1932

Abstract

Protease-activated receptors (PARs) are a unique class of G protein–coupled receptors (GPCRs) that transduce cellular responses to extracellular proteases. PARs have important functions in the vasculature, inflammation, and cancer and are important drug targets. A unique feature of PARs is their irreversible proteolytic mechanism of activation that results in the generation of a tethered ligand that cannot diffuse away. Despite the fact that GPCRs have proved to be the most successful class of druggable targets, the development of agents that target PARs specifically has been challenging. As a consequence, researchers have taken a remarkable diversity of approaches to develop pharmacological entities that modulate PAR function. Here, we present an overview of the diversity of therapeutic agents that have been developed against PARs. We further discuss PAR biased signaling and the influence of receptor compartmentalization, posttranslational modifications, and dimerization, which are important considerations for drug development.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-011613-140016
2017-01-06
2024-06-18
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/57/1/annurev-pharmtox-011613-140016.html?itemId=/content/journals/10.1146/annurev-pharmtox-011613-140016&mimeType=html&fmt=ahah

Literature Cited

  1. Vu TK, Hung DT, Wheaton VI, Coughlin SR. 1.  1991. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64:1057–68 [Google Scholar]
  2. Nystedt S, Emilsson K, Wahlestedt C, Sundelin J. 2.  1994. Molecular cloning of a potential novel proteinase activated receptor. PNAS 91:9208–12 [Google Scholar]
  3. Ishihara H, Connolly AJ, Zeng D, Kahn ML, Zheng YW. 3.  et al. 1997. Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 386:502–6 [Google Scholar]
  4. Kahn ML, Zheng YW, Huang W, Bigornia V, Zeng D. 4.  et al. 1998. A dual thrombin receptor system for platelet activation. Nature 394:690–94 [Google Scholar]
  5. Xu WF, Andersen H, Whitmore TE, Presnell SR, Yee DP. 5.  et al. 1998. Cloning and characterization of human protease-activated receptor 4. PNAS 95:6642–46 [Google Scholar]
  6. Vu TK, Wheaton VI, Hung DT, Coughlin SR. 6.  1991. Domains specifying thrombin-receptor interaction. Nature 353:674–77 [Google Scholar]
  7. Chen J, Ishii M, Wang L, Ishii K, Coughlin SR. 7.  1994. Thrombin receptor activation: confirmation of the intramolecular tethered liganding hypothesis and discovery of an alternative intermolecular liganding mode. J. Biol. Chem. 269:16041–45 [Google Scholar]
  8. Scarborough RM, Naughton MA, Teng W, Hung DT, Rose J. 8.  et al. 1992. Tethered ligand agonist peptides. Structural requirements for thrombin receptor activation reveal mechanism of proteolytic unmasking of agonist function. J. Biol. Chem. 267:13146–49 [Google Scholar]
  9. Soh UJK, Dores MR, Chen B, Trejo J. 9.  2010. Signal transduction by protease-activated receptors. Br. J. Pharmacol. 160:191–203 [Google Scholar]
  10. Arora P, Ricks TK, Trejo J. 10.  2007. Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer. J. Cell Sci. 120:921–28 [Google Scholar]
  11. DeFea KA, Zalevski J, Thoma MS, Déry O, Mullins RD, Bunnett NW. 11.  2000. β-Arrestin–dependent endocytosis of proteinase-activated receptor-2 is required for intracellular targeting of activated ERK1/2. J. Cell Biol. 148:1267–81 [Google Scholar]
  12. Stalheim L, Ding Y, Gullapalli A, Paing MM, Wolfe BL. 12.  et al. 2005. Multiple independent functions of arrestins in regulation of protease-activated receptor-2 signaling and trafficking. Mol. Pharm. 67:78–87 [Google Scholar]
  13. Grimsey NJ, Aguilar B, Smith TH, Le P, Soohoo AL. 13.  et al. 2015. Ubiquitin plays an atypical role in GPCR-induced p38 MAP kinase activation on endosomes. J. Cell Biol. 210:1117–31 [Google Scholar]
  14. Coughlin SR. 14.  2000. Thrombin signalling and protease-activated receptors. Nature 407:258–64 [Google Scholar]
  15. Coughlin SR. 15.  2005. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemost. 3:1800–14 [Google Scholar]
