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Seminars in Immunopathology

, Volume 34, Issue 1, pp 133–149 | Cite as

Protease-activated receptor 2 signaling in inflammation

  • Andrea S. Rothmeier
  • Wolfram Ruf
Review

Abstract

Protease-activated receptors (PARs) are G protein-coupled receptors that are activated by proteolytical cleavage of the amino-terminus and thereby act as sensors for extracellular proteases. While coagulation proteases activate PARs to regulate hemostasis, thrombosis, and cardiovascular function, PAR2 is also activated in extravascular locations by a broad array of serine proteases, including trypsin, tissue kallikreins, coagulation factors VIIa and Xa, mast cell tryptase, and transmembrane serine proteases. Administration of PAR2-specific agonistic and antagonistic peptides, as well as studies in PAR2 knockout mice, identified critical functions of PAR2 in development, inflammation, immunity, and angiogenesis. Here, we review these roles of PAR2 with an emphasis on the role of coagulation and other extracellular protease pathways that cleave PAR2 in epithelial, immune, and neuronal cells to regulate physiological and pathophysiological processes.

Keywords

Protease-activated receptors Tissue factor Coagulation Angiogenesis 

Notes

Acknowledgements

We thank Cheryl Johnson for the preparation of figures. The authors are supported by grants from the National Heart Lung Blood Institute (HL-60472 and HL-77753 to WR) and the Deutsche Forschungsgemeinschaft (RO 3795/2-1 to ASR).

References

  1. 1.
    Coughlin SR (2000) Thrombin signalling and protease-activated receptors. Nature 407:258–264PubMedGoogle Scholar
  2. 2.
    Trivedi V, Boire A, Tchernychev B, Kaneider NC, Leger AJ, O'Callaghan K et al (2009) Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site. Cell 137(2):332–343PubMedGoogle Scholar
  3. 3.
    Kahn ML, Zheng YW, Huang W, Bigornia V, Zeng DW, Moff S et al (1998) A dual thrombin receptor system for platelet activation. Nature 394:690–694PubMedGoogle Scholar
  4. 4.
    Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR (1999) Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest 103:879–887PubMedGoogle Scholar
  5. 5.
    Nakanishi-Matsui M, Zheng YW, Sulciner DJ, Weiss EJ, Ludeman MJ, Coughlin SR (2000) PAR3 is a cofactor for PAR4 activation by thrombin. Nature 404:609–613PubMedGoogle Scholar
  6. 6.
    McLaughlin JN, Patterson MM, Malik AB (2007) Protease-activated receptor-3 (PAR3) regulates PAR1 signaling by receptor dimerization. Proc Natl Acad Sci U S A 104(13):5662–5667PubMedGoogle Scholar
  7. 7.
    Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W (2002) Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296(5574):1880–1882PubMedGoogle Scholar
  8. 8.
    Riewald M, Kravchenko VV, Petrovan RJ, O'Brien PJ, Brass LF, Ulevitch RJ et al (2001) Gene induction by coagulation factor Xa is mediated by activation of PAR-1. Blood 97(10):3109–3116PubMedGoogle Scholar
  9. 9.
    Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A (2005) PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120(3):303–313PubMedGoogle Scholar
  10. 10.
    Lourbakos A, Yuan YP, Jenkins AL, Travis J, Andrade-Gordon P, Santulli R et al (2001) Activation of protease-activated receptors by gingipains from Porphyromonas gingivalis leads to platelet aggregation: a new trait in microbial pathogenicity. Blood 97(12):3790–3798PubMedGoogle Scholar
  11. 11.
    Nystedt S, Emilsson K, Wahlestedt C, Sundelin J (1994) Molecular cloning of a potential proteinase activated receptor. Proc Natl Acad Sci U S A 91:9208–9212PubMedGoogle Scholar
  12. 12.
    Nystedt S, Ramakrishnan V, Sundelin J (1996) The proteinase-activated receptor 2 is induced by inflammatory mediators in human endothelial cells—comparison with the thrombin receptor. J Biol Chem 271:14910–14915PubMedGoogle Scholar
  13. 13.
    O'Brien PJ, Prevost N, Molino M, Hollinger MK, Woolkalis MJ, Woulfe DS et al (2000) Thrombin responses in human endothelial cells. Contributions from receptors other than PAR1 include the transactivation of PAR2 by thrombin-cleaved PAR1. J Biol Chem 275:13502–13509PubMedGoogle Scholar
  14. 14.
    Sun G, Stacey MA, Schmidt M, Mori L, Mattoli S (2001) Interaction of mite allergens Der p3 and Der p9 with protease-activated receptor-2 expressed by lung epithelial cells. J Immunol 167(2):1014–1021PubMedGoogle Scholar
  15. 15.
    Jeong SK, Kim HJ, Youm JK, Ahn SK, Choi EH, Sohn MH et al (2008) Mite and cockroach allergens activate protease-activated receptor 2 and delay epidermal permeability barrier recovery. J Invest Dermatol 128(8):1930–1939PubMedGoogle Scholar
  16. 16.
    Lourbakos A, Chinni C, Thompson P, Potempa J, Travis J, Mackie EJ et al (1998) Cleavage and activation of proteinase-activated receptor-2 on human neutrophils by gingipain-R from Porphyromonas gingivalis. FEBS Lett 435(1):45–48PubMedGoogle Scholar
  17. 17.
    Kida Y, Higashimoto Y, Inoue H, Shimizu T, Kuwano K (2008) A novel secreted protease from Pseudomonas aeruginosa activates NF-kappaB through protease-activated receptors. Cell Microbiol 10(7):1491–1504PubMedGoogle Scholar
  18. 18.
    Kida Y, Inoue H, Shimizu T, Kuwano K (2007) Serratia marcescens serralysin induces inflammatory responses through protease-activated receptor 2. Infect Immun 75(1):164–174PubMedGoogle Scholar
  19. 19.
    Kong W, McConalogue K, Khitin LM, Hollenberg MD, Payan DG, Bohm SK et al (1997) Luminal trypsin may regulate enterocytes through proteinase-activated receptor 2. Proc Natl Acad Sci U S A 94(16):8884–8889PubMedGoogle Scholar
  20. 20.
