independent of fibrin formation. Am. J. Physiol., 1993, 264, C1302-C1307.
191. [191] Tsopanoglou, N.E.; Maragoudakis, M.E. The role of thrombin in angiogenesis. In Thrombin: Physiology and Disease. Maragoudakis, M.E.; Tsopanoglou, N.E., Eds.; Springer: New York, 2009, pp 93-113.
192. [192] Nelken, N.A.; Soifer, S.J.; O'Keefe, J.; Vu, T.K.; Charo, I.F.; Coughlin, S.R. Thrombin receptor expression in normal and atherosclerotic human arteries. J. Clin. Invest., 1992, 90, 1614-1621.
193. [193] Damiano, B.P.; D'Andra, M.R.; De Garavilla, L.; Cheung, W.-M.; Andrade-Gordon, P. Increased expression of protease activated receptor-2 (PAR-2) in balloon-injured rat carotid artery. Thromb. Haemostasis, 1999, 81, 808-814.
194. [194] Ku, D.D.; Dai, J. Expression of thrombin receptors in human atherosclerotic coronary arteries leads to an exaggerated vasoconstrictory response in vitro. J. Cardiovasc. Pharmacol., 1997, 30, 649-657.
195. [195] Capers, Q.I.V.; Laursen, J.B.; Fukui, T.; Rajagopalan, S.; Mori, I.; Lou, P.; Freeman, B.A.; Berrington, W.R.; Griendling, K.K.; Vascular thrombin receptor regulation in hypertensive rats. Circ. Res., 1997, 80, 838-844.
196. [196] Wilcox, J.N.; Rodriguez, J.; Subramanian, R.; Ollerenshaw, J.; Zhong, C.; Hayzer, D.J.; Horaist, C.; Hanson, S.R.; Lumsden, A.; et, a. Characterization of thrombin receptor expression during vascular lesion formation. Circ. Res., 1994, 75, 1029-1038.
197. [197] Cheung, W.-m.; D'Andrea, M.R.; Andrade-Gordon, P.; Damiano, B.P. Altered vascular injury responses in mice deficient in protease-activated receptor-1. Arterioscler. Thromb. Vasc. Biol., 1999, 19, 3014-3024.
198. [198] Sabri, A.; Muske, G.; Zhang, H.; Pak, E.; Darrow, A.; Andrade-Gordon, P.; Steinberg, S.F. Signaling properties and functions of two distinct cardiomyocyte protease-activated receptors. Circ. Res., 2000, 86, 1054-1061.
199. [199] Snead, A.N.; Insel, P.A. Defining the cellular repertoire of GPCRs identifies a profibrotic role for the most highly expressed receptor, protease-activated receptor 1, in cardiac fibroblasts. FASEB J., 2012, 26, 4540-4547, 4510.1096/fj.4512-213496.
200. [200] Moshal, K.S.; Tyagi, N.; Moss, V.; Henderson, B.; Steed, M.; Ovechkin, A.; Aru, G.M.; Tyagi, S.C. Early induction of matrix metalloproteinase-9 transduces signaling in human heart end stage failure. J. Cell. Mol. Med., 2005, 9, 704-713.
201. [201] Moshal, K.S.; Tyagi, N.; Henderson, B.; Ovechkin, A.V.; Tyagi, S.C. Protease-activated receptor and endothelial-myocyte uncoupling in chronic heart failure. Am. J. Physiol., 2005, 288, H2770-2777.
202. [202] Glembotski, C.C.; Irons, C.E.; Krown, K.A.; Murray, S.F.; Sprenkle, A.B.; Sei, C.A. Myocardial α-thrombin receptor activation induces hypertrophy and increases atrial natriuretic factor gene expression. J. Biol. Chem., 1993, 268, 20646-20652.
203. [203] Yasutake, M.; Haworth, R.S.; King, A.; Avkiran, M. Thrombin activates the sarcolemmal Na+-H+ exchanger. Evidence for a receptor-mediated mechanism involving protein kinase C. Circ. Res., 1996, 79, 705-715.
204. [204] Pinet, C.; Algalarrondo, V.; Sablayrolles, S.; Le Grand, B.; Pignier, C.; Cussac, D.; Perez, M.; Hatem, S.N.; Coulombe, A. Proteaseactivated receptor-1 mediates thrombin-induced persistent sodium current in human cardiomyocytes. Mol. Pharmacol., 2008, 73, 1622-1631.
205. [205] Sonin, D.L.; Wakatsuki, T.; Routhu, K.V.; Harmann, L.M.; Petersen, M.; Meyer, J.; Strande, J.L. Protease-activated receptor I inhibition by SCH79797 attenuates left ventricular remodeling and profibrotic activities of cardiac fibroblasts. J. Cardiovasc. Pharmacol. Ther., 2013, 18, 460-475.
206. [206] Shpacovitch, V.; Feld, M.; Hollenberg, M.D.; Luger, T.A.; Steinhoff, M. Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity. J. Leukocyte Biol., 2008, 83, 1309-1322.
207. [207] Vergnolle, N.; Cellars, L.; Mencarelli, A.; Rizzo, G.; Swaminathan, S.; Beck, P.; Steinhoff, M.; Andrade-Gordon, P.; Bunnett, N.W.; Hollenberg, M.D.; Wallace, J.L.; Cirino, G.; Fiorucci, S. A role for proteinase-activated receptor-1 in inflammatory bowel diseases. J. Clin. Invest., 2004, 114, 1444-1456.
208. [208] Cenac, N.; Cellars, L.; Steinhoff, M.; Andrade-Gordon, P.; Hollenberg, M.D.; Wallace, J.L.; Fiorucci, S.; Vergnolle, N. Proteinaseactivated receptor-1 is an anti-inflammatory signal for colitis mediated by a type 2 immune response. Inflamm. Bowel Dis., 2005, 11, 792-798.
209. [209] Moore, L.J.; Moore, F.A.; Todd, S.R.; Jones, S.L.; Turner, K.L.; Bass, B.L. Sepsis in general surgery: the 2005-2007 national surgical quality improvement program perspective. Arch. Surg., 2010, 145, 695-700.
210. [210] Rittirsch, D.; Flierl, M.A.; Ward, P.A. Harmful molecular mechanisms in sepsis. Nat. Rev. Immunol., 2008, 8, 776-787.
211. [211] Kerschen, E.J.; Fernández, J.A.; Cooley, B.C.; Yang, X.V.; Sood, R.; Mosnier, L.O.; Castellino, F.J.; Mackman, N.; Griffin, J.H.; Weiler, H. Endotoxemia and sepsis mortality reduction by nonanticoagulant-activated protein C. J. Exp. Med., 2007, 204, 2439-2448.
212. [212] Tressel, S.L.; Kaneider, N.C.; Kasuda, S.; Foley, C.; Koukos, G.; Austin, K.; Agarwal, A.; Covic, L.; Opal, S.M.; Kuliopulos, A. A matrix metalloprotease-PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis. EMBO Mol. Med., 2011, 3, 370-384.
213. [213] Vergnolle, N. Clinical relevance of proteinase activated receptors (PARS) in the gut. Gut, 2005, 54, 867-874.
214. [214] Buresi, M.C.; Vergnolle, N.; Sharkey, K.A.; Keenan, C.M.; Andrade-Gordon, P.; Cirino, G.; Cirillo, D.; Hollenberg, M.D.; MacNaughton, W.K. Activation of proteinase-activated receptor-1 inhibits neurally evoked chloride secretion in the mouse colon in vitro. Am. J. Physiol. Gastrointest. Liver Physiol., 2005, 288, G337-G345.
215. [215] Chin, A.C.; Vergnolle, N.; MacNaughton, W.K.; Wallace, J.L.; Hollenberg, M.D.; Buret, A.G. Proteinase-activated receptor 1 activation induces epithelial apoptosis and increases intestinal permeability. Proc. Natl. Acad. Sci. U. S. A., 2003, 100, 11104-11109.
216. [216] Kawabata, A.; Kuroda, R.; Nagata, N.; Kawao, N.; Masuko, T.; Nishikawa, H.; Kawai, K. In vivo evidence that protease-activated receptors 1 and 2 modulate gastrointestinal transit in the mouse. Br. J. Pharmacol., 2001, 133, 1213-1218.
217. [217] Saifeddine, M.; Al-Ani, B.; Cheng, C.-H.; Wang, L.; Hollenberg, M.D. Rat proteinase-activated receptor-2 (PAR-2): cDNA sequence and activity of receptor-derived peptides in gastric and vascular tissue. Br. J. Pharmacol., 1996, 118, 521-530.
218. [218] Mule, F.; Baffi, M.C.; Cerra, M.C. Dual effect mediated by protease-activated receptors on the mechanical activity of rat colon. Br. J. Pharmacol., 2002, 136, 367-374.
219. [219] Mule, F.; Baffi, M.C.; Falzone, M.; Cerra, M.C. Signal transduction pathways involved in the mechanical responses to proteaseactivated receptors in rat colon. J. Pharmacol. Exp. Ther., 2002, 303, 1265-1272.
220. [220] Wee, J.L.K.; Chionh, Y.-T.; Ng, G.Z.; Harbour, S.N.; Allison, C.; Pagel, C.N.; Mackie, E.J.; Mitchell, H.M.; Ferrero, R.L.; Sutton, P. Protease-activated receptor-1 down-regulates the murine inflammatory and humoral response to Helicobacter pylori. Gastroenterology, 2010, 138, 573-582.
221. [221] Vergnolle, N. Modulation of visceral pain and inflammation by protease-activated receptors. Br. J. Pharmacol., 2004, 141, 1264-1274.