  16. Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ. 16.  et al. 2012. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl. J. Med. 366:1404–13 [Google Scholar]
  17. French SL, Arthur JF, Tran HA, Hamilton JR. 17.  2015. Approval of the first protease-activated receptor antagonist: rationale, development, significance, and considerations of a novel anti-platelet agent. Blood Rev 29:179–89 [Google Scholar]
  18. Hung DT, Vu TK, Wheaton VI, Ishii K, Coughlin SR. 18.  1992. Cloned platelet thrombin receptor is necessary for thrombin-induced platelet activation. J. Clin. Investig. 89:1350–53 [Google Scholar]
  19. Cook JJ, Sitko GR, Bednar B, Condra C, Mellott MJ. 19.  et al. 1995. An antibody against the exosite of the cloned thrombin receptor inhibits experimental arterial thrombosis in the African green monkey. Circulation 91:2961–71 [Google Scholar]
  20. Brass LF, Vassallo RJ, Belmonte E, Ahuja M, Cichowski K, Hoxie JA. 20.  1992. Structure and function of the human platelet thrombin receptor: studies using monoclonal antibodies directed against a defined domain within the receptor N terminus. J. Biol. Chem. 267:13795–98 [Google Scholar]
  21. Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR. 21.  1999. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J. Clin. Investig. 103:879–87 [Google Scholar]
  22. Bernatowicz MS, Klimas CE, Hartl KS, Peluso M, Allegretto NJ, Seiler SM. 22.  1996. Development of potent thrombin receptor antagonist peptides. J. Med. Chem 39:4879–87 [Google Scholar]
  23. O'Brien PJ, Prevost N, Molino M, Hollinger MK, Woolkalis MJ. 23.  et al. 2000. Thrombin responses in human endothelial cells: Contributions from receptors other than PAR1 include transactivation of PAR2 by thrombin-cleaved PAR1. J. Biol. Chem. 275:13502–9 [Google Scholar]
  24. Kawabata A, Saifeddine M, Al-ani B, Leblond L, Hollenberg MD. 24.  1999. Evaluation of proteinase-activated receptor-1 (PAR1) agonists and antagonists using a cultured cell receptor desensitization assay: activation of PAR2 by PAR1-targeted ligands. J. Pharmacol. Exp. Ther. 288:358–70 [Google Scholar]
  25. Seiler SM, Bernatowicz MS. 25.  2003. Peptide-derived protease-activated receptor-1 (PAR-1) antagonists. Curr. Med. Chem. Cardiovasc. Hematol. Agents 1:1–11 [Google Scholar]
  26. Derian CK, Maryanoff BE, Zhang H-C, Andrade-Gordon P. 26.  2003. Therapeutic potential of protease-activated receptor-1 antagonists. Expert Opin. Investig. Drugs 12:209–21 [Google Scholar]
  27. Kogushi M, Matsuoka T, Kawata T, Kuramochi H, Kawaguchi S. 27.  et al. 2011. The novel and orally active thrombin receptor antagonist E5555 (Atopaxar) inhibits arterial thrombosis without affecting bleeding time in guinea pigs. Eur. J. Pharmacol. 657:131–37 [Google Scholar]
  28. O'Donoghue ML, Bhatt DL, Wiviott SD, Goodman SG, Fitzgerald DJ. 28.  et al. 2011. Safety and tolerability of atopaxar in the treatment of patients with acute coronary syndromes: the lessons from antagonizing the cellular effects of Thrombin-Acute Coronary Syndromes Trial. Circulation 123:1843–53 [Google Scholar]
  29. Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL, Investigators JL. 29.  2010. Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. Eur. Heart J. 31:2601–13 [Google Scholar]
  30. Wiviott SD, Flather MD, O'Donoghue ML, Goto S, Fitzgerald DJ. 30.  et al. 2011. Randomized trial of atopaxar in the treatment of patients with coronary artery disease: the lessons from antagonizing the cellular effect of Thrombin-Coronary Artery Disease Trial. Circulation 123:1854–63 [Google Scholar]
  31. Chackalamannil S, Wang Y, Greenlee WJ, Hu Z, Xia Y. 31.  et al. 2008. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J. Med. Chem 513061–64 [Google Scholar]
  32. Kosoglou T, Reyderman L, Tiessen RG, van Vliet AA, Fales RR. 32.  et al. 2012. Pharmacodynamics and pharmacokinetics of the novel PAR-1 antagonist vorapaxar (formerly SCH 530348) in healthy subjects. Eur. J. Clin. Pharmacol. 68:249–58 [Google Scholar]