    Cottrell GS, Amadesi S, Grady EF, Bunnett NW (2004) Trypsin IV, a novel agonist of protease-activated receptors 2 and 4. J Biol Chem 279(14):13532–13539PubMedGoogle Scholar
  21. 21.
    Oikonomopoulou K, Hansen KK, Saifeddine M, Vergnolle N, Tea I, Blaber M et al (2006) Kallikrein-mediated cell signalling: targeting proteinase-activated receptors (PARs). Biol Chem 387(6):817–824PubMedGoogle Scholar
  22. 22.
    Riewald M, Ruf W (2001) Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor. Proc Natl Acad Sci U S A 98(14):7742–7747PubMedGoogle Scholar
  23. 23.
    Camerer E, Huang W, Coughlin SR (2000) Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci U S A 97:5255–5260PubMedGoogle Scholar
  24. 24.
    Camerer E, Kataoka H, Kahn M, Lease K, Coughlin SR (2002) Genetic evidence that protease-activated receptors mediate factor Xa signaling in endothelial cells. J Biol Chem 277:16081–16087PubMedGoogle Scholar
  25. 25.
    Molino M, Barnathan ES, Numerof R, Clark J, Dreyer M, Cumashi A et al (1997) Interactions of mast cell tryptase with thrombin receptors and PAR-2. J Biol Chem 272:4043–4049PubMedGoogle Scholar
  26. 26.
    Takeuchi T, Harris JL, Huang W, Yan KW, Coughlin SR, Craik CS (2000) Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates. J Biol Chem 275:26333–26342PubMedGoogle Scholar
  27. 27.
    Wilson S, Greer B, Hooper J, Zijlstra A, Walker B, Quigley J et al (2005) The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells. Biochem J 388(Pt 3):967–972PubMedGoogle Scholar
  28. 28.
    Smith R, Jenkins A, Lourbakos A, Thompson P, Ramakrishnan V, Tomlinson J et al (2000) Evidence for the activation of PAR-2 by the sperm protease, acrosin: expression of the receptor on oocytes. FEBS Lett 484(3):285–290PubMedGoogle Scholar
  29. 29.
    DeFea KA, Zalevsky J, Thoma MS, Déry O, Mullins RD, Bunnett N (2000) b-Arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J Cell Biol 148(6):1267–1281PubMedGoogle Scholar
  30. 30.
    Seatter MJ, Drummond R, Kanke T, Macfarlane SR, Hollenberg MD, Plevin R (2004) The role of the C-terminal tail in protease-activated receptor-2-mediated Ca2+ signalling, proline-rich tyrosine kinase-2 activation, and mitogen-activated protein kinase activity. Cell Signal 16(1):21–29PubMedGoogle Scholar
  31. 31.
    Lau C, Lytle C, Straus DS, DeFea KA (2011) Apical and basolateral pools of proteinase-activated receptor-2 direct distinct signaling events in the intestinal epithelium. Am J Physiol Cell Physiol 300(1):C113–C123PubMedGoogle Scholar
  32. 32.
    Ricks TK, Trejo J (2009) Phosphorylation of protease-activated receptor-2 differentially regulates desensitization and internalization. J Biol Chem 284(49):34444–34457PubMedGoogle Scholar
  33. 33.
    Wang P, Jiang Y, Wang Y, Shyy JY, DeFea KA (2010) Beta-arrestin inhibits CAMKKbeta-dependent AMPK activation downstream of protease-activated-receptor-2. BMC Biochem 11:36PubMedGoogle Scholar
  34. 34.
    Stalheim L, Ding Y, Gullapalli A, Paing MM, Wolfe BL, Morris DR et al (2005) Multiple independent functions of arrestins in the regulation of protease-activated receptor-2 signaling and trafficking. Mol Pharmacol 67(1):78–87PubMedGoogle Scholar
  35. 35.
    Kumar P, Lau CS, Mathur M, Wang P, DeFea KA (2007) Differential effects of beta-arrestins on the internalization, desensitization and ERK1/2 activation downstream of protease activated receptor-2. Am J Physiol Cell Physiol 293(1):C346–C357PubMedGoogle Scholar
  36. 36.
    Ge L, Ly Y, Hollenberg M, DeFea K (2003) A b-arrestin-dependent scaffold is associated with prolonged MAPK activation in pseudopodia during protease-activated receptor-2 induced chemotaxis. J Biol Chem 278(36):34418–34426PubMedGoogle Scholar
  37. 37.
    Ge L, Shenoy SK, Lefkowitz RJ, DeFea K (2004) Constitutive protease-activated receptor-2-mediated migration of MDA MB-231 breast cancer cells requires both beta-arrestin-1 and −2. J Biol Chem 279(53):55419–55424PubMedGoogle Scholar
  38. 38.
    Wang P, Kumar P, Wang C, DeFea KA (2007) Differential regulation of class IA phosphoinositide 3-kinase catalytic subunits p110 alpha and beta by protease-activated receptor 2 and beta-arrestins. Biochem J 408(2):221–230PubMedGoogle Scholar
  39. 39.
    Wang P, DeFea KA (2006) Protease-activated receptor-2 simultaneously directs beta-arrestin-1-dependent inhibition and Galphaq-dependent activation of phosphatidylinositol 3-kinase. Biochemistry 45(31):9374–9385PubMedGoogle Scholar
  40. 40.
    Zoudilova M, Min J, Richards HL, Carter D, Huang T, DeFea KA (2010) beta-Arrestins scaffold cofilin with chronophin to direct localized actin filament severing and membrane protrusions downstream of protease-activated receptor-2. J Biol Chem 285(19):14318–14329PubMedGoogle Scholar
  41. 41.
    Zoudilova M, Kumar P, Ge L, Wang P, Bokoch GM, DeFea KA (2007) Beta-arrestin-dependent regulation of the cofilin pathway downstream of protease-activated receptor-2. J Biol Chem 282:20634–20646PubMedGoogle Scholar
  42. 42.
    Kanke T, Macfarlane SR, Seatter MJ, Davenport E, Paul A, McKenzie RC et al (2001) Proteinase-activated receptor-2-mediated activation of stress-activated protein kinases and inhibitory kappa B kinases in NCTC 2544 keratinocytes. J Biol Chem 276(34):31657–31666PubMedGoogle Scholar
  43. 43.