222. [222] Martin, L.; Auge, C.; Boue, J.; Buresi, M.C.; Chapman, K.; Asfaha, S.; Andrade-Gordon, P.; Steinhoff, M.; Cenac, N.; Dietrich, G.; Vergnolle, N. Thrombin receptor: An endogenous inhibitor of inflammatory pain, activating opioid pathways. Pain, 2009, 146, 121-129.
223. [223] Vera, P.L.; Wolfe, T.E.; Braley, A.E.; Meyer-Siegler, K.L. Thrombin induces macrophage migration inhibitory factor release and upregulation in urothelium: a possible contribution to bladder inflammation. PLoS One, 2010, 5, e15904.
224. [224] Sakai, T.; Nambu, T.; Katoh, M.; Uehara, S.; Fukuroda, T.; Nishikibe, M. Up-regulation of protease-activated receptor-1 in diabetic glomerulosclerosis. Biochem. Biophys. Res. Commun., 2009, 384, 173-179.
225. [225] Idell, S. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit. Care Med., 2003, 31, S213-S220.
226. [226] Chambers, R.C.; Dabbagh, K.; McAnulty, R.J.; Gray, A.J.; Blanc-Brude, O.P.; Laurent, G.J. Thrombin stimulates fibroblast procollagen production via proteolytic activation of protease-activated receptor 1. Biochem. J., 1998, 333, 121-127.
227. [227] Chambers, R.C.; Leoni, P.; Blanc-Brude, O.P.; Wembridge, D.E.; Laurent, G.J. Thrombin is a potent inducer of connective tissue growth factor production via proteolytic activation of proteaseactivated receptor-1. J. Biol. Chem., 2000, 275, 35584-35591.
228. [228] Blanc-Brude, O.P.; Chambers, R.C.; Leoni, P.; Dik, W.A.; Laurent, G.J. Factor Xa is a fibroblast mitogen via binding to effector-cell protease receptor-1 and autocrine release of PDGF. Am. J. Physiol. Cell Physiol., 2001, 281, C681-C689.
229. [229] Trejo, J.; Connolly, A.J.; Coughlin, S.R. The cloned thrombin receptor is necessary and sufficient for activation of mitogenactivated protein kinase and mitogenesis in mouse lung fibroblasts. Loss of responses in fibroblasts from receptor knockout mice. J. Biol. Chem., 1996, 271, 21536-21541.
230. [230] Bogatkevich, G.S.; Tourkina, E.; Silver, R.M.; Ludwicka-Bradley, A. Thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via the proteolytically activated receptor-1 and a protein kinase C-dependent pathway. J. Biol. Chem., 2001, 276, 45184-45192.
231. [231] Hauck, R.W.; Schulz, C.; Schomig, A.; Hoffman, R.K.; Panettieri, R.A., Jr. α-Thrombin stimulates contraction of human bronchial rings by activation of protease-activated receptors. Am. J. Physiol., 1999, 277, L22-L29.
232. [232] Lan, R.S.; Stewart, G.A.; Henry, P.J. Modulation of airway smooth muscle tone by protease activated receptor-1,-2,-3 and-4 in trachea isolated from influenza A virus-infected mice. Br. J. Pharmacol., 2000, 129, 63-70.
233. [233] Lan, R.S.; Knight, D.A.; Stewart, G.A.; Henry, P.J. Role of PGE2 in protease-activated receptor-1,-2 and-4 mediated relaxation in the mouse isolated trachea. Br. J. Pharmacol., 2001, 132, 93-100.
234. [234] Wang, Y.; Gu, Y.; Lucas, M.J. Expression of thrombin receptors in endothelial cells and neutrophils from normal and preeclamptic pregnancies. J. Clin. Endocrinol. Metab., 2002, 87, 3728-3734.
235. [235] Bolton, S.J.; McNulty, C.A.; Thomas, R.J.; Hewitt, C.R.A.; Wardlaw, A.J. Expression of and functional responses to proteaseactivated receptors on human eosinophils. J. Leukocyte Biol., 2003, 74, 60-68.
236. [236] Feistritzer, C.; Mosheimer, B.A.; Kaneider, N.C.; Riewald, M.; Patsch, J.R.; Wiedermann, C.J. Thrombin Affects Eosinophil Migration via Protease-Activated Receptor-1. Int. Arch. Allergy Immunol., 2004, 135, 12-16.
237. [237] Colognato, R.; Slupsky, J.R.; Jendrach, M.; Burysek, L.; Syrovets, T.; Simmet, T. Differential expression and regulation of proteaseactivated receptors in human peripheral monocytes and monocytederived antigen-presenting cells. Blood, 2003, 102, 2645-2652.
238. [238] Mitchell, J.W.; Baik, N.; Castellino, F.J.; Miles, L.A. Plasminogen inhibits TNFα-induced apoptosis in monocytes. Blood, 2006, 107, 4383-4390.
239. [239] Lippuner, N.; Morell, B.; Schaffner, A.; Schaer, D.J. Proteinaseactivated receptors induce nonoxidative, antimicrobial peptides and increased antimicrobial activity in human mononuclear phagocytes. J. Leukocyte Biol., 2006, 81, 465-473.
240. [240] Roche, N.; Stirling, R.G.; Lim, S.; Oliver, B.G.; Oates, T.; Jazrawi, E.; Caramori, G.; Chung, K.F. Effect of acute and chronic inflammatory stimuli on expression of protease-activated receptors 1 and 2 alveolar macrophages. J. Allergy Clin. Immunol., 2003, 111, 367-373.
241. [241] Raza, S.L.; Nehring, L.C.; Shapiro, S.D.; Cornelius, L.A. Proteinase-activated receptor-1 regulation of macrophage elastase (MMP-12) secretion by serine proteinases. J. Biol. Chem., 2000, 275, 41243-41250.
242. [242] Kallis, Y.N.; Scotton, C.J.; MacKinnon, A.C.; Goldin, R.D.; Wright, N.A.; Iredale, J.P.; Chambers, R.C.; Forbes, S.J. Proteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: a role for bone marrow derived macrophages. PLoS One, 2014, 9, e86241/86241-e86241/86247, 86247 pp.
243. [243] Tordai, A.; Fenton, J.W., II; Andersen, T.; Gelfand, E.W. Functional thrombin receptors on human T lymphoblastoid cells. J. Immunol., 1993, 150, 4876-4886.
244. [244] Mari, B.; Imbert, V.; Belhacene, N.; Far, D.F.; Peyron, J.F.; Pouyssegur, J.; Van Obberghen-Schilling, E.; Rossi, B.; Auberger, P. Thrombin and thrombin receptor agonist peptide induce early events of T cell activation and synergize with TCR crosslinking for CD69 expression and interleukin 2 production. J. Biol. Chem., 1994, 269, 8517-8523.
245. [245] Bar-Shavit, R.; Maoz, M.; Yin, Y.; Groysman, M.; Dekel, I.; Katzav, S. Signalling pathways induced by protease-activated receptors and integrins in T cells. Immunology, 2002, 105, 35-46.
246. [246] Li, T.; He, S. Induction of IL-6 release from human T cells by PAR-1 and PAR-2 agonists. Immunol. Cell Biol., 2006, 84, 461-466.
247. [247] Yanagita, M.; Kobayashi, R.; Kashiwagi, Y.; Shimabukuro, Y.; Murakami, S. Thrombin regulates the function of human blood dendritic cells. Biochem. Biophys. Res. Commun., 2007, 364, 318-324.
248. [248] Moormann, C.; Artuc, M.; Pohl, E.; Varga, G.; Buddenkotte, J.; Vergnolle, N.; Brehler, R.; Henz, B.M.; Schneider, S.W.; Luger, T.A.; Steinhoff, M. Functional characterization and expression analysis of the proteinase-activated receptor-2 in human cutaneous mast cells. J. Invest. Dermatol., 2006, 126, 746-755.
249. [249] Gordon, J.R.; Zhang, X.; Stevenson, K.; Cosford, K. Thrombin Induces IL-6 but Not TNFα Secretion by Mouse Mast Cells: Threshold-Level Thrombin Receptor and Very Low Level FcεRI Signaling Synergistically Enhance IL-6 Secretion. Cell. Immunol., 2000, 205, 128-135.
250. [250] Vliagoftis, H. Thrombin induces mast cell adhesion to fibronectin: evidence for involvement of protease-activated receptor-1. J. Immunol., 2002, 169, 4551-4558.
251. [251] Zhang, H.; Yang, H.; Ma, W.; He, S. Induction of IL-13 production and upregulated expression of protease activated receptor-1 by RANTES in a mast cell line. Cytokine, 2011, 53, 231-238.
252. [252] Rohani, M.G.; DiJulio, D.H.; An, J.Y.; Hacker, B.M.; Dale, B.A.; Chung, W.O. PAR1-and PAR2-induced innate immune markers are negatively regulated by PI3K/Akt signaling pathway in oral keratinocytes. BMC Immunol., 2010, 11, 53.
253. [253] Rana, T.; Misra, S.; Mittal, M.K.; Farrow, A.L.; Wilson, K.T.; Linton, M.F.; Fazio, S.; Willis, I.M.; Chaudhuri, G. Mechanism of down-regulation of RNA polymerase III-transcribed non-coding RNA genes in macrophages by Leishmania. J. Biol. Chem., 2011, 286, 6614-6626.
254. [254] Lan, R.S.; Stewart, G.A.; Goldie, R.G.; Henry, P.J. Altered expression and in vivo lung function of protease-activated receptors during influenza A virus infection in mice. Am. J. Physiol. Lung Cell Mol. Physiol., 2004, 286, L388-L398.