  33. Becker RC, Moliterno DJ, Jennings LK, Pieper KS, Pei J. 33.  et al. 2009. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled Phase II study. Lancet 373:919–28 [Google Scholar]
  34. Ghosal A, Lu X, Penner N, Gao L, Ramanathan R. 34.  et al. 2011. Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 530348 (Vorapaxar), a potent oral thrombin protease-activated receptor 1 antagonist. Drug Metab. Dispos. 39:30–38 [Google Scholar]
  35. French SL, Arthur JF, Lee H, Nesbitt WS, Andrews RK. 35.  et al. 2016. Inhibition of protease-activated receptor 4 impairs platelet procoagulant activity during thrombus formation in human blood. J. Thromb. Haemost. 14:1642–54 [Google Scholar]
  36. Ahn HS, Foster C, Boykow G, Stamford A, Manna M, Graziano M. 36.  2000. 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 60:1425–34 [Google Scholar]
  37. Sonin DL, Wakatsuki T, Routhu KV, Harmann LM, Petersen M. 37.  et al. 2013. Protease-activated receptor 1 inhibition by SCH79797 attenuates left ventricular remodeling and profibrotic activities of cardiac fibroblasts. J. Cardiovasc. Pharmacol. Ther. 18:460–75 [Google Scholar]
  38. Yan J, Manaenko A, Chen S, Klebe D, Ma Q. 38.  et al. 2013. Role of SCH79797 in maintaining vascular integrity in rat model of subarachnoid hemorrhage. Stroke 44:1410–17 [Google Scholar]
  39. Létienne R, Leparq-Panissié A, Bocquet A, Calmettes Y, Culié C, Le Grand B. 39.  2010. PAR1 antagonist mediated antithrombotic activity in extracorporeal arterio-venous shunt in the rat. Thromb. Res. 125:257–61 [Google Scholar]
  40. Lee H, Hamilton JR. 40.  2013. The PAR1 antagonist, SCH79797, alters platelet morphology and function independently of PARs. Thromb. Haemost. 109:164–67 [Google Scholar]
  41. Di Serio C, Pellerito S, Duarte M, Massi D, Naldini A. 41.  et al. 2007. 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. 101:63–69 [Google Scholar]
  42. Covic L, Gresser AL, Talavera J, Swift S, Kuliopulos A. 42.  2002. Activation and inhibition of G protein-coupled receptors by cell-penetrating membrane-tethered peptides. PNAS 99:643–48 [Google Scholar]
  43. Covic L, Misra M, Badar J, Singh C, Kuliopulos A. 43.  2002. Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activation. Nat. Med. 8:1161–65 [Google Scholar]
  44. Winther M, Gabl M, Welin A, Dahlgren C, Forsman H. 44.  2015. A neutrophil inhibitory pepducin derived from FPR1 expected to target FPR1 signaling hijacks the closely related FPR2 instead. FEBS Lett 589:1832–39 [Google Scholar]
  45. Quoyer J, Janz JM, Luo J, Ren Y, Armando S. 45.  et al. 2013. Pepducin targeting the C-X-C chemokine receptor type 4 acts as a biased agonist favoring activation of the inhibitory G protein. PNAS 110:E5088–97 [Google Scholar]
  46. Stampfuss JJ, Schrör K, Weber AA. 46.  2003. Inhibition of platelet thromboxane receptor function by a thrombin receptor–targeted pepducin. Nat. Med. 9:1447 [Google Scholar]
  47. O'Callaghan K, Kuliopulos A, Covic L. 47.  2012. Turning receptors on and off with intracellular pepducins: new insights into G-protein-coupled receptor drug development. J. Biol. Chem. 287:12787–96 [Google Scholar]
  48. Gurbel PA, Bliden KP, Turner SE, Tantry US, Gesheff MG. 48.  et al. 2016. Cell-penetrating pepducin therapy targeting PAR1 in subjects with coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 36:189–97 [Google Scholar]
  49. Zhang P, Gruber A, Kasuda S, Kimmelstiel C, O'Callaghan K. 49.  et al. 2012. Suppression of arterial thrombosis without affecting hemostatic parameters with a cell-penetrating PAR1 pepducin. Circulation 126:83–91 [Google Scholar]
  50. Dowal L, Sim DS, Dilks JR, Blair P, Beaudry S. 50.  et al. 2011. Identification of an antithrombotic allosteric modulator that acts through helix 8 of PAR1. PNAS 108:2951–56 [Google Scholar]
  51. Aisiku O, Peters CG, De Ceunynck K, Ghosh CC, Dilks JR. 51.  et al. 2015. Parmodulins inhibit thrombus formation without inducing endothelial injury caused by vorapaxar. Blood 125:1976–85 [Google Scholar]
  52. Ramachandran R, Noorbakhsh F, Defea K, Hollenberg MD. 52.  2012. Targeting proteinase-activated receptors: therapeutic potential and challenges. Nat. Rev. Drug Discov. 11:69–86 [Google Scholar]