    Sevigny LM, Zhang P, Bohm A, Lazarides K, Perides G, Covic L et al (2011) Interdicting protease-activated receptor-2-driven inflammation with cell-penetrating pepducins. Proc Natl Acad Sci U S A 108(20):8491–8496PubMedGoogle Scholar
  44. 44.
    Corvera CU, Dery O, McConalogue K, Gamp P, Thoma M, Al-Ani B et al (1999) Thrombin and mast cell tryptase regulate guinea-pig myenteric neurons through proteinase-activated receptors-1 and −2. J Physiol 517(Pt 3):741–756PubMedGoogle Scholar
  45. 45.
    Corvera CU, Dery O, McConalogue K, Bohm SK, Khitin LM, Caughey GH et al (1997) Mast cell tryptase regulates rat colonic myocytes through proteinase-activated receptor 2. J Clin Invest 100(6):1383–1393PubMedGoogle Scholar
  46. 46.
    Bohm SK, Kong W, Bromme D, Smeekens SP, Anderson DC, Connolly A et al (1996) Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2. Biochem J 314(Pt 3):1009–1016PubMedGoogle Scholar
  47. 47.
    Santulli RJ, Derian CK, Darrow AL, Tomko KA, Eckardt AJ, Seiberg M et al (1995) Evidence for the presence of a protease-activated receptor distinct from the thrombin receptor in human keratinocytes. Proc Natl Acad Sci U S A 92:9151–9155PubMedGoogle Scholar
  48. 48.
    Wang H, Ubl JJ, Reiser G (2002) Four subtypes of protease-activated receptors, co-expressed in rat astrocytes, evoke different physiological signaling. Glia 37(1):53–63PubMedGoogle Scholar
  49. 49.
    Böhm SK, Kong W, Brömme D, Smeekens SP, Anderson DC, Connolly A et al (1996) Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2. Biochem J 314:1009–1016PubMedGoogle Scholar
  50. 50.
    Macfarlane SR, Sloss CM, Cameron P, Kanke T, McKenzie RC, Plevin R (2005) The role of intracellular Ca2+ in the regulation of proteinase-activated receptor-2 mediated nuclear factor kappa B signalling in keratinocytes. Br J Pharmacol 145(4):535–544PubMedGoogle Scholar
  51. 51.
    Buddenkotte J, Stroh C, Engels IH, Moormann C, Shpacovitch VM, Seeliger S et al (2005) Agonists of proteinase-activated receptor-2 stimulate upregulation of intercellular cell adhesion molecule-1 in primary human keratinocytes via activation of NF-kappa B. J Invest Dermatol 124(1):38–45PubMedGoogle Scholar
  52. 52.
    Shpacovitch VM, Brzoska T, Buddenkotte J, Stroh C, Sommerhoff CP, Ansel JC et al (2002) Agonists of proteinase-activated receptor 2 induce cytokine release and activation of nuclear transcription factor kB in human dermal microvascular endothelial cells. J Invest Dermatol 118(2):380–385PubMedGoogle Scholar
  53. 53.
    Syeda F, Grosjean J, Houliston RA, Keogh RJ, Carter TD, Paleolog E et al (2006) Cyclooxygenase-2 induction and prostacyclin release by protease-activated receptors in endothelial cells require cooperation between mitogen-activated protein kinase and NF-kappaB pathways. J Biol Chem 281(17):11792–11804PubMedGoogle Scholar
  54. 54.
    Dery O, Thoma MS, Wong H, Grady EF, Bunnett NW (1999) Trafficking of proteinase-activated receptor-2 and b-arrestin-1 tagged with green fluorescent protein. b-Arrestin-dependent endocytosis of a proteinase receptor. J Biol Chem 274(26):18524–18535PubMedGoogle Scholar
  55. 55.
    Roosterman D, Schmidlin F, Bunnett NW (2003) Rab5a and rab11a mediate agonist-induced trafficking of protease-activated receptor 2. Am J Physiol Cell Physiol 284(5):C1319–C1329PubMedGoogle Scholar
  56. 56.
    Jacob C, Cottrell GS, Gehringer D, Schmidlin F, Grady EF, Bunnett NW (2005) c-Cbl mediates ubiquitination, degradation, and down-regulation of human protease-activated receptor 2. J Biol Chem 280(16):16076–16087PubMedGoogle Scholar
  57. 57.
    Hasdemir B, Murphy JE, Cottrell GS, Bunnett NW (2009) Endosomal deubiquitinating enzymes control ubiquitination and down-regulation of protease-activated receptor 2. J Biol Chem 284(41):28453–28466PubMedGoogle Scholar
  58. 58.
    Böhm SK, Khitin LM, Grady EF, Aponte G, Payan DG, Bunnett NW (1996) Mechanisms of desensitization and resensitization of proteinase-activated receptor-2. J Biol Chem 271:22003–22016PubMedGoogle Scholar
  59. 59.
    Ruf W, Riewald M (2003) Regulation of tissue factor expression. In: Ten Cate H, Levi M (eds) Molecular mechanisms of disseminated intravascular coagulation. Landes Bioscience, Georgetown, pp 61–80, Available at: www.Eurekah.com Google Scholar
  60. 60.
    Levi M, Van der Poll T (2010) Inflammation and coagulation. Crit Care Med 38(2 Suppl):S26–S34PubMedGoogle Scholar
  61. 61.
    Ahamed J, Versteeg HH, Kerver M, Chen VM, Mueller BM, Hogg PJ et al (2006) Disulfide isomerization switches tissue factor from coagulation to cell signaling. Proc Natl Acad Sci U S A 103(38):13932–13937PubMedGoogle Scholar
  62. 62.
    Disse J, Petersen HH, Larsen KS, Persson E, Esmon N, Esmon CT et al (2011) The endothelial protein C receptor supports tissue factor ternary coagulation initiation complex signaling through protease-activated receptors. J Biol Chem 286(7):5756–5767PubMedGoogle Scholar
  63. 63.
    Bazan JF (1990) Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A 87:6934–6938PubMedGoogle Scholar
  64. 64.