255. [255] Khoufache, K.; Berri, F.; Nacken, W.; Vogel, A.B.; Delenne, M.; Camerer, E.; Coughlin, S.R.; Carmeliet, P.; Lina, B.; Rimmelzwaan, G.F.; Planz, O.; Ludwig, S.; Riteau, B. PAR1 contributes to influenza A virus pathogenicity in mice. J. Clin. Invest., 2013, 123, 206-214.
256. [256] Niclou, S.P.; Suidan, H.S.; Pavlik, A.; Vejsada, R.; Monard, D. Changes in the expression of protease-activated receptor 1 and protease nexin-1 mRNA during rat nervous system development and after nerve lesion. Eur. J. Neurosci., 1998, 10, 1590-1607.
257. [257] Striggow, F.; Riek-Burchardt, M.; Kiesel, A.; Schmidt, W.; Henrich-Noack, P.; Breder, J.; Krug, M.; Reymann, K.G.; Reiser, G. Four different types of protease-activated receptors are widely expressed in the brain and are up-regulated in hippocampus by severe ischemia. Eur. J. Neurosci., 2001, 14, 595-608.
258. [258] Ubl, J.J.; Vohringer, C.; Reiser, G. Co-existence of two types of [Ca2+]i-inducing protease-activated receptors (PAR-1 and PAR-2) in rat astrocytes and C6 glioma cells. Neuroscience, 1998, 86, 597-609.
259. [259] Suo, Z.; Wu, M.; Ameenuddin, S.; Anderson, H.E.; Zoloty, J.E.; Citron, B.A.; Andrade-Gordon, P.; Festoff, B.W. Participation of protease-activated receptor-1 in thrombin-induced microglial activation. J. Neurochem., 2002, 80, 655-666.
260. [260] Wang, H.; Ubl, J.J.; Reiser, G. Four subtypes of protease-activated receptors, co-expressed in rat astrocytes, evoke different physiological signaling. Glia, 2002, 37, 53-63.
261. [261] Wang, Y.; Richter-Landsberg, C.; Reiser, G. Expression of protease-activated receptors (PARs) in OLN-93 oligodendroglial cells and mechanism of PAR-1-induced calcium signaling. Neuroscience, 2004, 126, 69-82.
262. [262] Henrich-Noack, P.; Riek-Burchardt, M.; Baldauf, K.; Reiser, G.; Reymann, K.G. Focal ischemia induces expression of proteaseactivated receptor1 (PAR1) and PAR3 on microglia and enhances PAR4 labeling in the penumbra. Brain Res., 2006, 1070, 232-241.
263. [263] Jalink, K.; van Corven, E.J.; Hengeveld, T.; Morii, N.; Narumiya, S.; Moolenaar, W.H. Inhibition of lysophosphatidate-and thrombin-induced neurite retraction and neuronal cell rounding by ADP ribosylation of the small GTP-binding protein Rho. J. Cell Biol., 1994, 126, 801-810.
264. [264] Mahajan, V.B.; Pai, K.S.; Lau, A.; Cunningham, D.D. Creatine kinase, an ATP-generating enzyme, is required for thrombin receptor signaling to the cytoskeleton. Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 12062-12067.
265. [265] Pai, K.S.; Mahajan, V.B.; Lau, A.; Cunningham, D.D. Thrombin receptor signaling to cytoskeleton requires Hsp90. J. Biol. Chem., 2001, 276, 32642-32647.
266. [266] Liu, Y.; Fields, R.D.; Festoff, B.W.; Nelson, P.G. Proteolytic action of thrombin is required for electrical activity-dependent synapse reduction. Proc. Natl. Acad. Sci. U. S. A., 1994, 91, 10300-10304.
267. [267] Lanuza, M.A.; Garcia, N.; Gonzalez, C.M.; Santafe, M.M.; Nelson, P.G.; Tomas, J. Role and expression of thrombin receptor PAR-1 in muscle cells and neuromuscular junctions during the synapse elimination period in the neonatal rat. J. Neurosci. Res., 2003, 73, 10-21.
268. [268] Almonte, A.G.; Qadri, L.H.; Sultan, F.A.; Watson, J.A.; Mount, D.J.; Rumbaugh, G.; Sweatt, J.D. Protease-activated receptor-1 modulates hippocampal memory formation and synaptic plasticity. J. Neurochem., 2013, 124, 109-122.
269. [269] Han, K.-S.; Woo, J.; Park, H.; Yoon, B.-J.; Choi, S.; Lee, C.J. Channel-mediated astrocytic glutamate release via Bestrophin-1 targets synaptic NMDARs. Mol. Brain, 2013, 6, 4.
270. [270] Almonte, A.G.; Hamill, C.E.; Chhatwal, J.P.; Wingo, T.S.; Barber, J.A.; Lyuboslavsky, P.N.; Sweatt, J.D.; Ressler, K.J.; White, D.A.; Traynelis, S.F. Learning and memory deficits in mice lacking protease activated receptor-1. Neurobiol. Learn. Mem., 2007, 88, 295-304.
271. [271] Maggio, N.; Itsekson, Z.; Ikenberg, B.; Strehl, A.; Vlachos, A.; Blatt, I.; Tanne, D.; Chapman, J. The anticoagulant activated protein C (aPC) promotes metaplasticity in the hippocampus through an EPCR-PAR1-S1P1 receptors dependent mechanism. Hippocampus, 2014, 24, 1030-1038.
272. [272] Han, K.-S.; Mannaioni, G.; Hamill, C.E.; Lee, J.; Junge, C.E.; Lee, C.J.; Traynelis, S.F. Activation of protease-activated receptor 1 increases the excitability of the dentate granule neurons of hippocampus. Mol. Brain, 2011, 4, 32.
273. [273] Wang, Y.; Luo, W.; Stricker, R.; Reiser, G. Protease-activated receptor-1 protects rat astrocytes from apoptotic cell death via JNK-mediated release of the chemokine GRO/CINC-1. J. Neurochem., 2006, 98, 1046-1060.
274. [274] Wang, Y.; Luo, W.; Reiser, G. Proteinase-activated receptor-1 and-2 induce the release of chemokine GRO/CINC-1 from rat astrocytes via differential activation of JNK isoforms, evoking multiple protective pathways in brain. Biochem. J., 2007, 401, 65-78.
275. [275] Wang, Y.; Luo, W.; Reiser, G. Activation of protease-activated receptors in astrocytes evokes a novel neuroprotective pathway through release of chemokines of the growth-regulated oncogene/ cytokine-induced neutrophil chemoattractant family. Eur. J. Neurosci., 2007, 26, 3159-3168.
276. [276] Junge, C.E.; Sugawara, T.; Mannaioni, G.; Alagarsamy, S.; Conn, P.J.; Brat, D.J.; Chan, P.H.; Traynelis, S.F. The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia. Proc. Natl. Acad. Sci. U. S. A., 2003, 100, 13019-13024.
277. [277] Donovan, F.M.; Pike, C.J.; Cotman, C.W.; Cunningham, D.D. Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities. J. Neurosci., 1997, 17, 5316-5326.
278. [278] Donovan, F.M.; Cunningham, D.D. Signaling pathways involved in thrombin-induced cell protection. J. Biol. Chem., 1998, 273, 12746-12752.
279. [279] Xue, M.; Hollenberg, M.D.; Yong, V.W. Combination of thrombin and matrix metalloproteinase-9 exacerbates neurotoxicity in cell culture and intracerebral hemorrhage in mice. J. Neurosci., 2006, 26, 10281-10291.
280. [280] Svedin, P.; Hagberg, H.; Saevman, K.; Zhu, C.; Mallard, C. Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia. J. Neurosci., 2007, 27, 1511-1518.
281. [281] Heneka, M.T.; O'Banion, M.K. Inflammatory processes in Alzheimer's disease. J. Neuroimmunol., 2007, 184, 69-91.
282. [282] Arai, T.; Miklossy, J.; Klegeris, A.; Guo, J.-P.; McGeer, P.L. Thrombin and prothrombin are expressed by neurons and glial cells and accumulate in neurofibrillary tangles in alzheimer disease brain. J. Neuropathol. Exp. Neurol., 2006, 65, 19-25.
283. [283] Grammas, P.; Samany, P.G.; Thirumangalakudi, L. Thrombin and inflammatory proteins are elevated in Alzheimer's disease microvessels: implications for disease pathogenesis. J. Alzheimers Dis., 2006, 9, 51-58.
284. [284] Suo, Z.; Wu, M.; Citron, B.A.; Palazzo, R.E.; Festoff, B.W. Rapid Tau Aggregation and Delayed Hippocampal Neuronal Death Induced by Persistent Thrombin Signaling. J. Biol. Chem., 2003, 278, 37681-37689.
285. [285] Pike, C.J.; Vaughan, P.J.; Cunningham, D.D.; Cotman, C.W. Thrombin attenuates neuronal cell death and modulates astrocyte reactivity induced by β-amyloid in vitro. J. Neurochem., 1996, 66, 1374-1382.
286. [286] Thirumangalakudi, L.; Samany, P.G.; Owoso, A.; Wiskar, B.; Grammas, P. Angiogenic proteins are expressed by brain blood vessels in Alzheimer's disease. J. Alzheimers Dis., 2006, 10, 111-118.
287. [287] Ishida, Y.; Nagai, A.; Kobayashi, S.; Kim, S.U. Upregulation of protease-activated receptor-1 astrocytes in Parkinson disease: astrocyte-mediated neuroprotection through increased levels of glutathione peroxidase. J. Neuropathol. Exp. Neurol., 2006, 65, 66-77.
288. [288] Hamill, C.E.; Caudle, W.M.; Richardson, J.R.; Yuan, H.; Pennell, K.D.; Greene, J.G.; Miller, G.W.; Traynelis, S.F. Exacerbation of dopaminergic terminal damage in a mouse model of Parkinson's disease by the G-protein-coupled receptor protease-activated receptor 1. Mol. Pharmacol., 2007, 72, 653-664.