  53. Russell FA, McDougall JJ. 53.  2009. Proteinase activated receptor (PAR) involvement in mediating arthritis pain and inflammation. Inflamm. Res. 58:119–26 [Google Scholar]
  54. Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S. 54.  et al. 2000. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat. Med. 6:151–58 [Google Scholar]
  55. Vergnolle N, Bunnett NW, Sharkey KA, Brussee V, Compton SJ. 55.  et al. 2001. Proteinase-activated receptor-2 and hyperalgesia: a novel pain pathway. Nat. Med. 7:821–26 [Google Scholar]
  56. Arizmendi NG, Abel M, Mihara K, Davidson C, Polley D. 56.  et al. 2011. Mucosal allergic sensitization to cockroach allergens is dependent on proteinase activity and proteinase-activated receptor-2 activation. J. Immunol. 186:3164–72 [Google Scholar]
  57. Ferrell WR, Lockhart JC, Kelso EB, Dunning L, Plevin R. 57.  et al. 2003. Essential role for proteinase-activated receptor-2 in arthritis. J. Clin. Investig. 111:35–41 [Google Scholar]
  58. Lohman RJ, Cotterell AJ, Barry GD, Liu L, Suen JY. 58.  et al. 2012. An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats. FASEB J 26:2877–87 [Google Scholar]
  59. Suen JY, Barry GD, Lohman RJ, Halili MA, Cotterell AJ. 59.  et al. 2012. Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110). Br. J. Pharmacol. 165:1413–23 [Google Scholar]
  60. Sevigny LM, Zhang P, Bohm A, Lazarides K, Perides G. 60.  et al. 2011. Interdicting protease-activated receptor-2-driven inflammation with cell-penetrating pepducins. PNAS 108:8491–96 [Google Scholar]
  61. Mumaw MM, de la Fuente M, Noble DN, Nieman MT. 61.  2014. Targeting the anionic region of human protease-activated receptor 4 inhibits platelet aggregation and thrombosis without interfering with hemostasis. J. Thromb. Haemost. 12:1331–41 [Google Scholar]
  62. Mumaw MM, de la Fuente M, Arachiche A, Wahl JK III, Nieman MT. 62.  2015. Development and characterization of monoclonal antibodies against protease activated receptor 4 (PAR4). Thromb. Res. 135:1165–71 [Google Scholar]
  63. Hollenberg MD, Saifeddine M. 63.  2001. Proteinase-activated receptor 4 (PAR4): activation and inhibition of rat platelet aggregation by PAR4-derived peptides. Can. J. Physiol. Pharmacol. 79:439–42 [Google Scholar]
  64. Ma L, Perini R, McKnight W, Dicay M, Klein A. 64.  et al. 2005. Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets. PNAS 102:216–20 [Google Scholar]
  65. Compton SJ, Cairns JA, Palmer KJ, Al-Ani B, Hollenberg MD, Walls AF. 65.  2000. A polymorphic protease-activated receptor 2 (PAR2) displaying reduced sensitivity to trypsin and differential responses to PAR agonists. J. Biol. Chem. 275:39207–12 [Google Scholar]
  66. Carr R III, Koziol-White C, Zhang J, Lam H, An SS. 66.  et al. 2016. Interdicting Gq activation in airway disease by receptor-dependent and receptor-independent mechanisms. Mol. Pharmacol. 89:94–104 [Google Scholar]
  67. Leger AJ, Jacques SL, Badar J, Kaneider NC, Derian CK. 67.  et al. 2006. Blocking the protease-activated receptor 1–4 heterodimer in platelet-mediated thrombosis. Circulation 113:1244–54 [Google Scholar]
  68. Wu CC, Huang SW, Hwang TL, Kuo SC, Lee FY, Teng CM. 68.  2000. YD-3, a novel inhibitor of protease-induced platelet activation. Br. J. Pharmacol. 130:1289–96 [Google Scholar]
  69. Wu CC, Hwang TL, Liao CH, Kuo SC, Lee FY. 69.  et al. 2002. Selective inhibition of protease-activated receptor 4-dependent platelet activation by YD-3. Thromb. Haemost. 87:1026–33 [Google Scholar]
  70. Lee FY, Lien JC, Huang LJ, Huang TM, Tsai SC. 70.  et al. 2001. Synthesis of 1-benzyl-3-(5′-hydroxymethyl-2′-furyl)indazole analogues as novel antiplatelet agents. J. Med. Chem 44:3746–49 [Google Scholar]
  71. Wu CC, Hwang TL, Liao CH, Kuo SC, Lee FY, Teng CM. 71.  2003. The role of PAR4 in thrombin-induced thromboxane production in human platelets. Thromb. Haemost. 90:299–308 [Google Scholar]