    Carson SD, Bromberg ME (2000) Tissue factor encryption/de-encryption is not altered in the absence of the cytoplasmic domain. Thromb Haemost 84:657–663PubMedGoogle Scholar
  65. 65.
    Paborsky LR, Caras IW, Fisher KL, Gorman CM (1991) Lipid association, but not the transmembrane domain, is required for tissue factor activity. Substitution of the transmembrane domain with a phosphatidylinositol anchor. J Biol Chem 266:21911–21916PubMedGoogle Scholar
  66. 66.
    Collier ME, Ettelaie C (2011) Regulation of the incorporation of tissue factor into microparticles by serine phosphorylation of the cytoplasmic domain of tissue factor. J Biol Chem 286(14):11977–11984PubMedGoogle Scholar
  67. 67.
    Zioncheck TF, Roy S, Vehar GA (1992) The cytoplasmic domain of tissue factor is phosphorylated by a protein kinase C-dependent mechanism. J Biol Chem 267:3561–3564PubMedGoogle Scholar
  68. 68.
    Ahamed J, Ruf W (2004) Protease-activated receptor 2-dependent phosphorylation of the tissue factor cytoplasmic domain. J Biol Chem 279(22):23038–23044PubMedGoogle Scholar
  69. 69.
    Sørensen BB, Freskgård P-O, Nielsen LS, Rao LVM, Ezban M, Petersen LC (1999) Factor VIIa-induced p44/42 mitogen-activated protein kinase activation requires the proteolytic activity of factor VIIa and is independent of the tissue factor cytoplasmic domain. J Biol Chem 274:21349–21354PubMedGoogle Scholar
  70. 70.
    Versteeg HH, Sørensen BB, Slofstra SH, Van den Brande JHM, Stam JC, van Bergen en Henegouwen PMP et al (2002) VIIa/tissue factor interaction results in a tissue factor cytoplasmic domain-independent activation of protein synthesis, p70 and p90 S6 kinase phosphorylation. J Biol Chem 277(30):27065–27072PubMedGoogle Scholar
  71. 71.
    Taylor FB Jr, Chang A, Ruf W, Morrissey JH, Hinshaw L, Catlett R et al (1991) Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 33(3):127–134PubMedGoogle Scholar
  72. 72.
    Taylor FB Jr, Chang ACK, Peer G, Li A, Ezban M, Hedner U (1998) Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and interleukin-6 and −8, but not tumor necrosis factor, responses of the baboon to LD100 Escherichia coli. Blood 91:1609–1615PubMedGoogle Scholar
  73. 73.
    Pawlinski R, Pedersen B, Schabbauer G, Tencati M, Holscher T, Boisvert W et al (2003) Role of tissue factor and protease activated receptors in a mouse model of endotoxemia. Blood 103(4):1342–1347PubMedGoogle Scholar
  74. 74.
    Pawlinski R, Wang JG, Owens AP III, Williams J, Antoniak S, Tencati M et al (2010) Hematopoietic and nonhematopoietic cell tissue factor activates the coagulation cascade in endotoxemic mice. Blood 116(5):806–814PubMedGoogle Scholar
  75. 75.
    Muth H, Kreis I, Zimmermann R, Tillmanns H, Holschermann H (2005) Differential gene expression in activated monocyte-derived macrophages following binding of factor VIIa to tissue factor. Thromb Haemost 94(5):1028–1034PubMedGoogle Scholar
  76. 76.
    Xu H, Ploplis VA, Castellino FJ (2006) A coagulation factor VII deficiency protects against acute inflammatory responses in mice. J Pathol 210(4):488–496PubMedGoogle Scholar
  77. 77.
    Lim SY, Tennant GM, Kennedy S, Wainwright CL, Kane KA (2006) Activation of mouse protease-activated receptor-2 induces lymphocyte adhesion and generation of reactive oxygen species. Br J Pharmacol 149(5):591–599PubMedGoogle Scholar
  78. 78.
    Cunningham MA, Romas P, Hutchinson P, Holdsworth SR, Tipping PG (1999) Tissue factor and factor VIIa receptor/ligand interactions induce proinflammatory effects in macrophages. Blood 94:3413–3420PubMedGoogle Scholar
  79. 79.
    Sharma L, Melis E, Hickey MJ, Clyne CD, Erlich J, Khachigian LM et al (2004) The cytoplasmic domain of tissue factor contributes to leukocyte recruitment and death in endotoxemia. Am J Pathol 165(1):331–340PubMedGoogle Scholar
  80. 80.
    Ahamed J, Niessen F, Kurokawa T, Lee YK, Bhattacharjee G, Morrissey JH et al (2007) Regulation of macrophage procoagulant responses by the tissue factor cytoplasmic domain in endotoxemia. Blood 109(12):5251–5259PubMedGoogle Scholar
  81. 81.
    Imamura T, Iyama K, Takeya M, Kambara T, Nakamura S (1993) Role of macrophage tissue factor in the development of the delayed hypersensitivity reaction in monkey skin. Cell Immunol 152:614–622PubMedGoogle Scholar
  82. 82.
    Apostolopoulos J, Hickey MJ, Sharma L, Davenport P, Moussa L, James WG et al (2008) The cytoplasmic domain of tissue factor in macrophages augments cutaneous delayed-type hypersensitivity. J Leukoc Biol 83:902–911PubMedGoogle Scholar
  83. 83.
    Busso N, Morard C, Salvi R, Peclat V, So A (2003) Role of the tissue factor pathway in synovial inflammation. Arthritis Rheum 48(3):651–659PubMedGoogle Scholar
  84. 84.
    Yang YH, Hall P, Little CB, Fosang AJ, Milenkovski G, Santos L et al (2005) Reduction of arthritis severity in protease-activated receptor-deficient mice. Arthritis Rheum 52(4):1325–1332PubMedGoogle Scholar
  85. 85.
    Ferrell WR, Lockhart JC, Kelso EB, Dunning L, Plevin R, Meek SE et al (2003) Essential role for proteinase-activated receptor-2 in arthritis. J Clin Invest 111(1):35–41PubMedGoogle Scholar
  86. 86.
    Yang YH, Hall P, Milenkovski G, Sharma L, Hutchinson P, Melis E et al (2004) Reduction in arthritis severity and modulation of immune function in tissue factor cytoplasmic domain mutant mice. Am J Pathol 164(1):109–117PubMedGoogle Scholar
  87. 87.