289. [289] Lee, E.-J.; Woo, M.-S.; Moon, P.-G.; Baek, M.-C.; Choi, I.-Y.; Kim, W.-K.; Junn, E.; Kim, H.-S. α-Synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1. J. Immunol., 2010, 185, 615-623.
290. [290] Cannon, J.R.; Keep, R.F.; Schallert, T.; Hua, Y.; Richardson, R.J.; Xi, G. Protease-activated receptor-1 mediates protection elicited by thrombin preconditioning in a rat 6-hydroxydopamine model of Parkinson's disease. Brain Res., 2006, 1116, 177-186.
291. [291] Paterson, P.Y.; Koh, C.S.; Kwaan, H.C. Role of the clotting system in the pathogenesis of neuroimmunologic disease. Fed. Proc., 1987, 46, 91-96.
292. [292] Lyman, G.H.; Khorana, A.A.; Kuderer, N.M.; Lee, A.Y. Cancer and thrombosis: back to the future renewed interest in an old problem. Cancer Invest., 2009, 27, 472-473.
293. [293] Trousseau, A. Phlegmasia alba dolens. In Lectures on Clinical Medicine, Delivered at the Hotel-Dieu, Paris; New Sydenham Society: London, 1865; Vol. 5, pp 281-332.
294. [294] Shen, V.S.; Pollak, E.W. Fatal pulmonary embolism in cancer patients: is heparin prophylaxis justified? South Med. J., 1980, 73, 841-843.
295. [295] Svendsen, E.; Karwinski, B. Prevalence of pulmonary embolism at necropsy in patients with cancer. J. Clin. Pathol., 1989, 42, 805-809.
296. [296] Rickles, F.R.; Edwards, R.L. Activation of blood coagulation in cancer: Trousseau's syndrome revisited. Blood, 1983, 62, 14-31.
297. [297] Petralia, G.A.; Kakkar, A.K. Anti-thrombotic therapy in cancer patients. In Thrombin: Physiology and Disease. Maragoudakis, M.E.; Tsopanoglou, N.E., Eds.; Springer: New York, 2009, pp 189-203.
298. [298] Prandoni, P.; Lensing, A.W.; Buller, H.R.; Cogo, A.; Prins, M.H.; Cattelan, A.M.; Cuppini, S.; Noventa, F.; ten Cate, J.W. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N. Engl. J. Med., 1992, 327, 1128-1133.
299. [299] Sørensen, H.T.; Mellemkjaer, L.; Olsen, J.H.; Baron, J.A. Prognosis of cancers associated with venous thromboembolism. N. Engl. J. Med., 2000, 343, 1846-1850.
300. [300] Kakkar, A.K. An expanding role for antithrombotic therapy in cancer patients. Cancer Treat. Rev., 2003, 29 Suppl 2, 23-26.
301. [301] Gronostaj, K.; Richter, P.; Nowak, W.; Undas, A. Altered plasma fibrin clot properties in patients with digestive tract cancers: Links with the increased thrombin generation. Thromb. Res., 2013, 131, 262-267.
302. [302] Nierodzik, M.L.; Karpatkin, S. Thrombin induces tumor growth, metastasis, and angiogenesis: Evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell, 2006, 10, 355-362.
303. [303] Zacharski, L.R.; Henderson, W.G.; Rickles, F.R.; Forman, W.B.; Cornell, C.J., Jr.; Forcier, R.J.; Edwards, R.L.; Headley, E.; Kim, S.H.; O'Donnell, J.F., et al. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study #75. Cancer, 1984, 53, 2046-2052.
304. [304] Lebeau, B.; Chastang, C.; Brechot, J.M.; Capron, F.; Dautzenberg, B.; Delaisements, C.; Mornet, M.; Brun, J.; Hurdebourcq, J.P.; Lemarie, E. Subcutaneous heparin treatment increases survival in small cell lung cancer. Petites Cellules Group. Cancer, 1994, 74, 38-45.
305. [305] Altinbas, M.; Coskun, H.S.; Er, O.; Ozkan, M.; Eser, B.; Unal, A.; Cetin, M.; Soyuer, S. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J. Thromb. Haemost., 2004, 2, 1266-1271.
306. [306] Kakkar, A.K.; Levine, M.N.; Kadziola, Z.; Lemoine, N.R.; Low, V.; Patel, H.K.; Rustin, G.; Thomas, M.; Quigley, M.; Williamson, R.C. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J. Clin. Oncol., 2004, 22, 1944-1948.
307. [307] Klerk, C.P.; Smorenburg, S.M.; Otten, H.M.; Lensing, A.W.; Prins, M.H.; Piovella, F.; Prandoni, P.; Bos, M.M.; Richel, D.J.; van Tienhoven, G.; Buller, H.R. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J. Clin. Oncol., 2005, 23, 2130-2135.
308. [308] Lee, A.Y.; Rickles, F.R.; Julian, J.A.; Gent, M.; Baker, R.I.; Bowden, C.; Kakkar, A.K.; Prins, M.; Levine, M.N. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J. Clin. Oncol., 2005, 23, 2123-2129.
309. [309] Leshchenko Iu, M.; Miasoiedov, D.V.; Oliinichenko, H.P.; Koshel, K.V.; Iatsenko, S.M. The effect of low-molecular-weight heparin on the late follow-up results of the combined and complex treatment of patients with rectal cancer. Klin. Khir, 2007, 21-24.
310. [310] Bobek, V.; Boubelik, M.; Fiserova, A.; L'Uptovcova, M.; Vannucci, L.; Kacprzak, G.; Kolodzej, J.; Majewski, A.M.; Hoffman, R.M. Anticoagulant drugs increase natural killer cell activity in lung cancer. Lung Cancer, 2005, 47, 215-223.
311. [311] Battinelli, E.M.; Markens, B.A.; Kulenthirarajan, R.A.; Machlus, K.R.; Flaumenhaft, R.; Italiano, J.E., Jr. Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response. Blood, 2014, 123, 101-112.
312. [312] Garnier, D.; Magnus, N.; D'Asti, E.; Hashemi, M.; Meehan, B.; Milsom, C.; Rak, J. Genetic pathways linking hemostasis and cancer. Thromb. Res., 2012, 129, S22-S29.
313. [313] Kakkar, A.K.; DeRuvo, N.; Chinswangwatanakul, V.; Tebbutt, S.; Williamson, R.C. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor. Lancet, 1995, 346, 1004-1005.
314. [314] Zhang, Y.; Deng, Y.; Luther, T.; Mueller, M.; Ziegler, R.; Waldherr, R.; Stern, D.M.; Nawroth, P.P. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J. Clin. Invest., 1994, 94, 1320-1327.
315. [315] Borensztajn, K.S.; Spek, C.A. Protease-activated receptors, apoptosis and tumor growth. Pathophysiol. Haemost. Thromb., 2008, 36, 137-147.
316. [316] Tellez, C.; Bar-Eli, M. Role and regulation of the thrombin receptor (PAR-1) in human melanoma. Oncogene, 2003, 22, 3130-3137.
317. [317] Granovsky-Grisaru, S.; Zaidoun, S.; Grisaru, D.; Yekel, Y.; Prus, D.; Beller, U.; Bar-Shavit, R. The pattern of Protease Activated Receptor 1 (PAR1) expression in endometrial carcinoma. Gynecol. Oncol., 2006, 103, 802-806.
318. [318] Even-Ram, S.; Uziely, B.; Cohen, P.; Grisaru-Granovsky, S.; Maoz, M.; Ginzburg, Y.; Reich, R.; Vlodavsky, I.; Bar-Shavit, R. Thrombin receptor overexpression in malignant and physiological invasion processes. Nat. Med., 1998, 4, 909-914.
319. [319] Salah, Z.; Uziely, B.; Jaber, M.; Maoz, M.; Cohen, I.; Hamburger, T.; Maly, B.; Peretz, T.; Bar-Shavit, R. Regulation of human protease-activated receptor 1 (hPar1) gene expression in breast cancer by estrogen. FASEB J., 2012, 26, 2031-2042.
320. [320] Yuan, T.C.; Lin, M.F. Protease-activated receptor 1: a role in prostate cancer metastasis. Clin. Prostate Cancer, 2004, 3, 189-191.
321. [321] Black, P.C.; Mize, G.J.; Karlin, P.; Greenberg, D.L.; Hawley, S.J.; True, L.D.; Vessella, R.L.; Takayama, T.K. Overexpression of protease-activated receptors-1,-2, and-4 (PAR-1,-2, and-4) in prostate cancer. Prostate, 2007, 67, 743-756.
322. [322] Zhang, X.; Wang, W.; True, L.D.; Vessella, R.L.; Takayama, T.K. Protease-activated receptor-1 is upregulated in reactive stroma of primary prostate cancer and bone metastasis. Prostate, 2009, 69, 727-736.
323. [323] Rudroff, C.; Seibold, S.; Kaufmann, R.; Zetina, C.C.; Reise, K.; Schafer, U.; Schneider, A.; Brockmann, M.; Scheele, J.; Neugebauer, E.A. Expression of the thrombin receptor PAR-1 correlates with tumour cell differentiation of pancreatic adenocarcinoma in vitro. Clin. Exp. Metastasis, 2002, 19, 181-189.
324. [324] Grisaru-Granovsky, S.; Salah, Z.; Maoz, M.; Pruss, D.; Beller, U.; Bar-Shavit, R. Differential expression of protease activated receptor 1 (Par1) and pY397FAK in benign and malignant human ovarian tissue samples. Int. J. Cancer, 2005, 113, 372-378.