  72. Pan SL, Guh JH, Peng CY, Wang SW, Chang YL. 72.  et al. 2005. YC-1 [3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole] inhibits endothelial cell functions induced by angiogenic factors in vitro and angiogenesis in vivo models. J. Pharmacol. Exp. Ther. 314:35–42 [Google Scholar]
  73. Peng CY, Pan SL, Pai HC, Tsai AC, Guh JH. 73.  et al. 2010. The indazole derivative YD-3 specifically inhibits thrombin-induced angiogenesis in vitro and in vivo. Shock 34:580–85 [Google Scholar]
  74. Edelstein LC, Simon LM, Lindsay CR, Kong X, Teruel-Montoya R. 74.  et al. 2014. Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race. Blood 124:3450–58 [Google Scholar]
  75. Hosokawa K, Ohnishi T, Miura N, Sameshima H, Koide T. 75.  et al. 2014. Antithrombotic effects of PAR1 and PAR4 antagonists evaluated under flow and static conditions. Thromb. Res. 133:66–72 [Google Scholar]
  76. Peng CY, Pan SL, Guh JH, Liu YN, Chang YL. 76.  et al. 2004. The indazole derivative YD-3 inhibits thrombin-induced vascular smooth muscle cell proliferation and attenuates intimal thickening after balloon injury. Thromb. Haemost. 92:1232–39 [Google Scholar]
  77. Young SE, Duvernay MT, Schulte ML, Lindsley CW, Hamm HE. 77.  2013. Synthesis of indole derived protease-activated receptor 4 antagonists and characterization in human platelets. PLOS ONE 8:e65528 [Google Scholar]
  78. Wen W, Young SE, Duvernay MT, Schulte ML, Nance KD. 78.  et al. 2014. Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: discovery and SAR of ML354. Bioorg. Med. Chem. Lett 24:4708–13 [Google Scholar]
  79. Friedman EA, Texeira L, Delaney J, Weeke PE, Lynch DR Jr. 79.  et al. 2015. Evaluation of the F2R IVS-14A/T PAR1 polymorphism with subsequent cardiovascular events and bleeding in patients who have undergone percutaneous coronary intervention. J. Thromb. Thrombolysis 41:656–62 [Google Scholar]
  80. Smith SM, Judge HM, Peters G, Armstrong M, Dupont A. 80.  et al. 2005. PAR-1 genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy. Platelets 16:340–45 [Google Scholar]
  81. Patel YM, Lordkipanidze M, Lowe GC, Nisar SP, Garner K. 81.  et al. 2014. A novel mutation in the P2Y12 receptor and a function-reducing polymorphism in protease-activated receptor 1 in a patient with chronic bleeding. J. Thromb. Haemost. 12:716–25 [Google Scholar]
  82. Zhang JH, Wang J, Tang XF, Yao Y, Zhang Y. 82.  et al. 2016. Effect of platelet receptor gene polymorphisms on outcomes in ST-elevation myocardial infarction patients after percutaneous coronary intervention. Platelets 27:75–79 [Google Scholar]
  83. Yun CM, Sang XY. 83.  2015. Role of proteinase-activated receptor-1 gene polymorphisms in susceptibility to chronic obstructive pulmonary disease. Genet. Mol. Res. 14:13215–20 [Google Scholar]
  84. de Martino M, Haitel A, Schatzl G, Klatte T. 84.  2013. The protease activated receptor 1 gene variation IVSn –14 A>T is associated with distant metastasis and cancer specific survival in renal cell carcinoma. J. Urol. 190:1392–97 [Google Scholar]
  85. Arnaud E, Nicaud V, Poirier O, Rendu F, Alhenc-Gelas M. 85.  et al. 2000. Protective effect of a thrombin receptor (protease-activated receptor 1) gene polymorphism toward venous thromboembolism. Arterioscler. Thromb. Vasc. Biol. 20:585–92 [Google Scholar]
  86. Lurje G, Husain H, Power DG, Yang D, Groshen S. 86.  et al. 2010. Genetic variations in angiogenesis pathway genes associated with clinical outcome in localized gastric adenocarcinoma. Ann. Oncol. 21:78–86 [Google Scholar]
  87. Lurje G, Leers JM, Pohl A, Oezcelik A, Zhang W. 87.  et al. 2010. Genetic variations in angiogenesis pathway genes predict tumor recurrence in localized adenocarcinoma of the esophagus. Ann. Surg. 251:857–64 [Google Scholar]
  88. Eroglu A, Karabiyik A, Akar N. 88.  2012. The association of protease activated receptor 1 gene –506 I/D polymorphism with disease-free survival in breast cancer patients. Ann. Surg. Oncol. 19:1365–69 [Google Scholar]
  89. Grisaru-Granovsky S, Tevet A, Bar-Shavit R, Salah Z, Elstein D. 89.  et al. 2007. Association study of protease activated receptor 1 gene polymorphisms and adverse pregnancy outcomes: results of a pilot study in Israel. Am. J. Med. Genet. A 143A:2557–63 [Google Scholar]