    Redecha P, Franzke CW, Ruf W, Mackman N, Girardi G (2008) Activation of neutrophils by the Tissue Factor-Factor VIIa-PAR2 axis mediates fetal death in antiphospholipid syndrome. J Clin Invest 118(10):3453–3461PubMedGoogle Scholar
  88. 88.
    Noorbakhsh F, Tsutsui S, Vergnolle N, Boven LA, Shariat N, Vodjgani M et al (2006) Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis. J Exp Med 203(2):425–435PubMedGoogle Scholar
  89. 89.
    Fields RC, Schoenecker JG, Hart JP, Hoffman MR, Pizzo SV, Lawson JH (2003) Protease-activated receptor-2 signaling triggers dendritic cell development. Am J Pathol 162(6):1817–1822PubMedGoogle Scholar
  90. 90.
    Csernok E, Ai M, Gross WL, Wicklein D, Petersen A, Lindner B et al (2006) Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway. Blood 107(11):4440–4448PubMedGoogle Scholar
  91. 91.
    Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246PubMedGoogle Scholar
  92. 92.
    Samad F, Pandey M, Loskutoff DJ (1998) Tissue factor gene expression in the adipose tissues of obese mice. Proc Natl Acad Sci U S A 95(13):7591–7596PubMedGoogle Scholar
  93. 93.
    Nakagomi A, Sasaki M, Ishikawa Y, Morikawa M, Shibui T, Kusama Y et al (2010) Upregulation of monocyte tissue factor activity is significantly associated with low-grade chronic inflammation and insulin resistance in patients with metabolic syndrome. Circ J 74(3):572–577PubMedGoogle Scholar
  94. 94.
    Mihara M, Aihara K, Ikeda Y, Yoshida S, Kinouchi M, Kurahashi K et al (2010) Inhibition of thrombin action ameliorates insulin resistance in type 2 diabetic db/db mice. Endocrinology 151(2):513–519PubMedGoogle Scholar
  95. 95.
    Badeanlou L, Furlan-Freguia C, Yang G, Ruf W, Samad F (2011) Tissue factor-PAR2 signaling promotes diet-induced obesity and adipose inflammation. Nat Med (in press)Google Scholar
  96. 96.
    Qi Y, Takahashi N, Hileman SM, Patel HR, Berg AH, Pajvani UB et al (2004) Adiponectin acts in the brain to decrease body weight. Nat Med 10(5):524–529PubMedGoogle Scholar
  97. 97.
    Holzer P (1998) Neurogenic vasodilatation and plasma leakage in the skin. Gen Pharmacol 30(1):5–11PubMedGoogle Scholar
  98. 98.
    Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS et al (2000) Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nature Med 6:151–158PubMedGoogle Scholar
  99. 99.
    Kawabata A, Kuroda R, Minami T, Kataoka K, Taneda M (1998) Increased vascular permeability by a specific agonist of protease-activated receptor-2 in rat hindpaw. Br J Pharmacol 125(3):419–422PubMedGoogle Scholar
  100. 100.
    Vergnolle N, Hollenberg MD, Sharkey KA, Wallace JL (1999) Characterization of the inflammatory response to proteinase-activated receptor-2 (PAR2)-activating peptides in the rat paw. Br J Pharmacol 127(5):1083–1090PubMedGoogle Scholar
  101. 101.
    Suckow SK, Caudle RM (2008) Identification and immunohistochemical characterization of colospinal afferent neurons in the rat. Neuroscience 153(3):803–813PubMedGoogle Scholar
  102. 102.
    Nguyen C, Coelho AM, Grady E, Compton SJ, Wallace JL, Hollenberg MD et al (2003) Colitis induced by proteinase-activated receptor-2 agonists is mediated by a neurogenic mechanism. Can J Physiol Pharmacol 81(9):920–927PubMedGoogle Scholar
  103. 103.
    Cenac N, Garcia-Villar R, Ferrier L, Larauche M, Vergnolle N, Bunnett NW et al (2003) Proteinase-activated receptor-2-induced colonic inflammation in mice: possible involvement of afferent neurons, nitric oxide, and paracellular permeability. J Immunol 170(8):4296–4300PubMedGoogle Scholar
  104. 104.
    Vergnolle N, Bunnett N, Sharkey KA, Brussee V, Compton SJ, Grady EF et al (2001) Proteinase-activated receptor-2 and hyperalgesia: a novel pain pathway. Nature Med 7:821–826PubMedGoogle Scholar
  105. 105.
    Dai Y, Moriyama T, Higashi T, Togashi K, Kobayashi K, Yamanaka H et al (2004) Proteinase-activated receptor 2-mediated potentiation of transient receptor potential vanilloid subfamily 1 activity reveals a mechanism for proteinase-induced inflammatory pain. J Neurosci 24(18):4293–4299PubMedGoogle Scholar
  106. 106.
    Amadesi S, Nie J, Vergnolle N, Cottrell GS, Grady EF, Trevisani M et al (2004) Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia. J Neurosci 24(18):4300–4312PubMedGoogle Scholar
  107. 107.
    Amadesi S, Cottrell GS, Divino L, Chapman K, Grady EF, Bautista F et al (2006) Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice. J Physiol 575(Pt 2):555–571PubMedGoogle Scholar
  108. 108.
    Cenac N, Altier C, Chapman K, Liedtke W, Zamponi G, Vergnolle N (2008) Transient receptor potential vanilloid-4 has a major role in visceral hypersensitivity symptoms. Gastroenterology 135(3):937–946PubMedGoogle Scholar
  109. 109.
    Grant AD, Cottrell GS, Amadesi S, Trevisani M, Nicoletti P, Materazzi S et al (2007) Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice. J Physiol 578(Pt 3):715–733PubMedGoogle Scholar
  110. 110.
    Nishimura S, Ishikura H, Matsunami M, Shinozaki Y, Sekiguchi F, Naruse M et al (2010) The proteinase/proteinase-activated receptor-2/transient receptor potential vanilloid-1 cascade impacts pancreatic pain in mice. Life Sci 87(19–22):643–650PubMedGoogle Scholar
  111. 111.