325. [325] Darmoul, D.; Gratio, V.; Devaud, H.; Lehy, T.; Laburthe, M. Aberrant expression and activation of the thrombin receptor proteaseactivated receptor-1 induces cell proliferation and motility in human colon cancer cells. Am. J. Pathol., 2003, 162, 1503-1513.
326. [326] Zhang, X.; Hunt, J.L.; Landsittel, D.P.; Muller, S.; Adler-Storthz, K.; Ferris, R.L.; Shin, D.M.; Chen, Z.G. Correlation of proteaseactivated receptor-1 with differentiation markers in squamous cell carcinoma of the head and neck and its implication in lymph node metastasis. Clin. Cancer Res., 2004, 10, 8451-8459.
327. [327] Veiga, C.d.S.B.; Carneiro-Lobo, T.C.; Coelho, C.J.B.P.; Carvalho, S.M.F.; Maia, R.C.; Vasconcelos, F.C.; Abdelhay, E.; Mencalha, A.L.; Ferreira, A.F.; Castro, F.A.; Monteiro, R.Q. Increased expression of protease-activated receptor 1 (PAR-1) in human leukemias. Blood Cells, Mol., Dis., 2011, 46, 230-234.
328. [328] Diaz, J.; Aranda, E.; Henriquez, S.; Quezada, M.; Espinoza, E.; Bravo, M.L.; Oliva, B.; Lange, S.; Villalon, M.; Jones, M.; Brosens, J.J.; Kato, S.; Cuello, M.A.; Knutson, T.P.; Lange, C.A.; Leyton, L.; Owen, G.I. Progesterone promotes focal adhesion formation and migration in breast cancer cells through induction of protease-activated receptor-1. J. Endocrinol., 2012, 214, 165-175.
329. [329] Chu, H.-W.; Cheng, C.-W.; Chou, W.-C.; Hu, L.-Y.; Wang, H.-W.; Hsiung, C.-N.; Hsu, H.-M.; Wu, P.-E.; Hou, M.-F.; Shen, C.-Y.; Yu, J.-C. A novel estrogen receptor-microRNA 190a-PAR-1-pathway regulates breast cancer progression, a finding initially suggested by genome-wide analysis of loci associated with lymphnode metastasis. Hum. Mol. Genet., 2014, 23, 355-367.
330. [330] Jin, E.; Fujiwara, M.; Pan, X.; Ghazizadeh, M.; Arai, S.; Ohaki, Y.; Kajiwara, K.; Takemura, T.; Kawanami, O. Protease-activated receptor (PAR)-1 and PAR-2 participate in the cell growth of alveolar capillary endothelium in primary lung adenocarcinomas. Cancer, 2003, 97, 703-713.
331. [331] Ghio, P.; Cappia, S.; Selvaggi, G.; Novello, S.; Lausi, P.; Zecchina, G.; Papotti, M.; Borasio, P.; Scagliotti, G.V. Prognostic role of protease-activated receptors 1 and 4 in resected stage IB non-smallcell lung cancer. Clin. Lung Cancer, 2006, 7, 395-400.
332. [332] D'Andrea, M.R.; Derian, C.K.; Santulli, R.J.; Andrade-Gordon, P. Differential expression of protease-activated receptors-1 and-2 in stromal fibroblasts of normal, benign, and malignant human tissues. Am. J. Pathol., 2001, 158, 2031-2041.
333. [333] Eroglu, A.; Karabiyik, A.; Akar, N. The association of protease activated receptor 1 gene-506 I/D polymorphism with disease-free survival in breast cancer patients. Ann. Surg. Oncol., 2012, 19, 1365-1369.
334. [334] Lurje, G.; Leers, J.M.; Pohl, A.; Oezcelik, A.; Zhang, W.; Ayazi, S.; Winder, T.; Ning, Y.; Yang, D.; Klipfel, N.E.; Chandrasoma, P.; Hagen, J.A.; DeMeester, S.R.; DeMeester, T.R.; Lenz, H.-J. Genetic variations in angiogenesis pathway genes predict tumor recurrence in localized adenocarcinoma of the esophagus. Ann. Surg. Oncol., 2010, 251, 857-864.
335. [335] Lurje, G.; Husain, H.; Power, D.G.; Yang, D.; Groshen, S.; Pohl, A.; Zhang, W.; Ning, Y.; Manegold, P.C.; El-Khoueiry, A.; Iqbal, S.; Tang, L.H.; Shah, M.A.; Lenz, H.J. Genetic variations in angiogenesis pathway genes associated with clinical outcome in localized gastric adenocarcinoma. Ann. Oncol., 2010, 21, 78-86.
336. [336] Martin, C.B.; Mahon, G.M.; Klinger, M.B.; Kay, R.J.; Symons, M.; Der, C.J.; Whitehead, I.P. The thrombin receptor, PAR-1, causes transformation by activation of Rho-mediated signaling pathways. Oncogene, 2001, 20, 1953-1963.
337. [337] Wu, Z.; Zeng, Y.; Zhong, M.; Wang, B. Targeting A549 lung adenocarcinoma cell growth and invasion with protease-activated receptor-1 siRNA. Mol. Med. Rep., 2014, 9, 1787-1793.
338. [338] Salah, Z.; Maoz, M.; Pokroy, E.; Lotem, M.; Bar-Shavit, R.; Uziely, B. Protease-activated receptor-1 (hPar1), a survival factor eliciting tumor progression. Mol. Cancer Res., 2007, 5, 229-240.
339. [339] Villares, G.J.; Zigler, M.; Wang, H.; Melnikova, V.O.; Wu, H.; Friedman, R.; Leslie, M.C.; Vivas-Mejia, P.E.; López-Berestein, G.; Sood, A.K.; Bar-Eli, M. Targeting melanoma growth and metastasis with systemic delivery of liposome-incorporated proteaseactivated receptor-1 small interfering RNA. Cancer Res., 2008, 68, 9078-9086.
340. [340] Kepner, N.; Lipton, A. A mitogenic factor for transformed fibroblasts from human platelets. Cancer Res., 1981, 41, 430-432.
341. [341] Möhle, R.; Green, D.; Moore, M.A.; Nachman, R.L.; Rafii, S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc. Natl. Acad. Sci. U S A, 1997, 94, 663-668.
342. [342] Li, J.J.; Huang, Y.Q.; Basch, R.; Karpatkin, S. Thrombin induces the release of angiopoietin-1 from platelets. Thromb. Haemost., 2001, 85, 204-206.
343. [343] Boucharaba, A.; Serre, C.-M.; Gres, S.; Saulnier-Blache, J.S.; Bordet, J.-C.; Guglielmi, J.; Clezardin, P.; Peyruchaud, O. Plateletderived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J. Clin. Invest., 2004, 114, 1714-1725.
344. [344] Nieswandt, B.; Hafner, M.; Echtenacher, B.; Mannel, D.N. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res., 1999, 59, 1295-1300.
345. [345] Melnikova, V.O.; Villares, G.J.; Bar-Eli, M. Emerging roles of PAR-1 and PAFR in melanoma metastasis. Cancer Microenviron., 2008, 1, 103-111.
346. [346] Beaulieu, L.M.; Church, F.C. Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1. Exp. Cell. Res., 2007, 313, 677-687.
347. [347] Keshava, S.; Kothari, H.; Rao, L.V.M.; Pendurthi, U.R. Influence of endothelial cell protein C receptor on breast cancer development. J. Thromb. Haemostasis, 2013, 11, 2062-2065.
348. [348] Suzuki, K.; Hayashi, T. Protein C and its inhibitor in malignancy. Semin. Thromb. Hemostasis, 2007, 33, 667-672.
349. [349] Agarwal, A.; Covic, L.; Sevigny, L.M.; Kaneider, N.C.; Lazarides, K.; Azabdaftari, G.; Sharifi, S.; Kuliopulos, A. Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer. Mol. Cancer Ther., 2008, 7, 2746-2757.
350. [350] Page-McCaw, A.; Ewald, A.J.; Werb, Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat. Rev. Mol. Cell Biol., 2007, 8, 221-233.
351. [351] Ala-aho, R.; Kahari, V.M. Collagenases in cancer. Biochimie, 2005, 87, 273-286.
352. [352] Sang, Q.X. Complex role of matrix metalloproteinases in angiogenesis. Cell Res., 1998, 8, 171-177.
353. [353] Blackburn, J.S.; Rhodes, C.H.; Coon, C.I.; Brinckerhoff, C.E. RNA interference inhibition of matrix metalloproteinase-1 prevents melanoma metastasis by reducing tumor collagenase activity and angiogenesis. Cancer Res., 2007, 67, 10849-10858.
354. [354] Nguyen, N.; Kuliopulos, A.; Graham, R.A.; Covic, L. Tumorderived Cyr61(CCN1) promotes stromal matrix metalloproteinase-1 production and protease-activated receptor 1-dependent migration of breast cancer cells. Cancer Res., 2006, 66, 2658-2665.
355. [355] Radjabi, A.R.; Sawada, K.; Jagadeeswaran, S.; Eichbichler, A.; Kenny, H.A.; Montag, A.; Bruno, K.; Lengyel, E. Thrombin Induces Tumor Invasion through the Induction and Association of Matrix Metalloproteinase-9 and β1-Integrin on the Cell Surface. J. Biol. Chem., 2008, 283, 2822-2834.
356. [356] Darmoul, D.; Gratio, V.; Devaud, H.; Peiretti, F.; Laburthe, M. Activation of proteinase-activated receptor 1 promotes human colon cancer cell proliferation through epidermal growth factor receptor transactivation. Mol. Cancer Res., 2004, 2, 514-522.