  90. Grisaru-Granovsky S, Salah Z, Maoz M, Tevet A, Margalioth E. 90.  et al. 2015. Protease-activated-receptor 1 polymorphisms correlate with risk for unexplained recurrent pregnancy loss: a pilot study querying an association beyond coagulation. Eur. J. Obstet. Gynecol. Reprod. Biol. 185:13–18 [Google Scholar]
  91. Ma JN, Burstein ES. 91.  2013. The protease activated receptor 2 (PAR2) polymorphic variant F240S constitutively activates PAR2 receptors and potentiates responses to small-molecule PAR2 agonists. J. Pharmacol. Exp. Ther. 347:697–704 [Google Scholar]
  92. Lee JH, Kim KW, Gee HY, Lee J, Lee KH. 92.  et al. 2011. A synonymous variation in protease-activated receptor-2 is associated with atopy in Korean children. J. Allergy Clin. Immunol. 128:1326–34e3 [Google Scholar]
  93. Tourdot BE, Conaway S, Niisuke K, Edelstein LC, Bray PF, Holinstat M. 93.  2014. Mechanism of race-dependent platelet activation through the protease-activated receptor-4 and Gq signaling axis. Arterioscler. Thromb. Vasc. Biol. 34:2644–50 [Google Scholar]
  94. Edelstein LC, Simon LM, Montoya RT, Holinstat M, Chen ES. 94.  et al. 2013. Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Nat. Med. 19:1609–16 [Google Scholar]
  95. Li JZ, Absher DM, Tang H, Southwick AM, Casto AM. 95.  et al. 2008. Worldwide human relationships inferred from genome-wide patterns of variation. Science 319:1100–4 [Google Scholar]
  96. Mosnier LO, Sinha RK, Burnier L, Bouwens EA, Griffin JH. 96.  2012. Biased agonism of protease-activated receptor 1 by activated protein C caused by noncanonical cleavage at Arg46. Blood 120:5237–46 [Google Scholar]
  97. Soh UJK, Trejo J. 97.  2011. Activated protein C promotes protease-activated receptor-1 cytoprotective signaling through β-arrestin and dishevelled-2 scaffolds. PNAS 108:E1372–80 [Google Scholar]
  98. Russo A, Soh UJK, Paing MM, Arora P, Trejo J. 98.  2009. Caveolae are required for protease-selective signaling by protease-activated receptor-1. PNAS 106:6393–97 [Google Scholar]
  99. Bae JS, Yang L, Rezaie AR. 99.  2007. Receptors of the protein C activation and activated protein C signaling pathways are colocalized in lipid rafts of endothelial cells. PNAS 104:2867–72 [Google Scholar]
  100. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF. 100.  et al. 2001. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 344:699–709 [Google Scholar]
  101. Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS. 101.  et al. 2012. Drotrecogin alfa (activated) in adults with septic shock. N. Engl. J. Med. 366:2055–64 [Google Scholar]
  102. Griffin JH, Zlokovic BV, Mosnier LO. 102.  2015. Activated protein C: biased for translation. Blood 125:2898–907 [Google Scholar]
  103. Kerschen EJ, Fernandez JA, Cooley BC, Yang XV, Sood R. 103.  et al. 2007. Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J. Exp. Med. 204:2439–48 [Google Scholar]
  104. Mosnier LO, Zampolli A, Kerschen EJ, Schuepbach RA, Banerjee Y. 104.  et al. 2009. Hyperantithrombotic, noncytoprotective Glu149Ala-activated protein C mutant. Blood 113:5970–78 [Google Scholar]
  105. Austin KM, Covic L, Kuliopulos A. 105.  2013. Matrix metalloproteases and PAR1 activation. Blood 121:431–69 [Google Scholar]
  106. Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A. 106.  2005. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120:303–13 [Google Scholar]
  107. Trivedi V, Boire A, Tchernychev B, Kaneider NC, Leger AJ. 107.  et al. 2009. Platelet matrix metallo-protease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site. Cell 137:332–43 [Google Scholar]
  108. Tressel SL, Kaneider NC, Kasuda S, Foley C, Koukos G. 108.  et al. 2011. A matrix metalloprotease-PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis. EMBO Mol. Med 3:370–84 [Google Scholar]
  109. Jaffré F, Friedman AE, Hu Z, Mackman N, Blaxall BC. 109.  2012. β-Adrenergic receptor stimulation transactivates protease-activated receptor 1 via matrix metalloproteinase 13 in cardiac cells. Circulation 125:2993–3003 [Google Scholar]