    Zhang W, Gao J, Zhao T, Wei L, Wu W, Bai Y et al (2011) Proteinase-activated receptor 2 mediates thermal hyperalgesia and is upregulated in a rat model of chronic pancreatitis. Pancreas 40(2):300–307PubMedGoogle Scholar
  112. 112.
    Lam DK, Schmidt BL (2010) Serine proteases and protease-activated receptor 2-dependent allodynia: a novel cancer pain pathway. Pain 149(2):263–272PubMedGoogle Scholar
  113. 113.
    Dai Y, Wang S, Tominaga M, Yamamoto S, Fukuoka T, Higashi T et al (2007) Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. J Clin Invest 117(7):1979–1987PubMedGoogle Scholar
  114. 114.
    Yu S, Gao G, Peterson BZ, Ouyang A (2009) TRPA1 in mast cell activation-induced long-lasting mechanical hypersensitivity of vagal afferent C-fibers in guinea pig esophagus. Am J Physiol Gastrointest Liver Physiol 297(1):G34–G42PubMedGoogle Scholar
  115. 115.
    D'Andrea MR, Derian CK, Leturcq D, Baker SM, Brunmark A, Ling P et al (1998) Characterization of protease-activated receptor-2 immunoreactivity in normal human tissues. J Histochem Cytochem 46(2):157–164PubMedGoogle Scholar
  116. 116.
    Nguyen TD, Moody MW, Steinhoff M, Okolo C, Koh DS, Bunnett NW (1999) Trypsin activates pancreatic duct epithelial cell ion channels through proteinase-activated receptor-2. J Clin Invest 103(2):261–269PubMedGoogle Scholar
  117. 117.
    Kawabata A, Matsunami M, Sekiguchi F (2008) Gastrointestinal roles for proteinase-activated receptors in health and disease. Br J Pharmacol 153(Suppl 1):S230–S240PubMedGoogle Scholar
  118. 118.
    Sekiguchi F, Hasegawa N, Inoshita K, Yonezawa D, Inoi N, Kanke T et al (2006) Mechanisms for modulation of mouse gastrointestinal motility by proteinase-activated receptor (PAR)-1 and −2 in vitro. Life Sci 78(9):950–957PubMedGoogle Scholar
  119. 119.
    Laukkarinen JM, Weiss ER, van Acker GJ, Steer ML, Perides G (2008) Protease-activated receptor-2 exerts contrasting model-specific effects on acute experimental pancreatitis. J Biol Chem 283(30):20703–20712PubMedGoogle Scholar
  120. 120.
    Kawabata A, Nishikawa H, Kuroda R, Kawai K, Hollenberg MD (2000) Proteinase-activated receptor-2 (PAR-2): regulation of salivary and pancreatic exocrine secretion in vivo in rats and mice. Br J Pharmacol 129:1808–1814PubMedGoogle Scholar
  121. 121.
    Singh VP, Bhagat L, Navina S, Sharif R, Dawra RK, Saluja AK (2007) Protease-activated receptor-2 protects against pancreatitis by stimulating exocrine secretion. Gut 56(7):958–964PubMedGoogle Scholar
  122. 122.
    Sharma A, Tao X, Gopal A, Ligon B, Andrade-Gordon P, Steer ML et al (2005) Protection against acute pancreatitis by activation of protease-activated receptor-2. Am J Physiol Gastrointest Liver Physiol 288(2):G388–G395PubMedGoogle Scholar
  123. 123.
    Cenac N, Andrews CN, Holzhausen M, Chapman K, Cottrell G, Andrade-Gordon P et al (2007) Role for protease activity in visceral pain in irritable bowel syndrome. J Clin Invest 117(3):636–647PubMedGoogle Scholar
  124. 124.
    Cenac N, Coelho AM, Nguyen C, Compton S, Andrade-Gordon P, Macnaughton WK et al (2002) Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2. Am J Pathol 161(5):1903–1915PubMedGoogle Scholar
  125. 125.
    Demaude J, Leveque M, Chaumaz G, Eutamene H, Fioramonti J, Bueno L et al (2009) Acute stress increases colonic paracellular permeability in mice through a mast cell-independent mechanism: involvement of pancreatic trypsin. Life Sci 84(23–24):847–852PubMedGoogle Scholar
  126. 126.
    Hansen KK, Sherman PM, Cellars L, Andrade-Gordon P, Pan Z, Baruch A et al (2005) A major role for proteolytic activity and proteinase-activated receptor-2 in the pathogenesis of infectious colitis. Proc Natl Acad Sci U S A 102(23):8363–8368PubMedGoogle Scholar
  127. 127.
    Hyun E, Andrade-Gordon P, Steinhoff M, Vergnolle N (2008) Protease-activated receptor-2 activation: a major actor in intestinal inflammation. Gut 57(9):1222–1229PubMedGoogle Scholar
  128. 128.
    Cenac N, Chin AC, Garcia-Villar R, Salvador-Cartier C, Ferrier L, Vergnolle N et al (2004) PAR2 activation alters colonic paracellular permeability in mice via IFN-gamma-dependent and -independent pathways. J Physiol 558(Pt 3):913–925PubMedGoogle Scholar
  129. 129.
    Jacob C, Yang PC, Darmoul D, Amadesi S, Saito T, Cottrell GS et al (2005) Mast cell tryptase controls paracellular permeability of the intestine. Role of protease-activated receptor 2 and beta-arrestins. J Biol Chem 280(36):31936–31948PubMedGoogle Scholar
  130. 130.
    Moriez R, Leveque M, Salvador-Cartier C, Barreau F, Theodorou V, Fioramonti J et al (2007) Mucosal mast cell proteases are involved in colonic permeability alterations and subsequent bacterial translocation in endotoxemic rats. Shock 28(1):118–124PubMedGoogle Scholar
  131. 131.
    Kim DH, Cho YJ, Kim JH, Kim YB, Lee KJ (2010) Stress-induced alterations in mast cell numbers and proteinase-activated receptor-2 expression of the colon: role of corticotrophin-releasing factor. J Korean Med Sci 25(9):1330–1335PubMedGoogle Scholar
  132. 132.