357. [357] Ohshiro, K.; Bui-Nguyen, T.M.; Natha, R.S.D.; Schwartz, A.M.; Levine, P.; Kumar, R. Thrombin stimulation of inflammatory breast cancer cells leads to aggressiveness via the EGFR-PAR1-Pak1 pathway. Int. J. Biol. Markers, 2012, 27, e305-e313.
358. [358] Cohen, I.; Maoz, M.; Turm, H.; Grisaru-Granovsky, S.; Maly, B.; Uziely, B.; Weiss, E.; Abramovitch, R.; Gross, E.; Barzilay, O.; Qiu, Y.; Bar-Shavit, R. Etk/Bmx regulates proteinase-activatedreceptor1 (PAR1) in breast cancer invasion: signaling partners, hierarchy and physiological significance. PLoS One, 2010, 5, e11135.
359. [359] Liu, J.; Schuff-Werner, P.; Steiner, M. Thrombin/thrombin receptor (PAR-1)-mediated induction of IL-8 and VEGF expression in prostate cancer cells. Biochem. Biophys. Res. Commun., 2006, 343, 183-189.
360. [360] Furukawa, Y.; Kawano, Y.; Fukuda, J.; Matsumoto, H.; Narahara, H. The production of vascular endothelial growth factor and metalloproteinase via protease-activated receptor in human endometrial stromal cells. Fertil. Steril., 2009, 91, 535-541.
361. [361] Yin, Y.J.; Katz, V.; Salah, Z.; Maoz, M.; Cohen, I.; Uziely, B.; Turm, H.; Grisaru-Granovsky, S.; Suzuki, H.; Bar-Shavit, R. Mammary gland tissue targeted overexpression of human proteaseactivated receptor 1 reveals a novel link to beta-catenin stabilization. Cancer Res., 2006, 66, 5224-5233.
362. [362] Grisaru-Granovsky, S.; Maoz, M.; Barzilay, O.; Yin, Y.J.; Prus, D.; Bar-Shavit, R. Protease activated receptor-1, PAR1, promotes placenta trophoblast invasion and beta-catenin stabilization. J. Cell Physiol., 2009, 218, 512-521.
363. [363] Salah, Z.; Maoz, M.; Cohen, I.; Pizov, G.; Pode, D.; Runge, M.S.; Bar-Shavit, R. Identification of a novel functional androgen response element within hPar1 promoter: implications to prostate cancer progression. FASEB J., 2005, 19, 62-72.
364. [364] Salah, Z.; Maoz, M.; Pizov, G.; Bar-Shavit, R. Transcriptional regulation of human protease-activated receptor 1: a role for the early growth response-1 protein in prostate cancer. Cancer Res., 2007, 67, 9835-9843.
365. [365] Salah, Z.; Haupt, S.; Maoz, M.; Baraz, L.; Rotter, V.; Peretz, T.; Haupt, Y.; Bar-Shavit, R. p53 controls hPar1 function and expression. Oncogene, 2008, 27, 6866-6874.
366. [366] Caunt, M.; Huang, Y.Q.; Brooks, P.C.; Karpatkin, S. Thrombin induces neoangiogenesis in the chick chorioallantoic membrane. J. Thromb. Haemost., 2003, 1, 2097-2102.
367. [367] Tsopanoglou, N.E.; Maragoudakis, M.E. On the mechanism of thrombin-induced angiogenesis. Potentiation of vascular endothelial growth factor activity on endothelial cells by up-regulation of its receptors. J. Biol. Chem., 1999, 274, 23969-23976.
368. [368] Huang, Y.Q.; Li, J.J.; Hu, L.; Lee, M.; Karpatkin, S. Thrombin induces increased expression and secretion of angiopoietin-2 from human umbilical vein endothelial cells. Blood, 2002, 99, 1646-1650.
369. [369] Caunt, M.; Hu, L.; Tang, T.; Brooks, P.C.; Ibrahim, S.; Karpatkin, S. Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis. Cancer Res., 2006, 66, 4125-4132.
370. [370] Zania, P.; Kritikou, S.; Flordellis, C.S.; Maragoudakis, M.E.; Tsopanoglou, N.E. Blockade of angiogenesis by small molecule antagonists to protease-activated receptor-1: association with endothelial cell growth suppression and induction of apoptosis. J. Pharmacol. Exp. Ther., 2006, 318, 246-254.
371. [371] Zania, P.; Gourni, D.; Aplin, A.C.; Nicosia, R.F.; Flordellis, C.S.; Maragoudakis, M.E.; Tsopanoglou, N.E. Parstatin, the cleaved peptide on proteinase-activated receptor 1 activation, is a potent inhibitor of angiogenesis. J. Pharmacol. Exp. Ther., 2009, 328, 378-389.
372. [372] Huang, H.; Vasilakis, P.; Zhong, X.; Shen, J.-K.; Geronatsiou, K.; Papadaki, H.; Maragoudakis, M.E.; Gartaganis, S.P.; Vinores, S.A.; Tsopanoglou, N.E. Parstatin suppresses ocular neovascularization and inflammation. Invest. Ophthalmol. Vis. Sci., 2010, 51, 5825-5832.
373. [373] Givvimani, S.; Narayanan, N.; Pushpakumar, S.B.; Tyagi, S.C. Anti-parstatin promotes angiogenesis and ameliorates left ventricular dysfunction during pressure overload. Int. J. Biomed. Sci., 2014, 10, 1-7.
374. [374] Vu, T.K.; Wheaton, V.I.; Hung, D.T.; Charo, I.; Coughlin, S.R. Domains specifying thrombin-receptor interaction. Nature, 1991, 353, 674-677.
375. [375] Nieman, M.T.; Schmaier, A.H. Interaction of thrombin with PAR1 and PAR4 at the thrombin cleavage site. Biochemistry, 2007, 46, 8603-8610.
376. [376] Ayala, Y.M.; Cantwell, A.M.; Rose, T.; Bush, L.A.; Arosio, D.; Di Cera, E. Molecular mapping of thrombin-receptor interactions. Proteins, 2001, 45, 107-116.
377. [377] Gandhi, P.S.; Chen, Z.; Di Cera, E. Crystal structure of thrombin bound to the uncleaved extracellular fragment of PAR1. J. Biol. Chem., 2010, 285, 15393-15398.
378. [378] Jacques, S.L.; LeMasurier, M.; Sheridan, P.J.; Seeley, S.K.; Kuliopulos, A. Substrate-assisted catalysis of the PAR1 thrombin receptor. Enhancement of macromolecular association and cleavage. J. Biol. Chem., 2000, 275, 40671-44068.
379. [379] Mathews, II; Padmanabhan, K.P.; Ganesh, V.; Tulinsky, A.; Ishii, M.; Chen, J.; Turck, C.W.; Coughlin, S.R.; Fenton, J.W., 2nd Crystallographic structures of thrombin complexed with thrombin receptor peptides: existence of expected and novel binding modes. Biochemistry, 1994, 33, 3266-3279.
380. [380] Myles, T.; Le Bonniec, B.F.; Stone, S.R. The dual role of thrombin’s anion-binding exosite-I in the recognition and cleavage of the protease-activated receptor 1. Eur. J. Biochem., 2001, 268, 70-77.
381. [381] Gandhi, P.S.; Chen, Z.; Mathews, F.S.; Di Cera, E. Structural identification of the pathway of long-range communication in an allosteric enzyme. Proc. Natl. Acad. Sci. U. S. A., 2008, 105, 1832-1837.
382. [382] Bahou, W.F.; Kutok, J.L.; Wong, A.; Potter, C.L.; Coller, B.S. Identification of a novel thrombin receptor sequence required for activation-dependent responses. Blood, 1994, 84, 4195-4202.
383. [383] 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.
384. [384] Feng, D.M.; Veber, D.F.; Connolly, T.M.; Condra, C.; Tang, M.J.; Nutt, R.F. Development of a potent thrombin receptor ligand. J. Med. Chem., 1995, 38, 4125-4130.
385. [385] Ceruso, M.A.; McComsey, D.F.; Leo, G.C.; Andrade-Gordon, P.; Addo, M.F.; Scarborough, R.M.; Oksenberg, D.; Maryanoff, B.E. Thrombin receptor-activating peptides (TRAPs): investigation of bioactive conformations via structure-activity, spectroscopic, and computational studies. Bioorg. Med. Chem., 1999, 7, 2353-2371.
386. [386] Scarborough, R.M.; Naughton, M.A.; Teng, W.; Hung, D.T.; Rose, J.; Vu, T.K.; Wheaton, V.I.; Turck, C.W.; Coughlin, S.R. Tethered ligand agonist peptides. Structural requirements for thrombin receptor activation reveal mechanism of proteolytic unmasking of agonist function. J. Biol. Chem., 1992, 267, 13146-13149.
387. [387] Chao, B.H.; Kalkunte, S.; Maraganore, J.M.; Stone, S.R. Essential groups in synthetic agonist peptides for activation of the platelet thrombin receptor. Biochemistry, 1992, 31, 6175-6178.
388. [388] Vassallo, R.R., Jr.; Kieber-Emmons, T.; Cichowski, K.; Brass, L.F. Structure-function relationships in the activation of platelet thrombin receptors by receptor-derived peptides. J. Biol. Chem., 1992, 267, 6081-6085.
389. [389] Sabo, T.; Gurwitz, D.; Motola, L.; Brodt, P.; Barak, R.; Elhanaty, E. Structure-activity studies of the thrombin receptor activating peptide. Biochem. Biophys. Res. Commun., 1992, 188, 604-610.