  110. Mihara K, Ramachandran R, Renaux B, Saifeddine M, Hollenberg MD. 110.  2013. Neutrophil elastase and proteinase-3 trigger G protein-biased signaling through proteinase-activated receptor-1 (PAR1). J. Biol. Chem. 288:32979–90 [Google Scholar]
  111. Landolt-Marticorena C, Reithmeier RA. 111.  1994. Asparagine-linked oligosaccharides are localized to single extracytosolic segments in multi-span membrane glycoproteins. Biochem. J. 302:253–60 [Google Scholar]
  112. Soto AG, Trejo J. 112.  2010. N-linked glycosylation of protease-activated receptor-1 second extracellular loop: a critical determinant for ligand-induced receptor activation and internalization. J. Biol. Chem. 285:18781–93 [Google Scholar]
  113. Compton SJ, Sandhu S, Wijesuriya SJ, Hollenberg MD. 113.  2002. Glycosylation of human protease-activated receptor-2 (hPAR2): role in cell surface expression and signalling. Biochem. J. 368:495–505 [Google Scholar]
  114. Soto AG, Smith TH, Chen B, Bhattacharya S, Cordova IC. 114.  et al. 2015. N-linked glycosylation of protease-activated receptor-1 at extracellular loop 2 regulates G-protein signaling bias. PNAS 112:E3600–8 [Google Scholar]
  115. van den Born LI, Van Schooneveld, de Jong LAMS MJ, Riemslag, de Jong PTVM FCC. 115.  et al. 1994. Thr4Lys rhodopsin mutation is associated with autosomal dominant retinitis pigmentosa of the cone-rod type in a small Dutch family. Ophthalmic Genet 15:51–60 [Google Scholar]
  116. Sullivan LJ, Makris GS, Dickinson P, Mulhall LE, Forrest S. 116.  et al. 1993. A new codon 15 rhodopsin gene mutation in autosomal dominant retinitis pigmentosa is associated with sectorial disease. Arch. Ophthalmol. 111:1512–17 [Google Scholar]
  117. Reiter E, Ahn S, Shukla AK, Lefkowitz RJ. 117.  2012. Molecular mechanism of β-arrestin-biased agonism at seven-transmembrane receptors. Annu. Rev. Pharmacol. Toxicol. 52:179–97 [Google Scholar]
  118. Tobin AB, Butcher AJ, Kong KC. 118.  2008. Location, location, location…site specific GPCR phosphorylation offers a mechanism for cell-type-specific signalling. Trends Pharmacol. Sci. 8:413–20 [Google Scholar]
  119. Nobles KN, Xiao K, Ahn S, Shukla AK, Lam CM. 119.  et al. 2011. Distinct phosphorylation sites on the β2-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin. Sci. Signal. 4:ra51 [Google Scholar]
  120. Ishii K, Chen J, Ishii M, Koch WJ, Freedman NJ. 120.  et al. 1994. Inhibition of thrombin receptor signaling by a G protein-coupled receptor kinase. Functional specificity among G protein-coupled receptor kinases. J. Biol. Chem. 269:1125–30 [Google Scholar]
  121. Canto I, Trejo J. 121.  2013. Palmitoylation of protease-activated receptor-1 regulates adaptor protein complex-2 and -3 interaction with tyrosine-based motifs and endocytic sorting. J. Biol. Chem. 288:15900–12 [Google Scholar]
  122. Botham A, Guo X, Xiao YP, Morice AH, Compton SJ, Sadofsky LR. 122.  2011. Palmitoylation of human proteinase-activated receptor-2 differentially regulates receptor-triggered ERK1/2 activation, calcium signalling and endocytosis. Biochem. J. 438:359–67 [Google Scholar]
  123. Adams MN, Christensen ME, He Y, Waterhouse NJ, Hooper JD. 123.  2011. The role of palmitoylation in signalling, cellular trafficking and plasma membrane localization of protease-activated receptor-2. PLOS ONE 6:e28018 [Google Scholar]
  124. Jacob C, Cottrell GS, Gehringer D, Schmidlin F, Grady EF, Bunnett NW. 124.  2005. c-Cbl mediates ubiquitination, degradation, and down-regulation of human protease-activated receptor 2. J. Biol. Chem. 280:16076–87 [Google Scholar]
  125. Swift S, Leger AJ, Talavera J, Zhang L, Bohm A, Kuliopulos A. 125.  2006. Role of the PAR1 receptor 8th helix in signaling: the 7-8-1 receptor activation mechanism. J. Biol. Chem. 281:4109–16 [Google Scholar]
  126. Nakanishi-Matsui M, Zheng Y-W, Weiss EJ, Sulciner D, Coughlin SR. 126.  2000. PAR3 is a cofactor for PAR4 activation by thrombin. Nature 404:609–13 [Google Scholar]