    Roka R, Demaude J, Cenac N, Ferrier L, Salvador-Cartier C, Garcia-Villar R et al (2007) Colonic luminal proteases activate colonocyte proteinase-activated receptor-2 and regulate paracellular permeability in mice. Neurogastroenterol Motil 19(1):57–65PubMedGoogle Scholar
  133. 133.
    Buzza MS, Netzel-Arnett S, Shea-Donohue T, Zhao A, Lin CY, List K et al (2010) Membrane-anchored serine protease matriptase regulates epithelial barrier formation and permeability in the intestine. Proc Natl Acad Sci U S A 107(9):4200–4205PubMedGoogle Scholar
  134. 134.
    Lindner JR, Kahn ML, Coughlin SR, Sambrano GR, Schauble E, Bernstein D et al (2000) Delayed onset of inflammation in protease-activated receptor-2-deficient mice. J Immunol 165:6504–6510PubMedGoogle Scholar
  135. 135.
    Hyun E, Andrade-Gordon P, Steinhoff M, Beck PL, Vergnolle N (2010) Contribution of bone marrow-derived cells to the pro-inflammatory effects of protease-activated receptor-2 in colitis. Inflamm Res 59(9):699–709PubMedGoogle Scholar
  136. 136.
    Anthoni C, Russell J, Wood KC, Stokes KY, Vowinkel T, Kirchhofer D et al (2007) Tissue factor: a mediator of inflammatory cell recruitment, tissue injury, and thrombus formation in experimental colitis. J Exp Med 204(7):1595–1601PubMedGoogle Scholar
  137. 137.
    Steinbrecher KA, Horowitz NA, Blevins EA, Barney KA, Shaw MA, Harmel-Laws E et al (2010) Colitis-associated cancer is dependent on the interplay between the hemostatic and inflammatory systems and supported by integrin alpha(M)beta(2) engagement of fibrinogen. Cancer Res 70(7):2634–2643PubMedGoogle Scholar
  138. 138.
    Giacaman RA, Asrani AC, Ross KF, Herzberg MC (2009) Cleavage of protease-activated receptors on an immortalized oral epithelial cell line by Porphyromonas gingivalis gingipains. Microbiology 155(Pt 10):3238–3246PubMedGoogle Scholar
  139. 139.
    Chung WO, Hansen SR, Rao D, Dale BA (2004) Protease-activated receptor signaling increases epithelial antimicrobial peptide expression. J Immunol 173(8):5165–5170PubMedGoogle Scholar
  140. 140.
    Dommisch H, Chung WO, Rohani MG, Williams D, Rangarajan M, Curtis MA et al (2007) Protease-activated receptor 2 mediates human beta-defensin 2 and CC chemokine ligand 20 mRNA expression in response to proteases secreted by Porphyromonas gingivalis. Infect Immun 75(9):4326–4333PubMedGoogle Scholar
  141. 141.
    Cocks TM, Fong B, Chow JM, Anderson GP, Frauman AG, Goldie RG et al (1999) A protective role for protease-activated receptors in the airways. Nature 398(6723):156–160PubMedGoogle Scholar
  142. 142.
    Khoufache K, LeBouder F, Morello E, Laurent F, Riffault S, Andrade-Gordon P et al (2009) Protective role for protease-activated receptor-2 against influenza virus pathogenesis via an IFN-gamma-dependent pathway. J Immunol 182(12):7795–7802PubMedGoogle Scholar
  143. 143.
    Schmidlin F, Amadesi S, Dabbagh K, Lewis DE, Knott P, Bunnett NW et al (2002) Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway. J Immunol 169(9):5315–5321PubMedGoogle Scholar
  144. 144.
    Takizawa T, Tamiya M, Hara T, Matsumoto J, Saito N, Kanke T et al (2005) Abrogation of bronchial eosinophilic inflammation and attenuated eotaxin content in protease-activated receptor 2-deficient mice. J Pharmacol Sci 98(1):99–102PubMedGoogle Scholar
  145. 145.
    Matsuwaki Y, Wada K, White TA, Benson LM, Charlesworth MC, Checkel JL et al (2009) Recognition of fungal protease activities induces cellular activation and eosinophil-derived neurotoxin release in human eosinophils. J Immunol 183(10):6708–6716PubMedGoogle Scholar
  146. 146.
    Moretti S, Bellocchio S, Bonifazi P, Bozza S, Zelante T, Bistoni F et al (2008) The contribution of PARs to inflammation and immunity to fungi. Mucosal Immunol 1(2):156–168PubMedGoogle Scholar
  147. 147.
    Antalis TM, Buzza MS, Hodge KM, Hooper JD, Netzel-Arnett S (2010) The cutting edge: membrane-anchored serine protease activities in the pericellular microenvironment. Biochem J 428(3):325–346PubMedGoogle Scholar
  148. 148.
    Szabo R, Kosa P, List K, Bugge TH (2009) Loss of matriptase suppression underlies spint1 mutation-associated ichthyosis and postnatal lethality. Am J Pathol 174(6):2015–2022PubMedGoogle Scholar
  149. 149.
    Netzel-Arnett S, Currie BM, Szabo R, Lin CY, Chen LM, Chai KX et al (2006) Evidence for a matriptase-prostasin proteolytic cascade regulating terminal epidermal differentiation. J Biol Chem 281(44):32941–32945PubMedGoogle Scholar
  150. 150.
    Camerer E, Barker A, Duong DN, Ganesan R, Kataoka H, Cornelissen I et al (2010) Local protease signaling contributes to neural tube closure in the mouse embryo. Dev Cell 18(1):25–38PubMedGoogle Scholar
  151. 151.
    Szabo R, Hobson JP, Christoph K, Kosa P, List K, Bugge TH (2009) Regulation of cell surface protease matriptase by HAI2 is essential for placental development, neural tube closure and embryonic survival in mice. Development 136(15):2653–2663PubMedGoogle Scholar
  152. 152.
    Sales KU, Masedunskas A, Bey AL, Rasmussen AL, Weigert R, List K et al (2010) Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome. Nat Genet 42(8):676–683PubMedGoogle Scholar
  153. 153.
    Hansson L, Backman A, Ny A, Edlund M, Ekholm E, Ekstrand HB et al (2002) Epidermal overexpression of stratum corneum chymotryptic enzyme in mice: a model for chronic itchy dermatitis. J Invest Dermatol 118(3):444–449PubMedGoogle Scholar
  154. 154.