390. [390] Natarajan, S.; Riexinger, D.; Peluso, M.; Seiler, S.M. 'Tethered ligand' derived pentapeptide agonists of thrombin receptor: a study of side chain requirements for human platelet activation and GTPase stimulation. Int. J. Pept. Protein Res., 1995, 45, 145-151.
391. [391] Barry, G.D.; Le, G.T.; Fairlie, D.P. Agonists and antagonists of protease activated receptors (PARs). Curr. Med. Chem., 2006, 13, 243-265.
392. [392] Chackalamannil, S. Thrombin receptor (protease activated receptor-1) antagonists as potent antithrombotic agents with strong antiplatelet effects. J. Med. Chem., 2006, 49, 5389-5403.
393. [393] Maryanoff, B.E.; Zhang, H.C.; Andrade-Gordon, P.; Derian, C.K. Discovery of potent peptide-mimetic antagonists for the human thrombin receptor, protease-activated receptor-1 (PAR-1). Curr. Med. Chem., 2003, 1, 13-36.
394. [394] Bernatowicz, M.S.; Klimas, C.E.; Hartl, K.S.; Peluso, M.; Allegretto, N.J.; Seiler, S.M. Development of potent thrombin receptor antagonist peptides. J. Med. Chem., 1996, 39, 4879-4887.
395. [395] Quinton, T.M.; Kim, S.; Derian, C.K.; Jin, J.; Kunapuli, S.P. Plasmin-mediated activation of platelets occurs by cleavage of protease-activated receptor 4. J. Biol. Chem., 2004, 279, 18434-18439.
396. [396] Kahn, M.L.; Nakanishi-Matsui, M.; Shapiro, M.J.; Ishihara, H.; Coughlin, S.R. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J. Clin. Invest., 1999, 103, 879-887.
397. [397] Zhang, H.C.; Derian, C.K.; Andrade-Gordon, P.; Hoekstra, W.J.; McComsey, D.F.; White, K.B.; Poulter, B.L.; Addo, M.F.; Cheung, W.M.; Damiano, B.P.; Oksenberg, D.; Reynolds, E.E.; Pandey, A.; Scarborough, R.M.; Maryanoff, B.E. Discovery and optimization of a novel series of thrombin receptor (par-1) antagonists: potent, selective peptide mimetics based on indole and indazole templates. J. Med. Chem., 2001, 44, 1021-1024.
398. [398] Derian, C.K.; Maryanoff, B.E.; Andrade-Gordon, P.; Zhang, H.C. Design and evaluation of potent peptide-mimetic PAR-1 antagonists. Drug Dev. Res., 2003, 59, 355-366.
399. [399] Tsopanoglou, N.E.; Maragoudakis, M.E. Inhibition of angiogenesis by small-molecule antagonists of protease-activated receptor-1. Semin. Thromb. Hemost., 2007, 33, 680-687.
400. [400] Valdivielso, A.M.; García-López, M.T.; Herranz, R. Improved synthesis of the PAR-1 thrombin receptor antagonist RWJ-58259. ARKIVOC 2008, 287-294.
401. [401] Damiano, B.P.; Derian, C.K.; Maryanoff, B.E.; Zhang, H.C.; Gordon, P.A. RWJ-58259: a selective antagonist of protease activated receptor-1. Cardiovasc. Drug Rev., 2003, 21, 313-326.
402. [402] Derian, C.K.; Damiano, B.P.; Addo, M.F.; Darrow, A.L.; D'Andrea, M.R.; Nedelman, M.; Zhang, H.C.; Maryanoff, B.E.; Andrade-Gordon, P. Blockade of the thrombin receptor proteaseactivated receptor-1 with a small-molecule antagonist prevents thrombus formation and vascular occlusion in nonhuman primates. J. Pharmacol. Exp. Ther., 2003, 304, 855-861.
403. [403] Severino, B.; Fiorino, F.; Perissutti, E.; Frecentese, F.; Cirino, G.; Roviezzo, F.; Santagada, V.; Caliendo, G. Synthesis and pharmacological evaluation of peptide-mimetic protease-activated receptor-1 antagonists containing novel heterocyclic scaffolds. Bioorg. Med. Chem., 2008, 16, 6009-6020.
404. [404] Androutsou, M.-E.; Saifeddine, M.; Hollenberg, M.D.; Matsoukas, J.; Agelis, G. Design, synthesis and biological evaluation of nonpeptide PAR1 thrombin receptor antagonists based on small bifunctional templates: arginine and phenylalanine side chain groups are keys for receptor activity. Amino Acids, 2010, 38, 985-990.
405. [405] Ventosa-Andrés, P.; Valdivielso, A.M.; Pappos, I.; García-López, M.T.; Tsopanoglou, N.E.; Herranz, R. Design, synthesis and biological evaluation of new peptide-based ureas and thioureas as potential antagonists of the thrombin receptor PAR1. Eur. J. Med. Chem., 2012, 58, 98-111.
406. [406] Valdivielso, A.M.; Ventosa-Andrés, P.; García-López, M.T.; Herranz, R.; Gutiérrez-Rodríguez, M. Synthesis and regioselective functionalization of piperazin-2-ones based on Phe-Gly pseudodipeptides. Eur. J. Org. Chem., 2013, 155-161.
407. [407] Valdivielso, A.M.; Ventosa-Andrés, P.; Tato, F.; Fernández-Ibanez, M.A.; Pappos, I.; Tsopanoglou, N.E.; García-López, M.T.; Gutiérrez-Rodríguez, M.; Herranz, R. Highly functionalized 2-oxopiperazine-based peptidomimetics: An approach to PAR1 antagonists. Eur. J. Med. Chem., 2013, 70, 199-224.
408. [408] Valdivielso, A.M.; García-López, M.T.; Gutiérrez-Rodríguez, M.; Herranz, R. Exploring the Phe-Gly dipeptide-derived piperazinone scaffold in the search for antagonists of the thrombin receptor PAR1. Molecules, 2014, 19, 4814-4846.
409. [409] Kato, Y.; Kita, Y.; Nishio, M.; Hirasawa, Y.; Ito, K.; Yamanaka, T.; Motoyama, Y.; Seki, J. In vitro antiplatelet profile of FR171113, a novel non-peptide thrombin receptor antagonist. Eur. J. Pharmacol., 1999, 384, 197-202.
410. [410] Kato, Y.; Kita, Y.; Hirasawa-Taniyama, Y.; Nishio, M.; Mihara, K.; Ito, K.; Yamanaka, T.; Seki, J.; Miyata, S.; Mutoh, S. Inhibition of arterial thrombosis by a protease-activated receptor 1 antagonist, FR171113, in the guinea pig. Eur. J. Pharmacol., 2003, 473, 163-169.
411. [411] Barrow, J.C.; Nantermet, P.G.; Selnick, H.G.; Glass, K.L.; Ngo, P.L.; Young, M.B.; Pellicore, J.M.; Breslin, M.J.; Hutchinson, J.H.; Freidinger, R.M.; Condra, C.; Karczewski, J.; Bednar, R.A.; Gaul, S.L.; Stern, A.; Gould, R.; Connolly, T.M. Discovery and initial structure-activity relationships of trisubstituted ureas as thrombin receptor (PAR-1) antagonists. Bioorg. Med. Chem. Lett., 2001, 11, 2691-2696.
412. [412] Nantermet, P.G.; Barrow, J.C.; Lundell, G.F.; Pellicore, J.M.; Rittle, K.E.; Young, M.; Freidinger, R.M.; Connolly, T.M.; Condra, C.; Karczewski, J.; Bednar, R.A.; Gaul, S.L.; Gould, R.J.; Prendergast, K.; Selnick, H.G. Discovery of a nonpeptidic small molecule antagonist of the human platelet thrombin receptor (PAR-1). Bioorg. Med. Chem. Lett., 2002, 12, 319-323.
413. [413] Suzuki, S.; Kotake, M.; Miyamoto, M.; Kawahara, T.; Kajiwara, A.; Hishinuma, I.; Okano, K.; Miyazawa, S.; Clark, R.; Ozaki, F.; Sato, N.; Shinoda, M.; Kamada, A.; Tsukada, I.; Matsuura, F.; Naoe, Y.; Terauchi, T.; Oohashi, Y.; Ito, O.; Tanaka, H.; Musya, T.; Kogushi, M.; Kawada, T.; Matsuoka, T.; Kobayashi, H.; Chiba, K.; Kimura, A.; Ono, N. Preparation of 2-iminoimidazole derivatives as thrombin receptor antagonists PCT Int. Appl. WO 2002088092, 2002.
414. [414] Suzuki, S.; Kotake, M.; Miyamoto, M.; Kawahara, T.; Kajiwara, A.; Hishinuma, I.; Okano, K.; Miyazawa, S.; Clark, R.; Ozaki, F. Preparation of 2-iminopyrrolidine derivatives as thrombin receptor antagonists PCT Int. Appl. WO 2002085855, 2002.
415. [415] Suzuki, S.; Kotake, M.; Miyamoto, M.; Kawahara, T.; Kajiwara, A.; Hishinuma, I.; Okano, K.; Miyazawa, S.; Clark, R.; Ozaki, F. Preparation of cyclic amidine derivatives as thrombin receptor antagonists. PCT Int. Appl. WO 2002085850, 2002.
416. [416] Safety and Tolerability of E5555 and Its Effects on Markers of Intravascular Inflammation in Subjects with Coronary Artery Disease. http://clinicaltrials.gov/ct2/show/NCT00312052 (February 21, 2011)
417. [417] Ahn, H.S.; Arik, L.; Boykow, G.; Burnett, D.A.; Caplen, M.A.; Czarniecki, M.; Domalski, M.S.; Foster, C.; Manna, M.; Stamford, A.W.; Wu, Y. Structure-activity relationships of pyrroloquinazolines as thrombin receptor antagonists. Bioorg. Med. Chem. Lett., 1999, 9, 2073-2078.