  127. Covic L, Gresser AL, Kuliopulos A. 127.  2000. Biphasic kinetics of activation and signaling for PAR1 and PAR4 thrombin receptors in platelets. Biochemistry 39:5458–67 [Google Scholar]
  128. Holinstat M, Voss B, Bilodeau ML, McLaughlin JN, Cleator J, Hamm HE. 128.  2006. PAR4, but not PAR1, signals in human platelet aggregation via Ca2+ mobilization and synergistic P2Y12 receptor activation. J. Biol. Chem. 281:26665–74 [Google Scholar]
  129. McLaughlin JN, Patterson MM, Malik AB. 129.  2007. Protease-activated receptor-3 (PAR3) regulates PAR1 signaling by receptor dimerization. PNAS 104:5662–67 [Google Scholar]
  130. Burnier L, Mosnier LO. 130.  2013. Novel mechanisms for activated protein C cytoprotective activities involving noncanonical activation of protease-activated receptor 3. Blood 122:807–16 [Google Scholar]
  131. Guo H, Liu D, Gelbard H, Cheng T, Insalasco R. 131.  et al. 2004. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron 41:563–72 [Google Scholar]
  132. Madhusudhan T, Wang H, Straub BK, Grone E, Zhou Q. 132.  et al. 2012. Cytoprotective signaling by activated protein C requires protease-activated receptor-3 in podocytes. Blood 119:874–83 [Google Scholar]
  133. Nystedt S, Ramakrishnan V, Sundelin J. 133.  1996. The proteinase-activated receptor 2 is induced by inflammatory mediators in human endothelial cells: comparison with the thrombin receptor. J. Biol. Chem. 271:14910–45 [Google Scholar]
  134. Kaneider NC, Leger AJ, Agarwal A, Nguyen N, Perides G. 134.  et al. 2007. “Role reversal” for the receptor PAR1 in sepsis-induced vascular damage. Nat. Immunol. 12:1303–12 [Google Scholar]
  135. Lin H, Trejo J. 135.  2013. Transactivation of the PAR1-PAR2 heterodimer by thrombin elicits β-arrestin-mediated endosomal signaling. J. Biol. Chem. 288:11203–15 [Google Scholar]
  136. Lin H, Liu AP, Smith TH, Trejo J. 136.  2013. Cofactoring and dimerization of proteinase-activated receptors. Pharmacol. Rev. 65:1198–213 [Google Scholar]
  137. Zhang C, Srinivasan Y, Arlow DH, Fung JJ, Palmer D. 137.  et al. 2012. High-resolution crystal structure of human protease-activated receptor 1. Nature 492:387–92 [Google Scholar]
  138. Kelso EB, Lockhart JC, Hembrough T, Dunning L, Plevin R. 138.  et al. 2006. Therapeutic promise of proteinase-activated receptor-2 antagonism in joint inflammation. J. Pharmacol. Exp. Ther. 316:1017–24 [Google Scholar]
  139. Wang Y, Lin M, Weng H, Wang X, Yang L, Liu F. 139.  2014. ENMD-1068, a protease-activated receptor 2 antagonist, inhibits the development of endometriosis in a mouse model. Am. J. Obstet. Gynecol. 210:531.e1–8 [Google Scholar]
  140. Hollenberg MD, Saifeddine M, Sandhu S, Houle S, Vergnolle N. 140.  2004. Proteinase-activated receptor-4: evaluation of tethered ligand-derived peptides as probes for receptor function and as inflammatory agonists in vivo. Br. J. Pharmacol. 143:443–54 [Google Scholar]
  141. Trejo J, Coughlin SR. 141.  1999. The cytoplasmic tails of protease-activated receptor-1 and substance P receptor specify sorting to lysosomes versus recycling. J. Biol. Chem. 274:2216–24 [Google Scholar]
  142. Paing MM, Stutts AB, Kohout TA, Lefkowitz RJ, Trejo J. 142.  2002. β-Arrestins regulate protease-activated receptor-1 desensitization but not internalization or down-regulation. J. Biol. Chem. 277:1292–300 [Google Scholar]
  143. Wolfe BL, Marchese A, Trejo J. 143.  2007. Ubiquitination differentially regulates clathrin-dependent internalization of protease-activated receptor-1. J. Cell Biol. 177:905–16 [Google Scholar]
  144. Ricks T, Trejo J. 144.  2009. Phosphorylation of protease-activated receptor-2 differentially regulates desensitization and internalization. J. Biol. Chem. 284:34444–57 [Google Scholar]
  145. Shapiro MJ, Weiss EJ, Faruqi TR, Coughlin SR. 145.  2000. Protease-activated receptors 1 and 4 are shut off with distinct kinetics after activation by thrombin. J. Biol. Chem. 275:25216–21 [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-011613-140016
Loading
/content/journals/10.1146/annurev-pharmtox-011613-140016
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error