418. [418] Ahn, H.S.; Foster, C.; Boykow, G.; Stamford, A.; Manna, M.; Graziano, M. Inhibition of cellular action of thrombin by N3-cyclopropyl-7-[[4-(1-methylethyl)phenyl]methyl]-7H-pyrrolo[3, 2-f]quinazoline-1,3-diamine (SCH 79797), a nonpeptide thrombin receptor antagonist. Biochem. Pharmacol, 2000, 60, 1425-1434.
419. [419] Ma, L.; Perini, R.; McKnight, W.; Dicay, M.; Klein, A.; Hollenberg, M.D.; Wallace, J.L. Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets. Proc. Natl. Acad. Sci. U. S. A., 2005, 102, 216-220.
420. [420] Strande, J.L.; Hsu, A.; Su, J.; Fu, X.; Gross, G.J.; Baker, J.E. SCH 79797, a selective PAR1 antagonist, limits myocardial ischemia/ reperfusion injury in rat hearts. Basic Res. Cardiol., 2007, 102, 350-358.
421. [421] Di Serio, C.; Pellerito, S.; Duarte, M.; Massi, D.; Naldini, A.; Cirino, G.; Prudovsky, I.; Santucci, M.; Geppetti, P.; Marchionni, N.; Masotti, G.; Tarantini, F. Protease-activated receptor 1-selective antagonist SCH79797 inhibits cell proliferation and induces apoptosis by a protease-activated receptor 1-independent mechanism. Basic Clin. Pharmacol. Toxicol, 2007, 101, 63-69.
422. [422] Chackalamannil, S.; Xia, Y.; Greenlee, W.J.; Clasby, M.; Doller, D.; Tsai, H.; Asberom, T.; Czarniecki, M.; Ahn, H.S.; Boykow, G.; Foster, C.; Agans-Fantuzzi, J.; Bryant, M.; Lau, J.; Chintala, M. Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents. J. Med. Chem., 2005, 48, 5884-5887.
423. [423] Shinohara, Y.; Goto, S.; Doi, M.; Jensen, P. Safety of the novel protease-activated receptor-1 antagonist vorapaxar in Japanese patients with a history of ischemic stroke. J. Stroke Cerebrovasc. Dis., 2012, 21, 318-324.
424. [424] Morrow, D.A.; Braunwald, E.; Bonaca, M.P.; Ameriso, S.F.; Dalby, A.J.; Fish, M.P.; Fox, K.A.A.; Lipka, L.J.; Liu, X.; Nicolau, J.C.; Oude Ophuis, A.J.; Paolasso, E.; Scirica, B.M.; Spinar, J.; Theroux, P.; Wiviott, S.D.; Strony, J.; Murphy, S.A. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl. J. Med., 2012, 366, 1404-1413.
425. [425] Statkevich, P.; Kosoglou, T.; Preston, R.A.; Kumar, B.; Xuan, F.; Trusley, C.; Schiller, J.E.; Langdon, R.B.; Cutler, D.L. Pharmacokinetics of the novel PAR-1 antagonist vorapaxar in patients with hepatic impairment. Eur. J. Clin. Pharmacol., 2012, 68, 1501-1508.
426. [426] Whellan, D.J.; Tricoci, P.; Chen, E.; Huang, Z.; Leibowitz, D.; Vranckx, P.; Marhefka, G.D.; Held, C.; Nicolau, J.C.; Storey, R.F.; Ruzyllo, W.; Huber, K.; Sinnaeve, P.; Weiss, A.T.; Dery, J.-P.; Moliterno, D.J.; Van de Werf, F.; Aylward, P.E.; White, H.D.; Armstrong, P.W.; Wallentin, L.; Strony, J.; Harrington, R.A.; Mahaffey, K.W. Vorapaxar in Acute Coronary Syndrome Patients Undergoing Coronary Artery Bypass Graft Surgery. J. Am. Coll. Cardiol., 2014, 63, 1048-1057.
427. [427] 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.
428. [428] Chelliah, M.V.; Eagen, K.; Guo, Z.; Chackalamannil, S.; Xia, Y.; Tsai, H.; Greenlee, W.J.; Ahn, H.-S.; Kurowski, S.; Boykow, G.; Hsieh, Y.; Chintala, M. Himbacine-Derived Thrombin Receptor Antagonists: C7-Spirocyclic Analogues of Vorapaxar. ACS Med. Chem. Lett., 2014, 5, 561-565.
429. [429] Kakarala, K.K.; Jamil, K. Screening of phytochemicals against protease activated receptor 1 (PAR1), a promising target for cancer. J. Recept. Signal Transduct. Res., 2014, 1-20.
430. [430] Lee, S.; Song, J.-H.; Park, C.M.; Kim, J.-S.; Jeong, J.-H.; Cho, W.-Y.; Lim, D.-C. Discovery of Octahydroindenes as PAR1 Antagonists. ACS Med. Chem. Lett., 2013, 4, 1054-1058.
431. [431] Rilatt, I.; Mirabel, E.; Le Grand, B.; Perez, M. Discovery and SAR of small molecule PAR1 antagonists. Bioorg. Med. Chem. Lett., 2010, 20, 903-906.
432. [432] Planty, B.; Pujol, C.; Lamothe, M.; Maraval, C.; Horn, C.; Le Grand, B.; Perez, M. Exploration of a new series of PAR1 antagonists. Bioorg. Med. Chem. Lett., 2010, 20, 1735-1739.
433. [433] Perez, M.; Lamothe, M.; Maraval, C.; Mirabel, E.; Loubat, C.; Planty, B.; Horn, C.; Michaux, J.; Marrot, S.; Letienne, R.; Pignier, C.; Bocquet, A.; Nadal-Wollbold, F.; Cussac, D.; de Vries, L.; Le Grand, B. Discovery of Novel Protease Activated Receptors 1 Antagonists with Potent Antithrombotic Activity in vivo. J. Med. Chem., 2009, 52, 5826-5836.
434. [434] Letienne, R.; Leparq-Panissie, A.; Calmettes, Y.; Nadal-Wollbold, F.; Perez, M.; Le Grand, B. Antithrombotic activity of F 16618, a new PAR1 antagonist evaluated in extracorporeal arterio-venous shunt in the rat. Biochem. Pharmacol., 2010, 79, 1616-1621.
435. [435] Chieng-Yane, P.; Bocquet, A.; Letienne, R.; Bourbon, T.; Sablayrolles, S.; Perez, M.; Hatem, S.N.; Lompre, A.-M.; Le Grand, B.; David-Dufilho, M. Protease-activated receptor-1 antagonist F 16618 reduces arterial restenosis by down-regulation of tumor necrosis factor α and matrix metalloproteinase 7 expression, migration, and proliferation of vascular smooth muscle cells. J. Pharmacol. Exp. Ther., 2011, 336, 643-651.
436. [436] Dumas, M.; Nadal-Wollbold, F.; Gaussem, P.; Perez, M.; Mirault, T.; Letienne, R.; Bourbon, T.; Grelac, F.; Le Grand, B.; Bachelot-Loza, C. Antiplatelet and antithrombotic effect of F 16618, a new thrombin proteinase-activated receptor-1 (PAR1) antagonist. Br. J. Pharmacol., 2012, 165, 1827-1835.
437. [437] Asteriti, S.; Daniele, S.; Porchia, F.; Dell'Anno, M.T.; Fazzini, A.; Pugliesi, I.; Trincavelli, M.L.; Taliani, S.; Martini, C.; Mazzoni, M.R.; Gilchrist, A. Modulation of PAR1 signalling by benzimidazole compounds. Br. J. Pharmacol., 2012, 167, 80-94.
438. [438] Zhang, P.; Gruber, A.; Kasuda, S.; Kimmelstiel, C.; O'Callaghan, K.; Cox, D.H.; Bohm, A.; Baleja, J.D.; Covic, L.; Kuliopulos, A. Suppression of Arterial Thrombosis Without Affecting Hemostatic Parameters With a Cell-Penetrating PAR1 Pepducin. Circulation, 2012, 126, 83-91.
439. [439] Tressel, S.L.; Koukos, G.; Tchernychev, B.; Jacques, S.L.; Covic, L.; Kuliopulos, A. Pharmacology, biodistribution, and efficacy of GPCR-based pepducins in disease models. In Methods Mol. Biol. Langel, Ü., Ed.; Springer, 2011; Vol. 683, pp 259-275.
440. [440] Covic, L.; Misra, M.; Badar, J.; Singh, C.; Kuliopulos, A. Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activation. Nat. Med., 2002, 8, 1161-1165.
441. [441] Kostenis, E.; Conklin, B.R.; Wess, J. Molecular basis of receptor/G protein coupling selectivity studied by coexpression of wild type and mutant m2 muscarinic receptors with mutant G alpha(q) subunits. Biochemistry, 1997, 36, 1487-1495.
442. [442] Yang, E.; Boire, A.; Agarwal, A.; Nguyen, N.; O'Callaghan, K.; Tu, P.; Kuliopulos, A.; Covic, L. Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis. Cancer Res., 2009, 69, 6223-6231.
443. [443] Cisowski, J.; O'Callaghan, K.; Kuliopulos, A.; Yang, J.; Nguyen, N.; Deng, Q.; Yang, E.; Fogel, M.; Tressel, S.; Foley, C.; Agarwal, A.; Hunt, S.W.; McMurry, T.; Brinckerhoff, L.; Covic, L. Targeting protease-activated receptor-1 with cell-penetrating pepducins in lung cancer. Am. J. Pathol., 2011, 179, 513-523.