    Oikonomopoulou K, Hansen KK, Saifeddine M, Tea I, Blaber M, Blaber SI et al (2006) Proteinase-activated receptors, targets for kallikrein signaling. J Biol Chem 281(43):32095–32112PubMedGoogle Scholar
  155. 155.
    Briot A, Deraison C, Lacroix M, Bonnart C, Robin A, Besson C et al (2009) Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med 206(5):1135–1147PubMedGoogle Scholar
  156. 156.
    Briot A, Lacroix M, Robin A, Steinhoff M, Deraison C, Hovnanian A (2010) Par2 inactivation inhibits early production of TSLP, but not cutaneous inflammation, in Netherton syndrome adult mouse model. J Invest Dermatol 130(12):2736–2742PubMedGoogle Scholar
  157. 157.
    Frateschi S, Camerer E, Crisante G, Rieser S, Membrez M, Charles RP et al (2011) PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin. Nat Commun 2(1):161PubMedGoogle Scholar
  158. 158.
    Chen M, Chen LM, Lin CY, Chai KX (2010) Hepsin activates prostasin and cleaves the extracellular domain of the epidermal growth factor receptor. Mol Cell Biochem 337(1–2):259–266PubMedGoogle Scholar
  159. 159.
    Kazama Y, Hamamoto T, Foster DC, Kisiel W (1995) Hepsin, a putative membrane-associated serine protease, activates human factor VII and initiates a pathway of blood coagulation on the cell surface leading to thrombin formation. J Biol Chem 270:66–72PubMedGoogle Scholar
  160. 160.
    Camerer E, Gjernes E, Wiiger M, Pringle S, Prydz H (2000) Binding of factor VIIa to tissue factor on keratinocytes induces gene expression. J Biol Chem 275:6580–6585PubMedGoogle Scholar
  161. 161.
    Xu Z, Xu H, Ploplis VA, Castellino FJ (2010) Factor VII deficiency impairs cutaneous wound healing in mice. Mol Med 16(5–6):167–176PubMedGoogle Scholar
  162. 162.
    Ruf W, Mueller BM (2006) Thrombin generation and the pathogenesis of cancer. Semin Thromb Hemost 32(Suppl 1):61–68PubMedGoogle Scholar
  163. 163.
    Camerer E, Qazi AA, Duong DN, Cornelissen I, Advincula R, Coughlin SR (2004) Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Blood 104(2):397–401PubMedGoogle Scholar
  164. 164.
    Shi X, Gangadharan B, Brass LF, Ruf W, Mueller BM (2004) Protease-activated receptor 1 (PAR1) and PAR2 contribute to tumor cell motility and metastasis. Mol Cancer Res 2(7):395–402PubMedGoogle Scholar
  165. 165.
    Schaffner F, Ruf W (2009) Tissue factor and PAR2 signaling in the tumor microenvironment. Arterioscler Thromb Vasc Biol 29(12):1999–2004PubMedGoogle Scholar
  166. 166.
    Yu JL, May L, Lhotak V, Shahrzad S, Shirasawa S, Weitz JI et al (2005) Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Blood 105(4):1734–1741PubMedGoogle Scholar
  167. 167.
    Milsom CC, Yu JL, Mackman N, Micallef J, Anderson GM, Guha A et al (2008) Tissue factor regulation by epidermal growth factor receptor and epithelial-to-mesenchymal transitions: effect on tumor initiation and angiogenesis. Cancer Res 68(24):10068–10076PubMedGoogle Scholar
  168. 168.
    Provencal M, Labbe D, Veitch R, Boivin D, Rivard GE, Sartelet H et al (2009) c-Met activation in medulloblastoma induces tissue factor expression and activity: effects on cell migration. Carcinogenesis 30(7):1089–1096PubMedGoogle Scholar
  169. 169.
    Rong Y, Hu F, Huang R, Mackman N, Horowitz JM, Jensen RL et al (2006) Early growth response gene-1 regulates hypoxia-induced expression of tissue factor in glioblastoma multiforme through hypoxia-inducible factor-1-independent mechanisms. Cancer Res 66(14):7067–7074PubMedGoogle Scholar
  170. 170.
    Rong Y, Belozerov VE, Tucker-Burden C, Chen G, Durden DL, Olson JJ et al (2009) Epidermal growth factor receptor and PTEN modulate tissue factor expression in glioblastoma through JunD/activator protein-1 transcriptional activity. Cancer Res 69(6):2540–2549PubMedGoogle Scholar
  171. 171.
    Rong Y, Post DE, Pieper RO, Durden DL, Van Meir EG, Brat DJ (2005) PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. Cancer Res 65(4):1406–1413PubMedGoogle Scholar
  172. 172.
    Koizume S, Jin M-S, Miyagi E, Hirahara F, Nakamura Y, Piao J-H et al (2006) Activation of cancer cell migration and invasion by ectopic synthesis of coagulation factor VII. Cancer Res 66(19):9453–9460PubMedGoogle Scholar
  173. 173.
    Magnus N, Garnier D, Rak J (2010) Oncogenic epidermal growth factor receptor up-regulates multiple elements of the tissue factor signaling pathway in human glioma cells. Blood 116(5):815–818PubMedGoogle Scholar
  174. 174.
    Ryden L, Grabau D, Schaffner F, Jonsson PE, Ruf W, Belting M (2010) Evidence for tissue factor phosphorylation and its correlation with protease activated receptor expression and the prognosis of primary breast cancer. Int J Cancer 126(10):2330–2340PubMedGoogle Scholar
  175. 175.
    Albrektsen T, Sorensen BB, Hjortoe GM, Fleckner J, Rao LVM, Petersen LC (2007) Transcriptional program induced by factor VIIa-tissue factor, PAR1 and PAR2 in MDA-MB-231 cells. J Thromb Haemost 5:1588–1597PubMedGoogle Scholar
  176. 176.
    Versteeg HH, Spek CA, Richel DJ, Peppelenbosch MP (2004) Coagulation factors VIIa and Xa inhibit apoptosis and anoikis. Oncogene 23(2):410–417PubMedGoogle Scholar
  177. 177.
    Sorensen BB, Rao LVM, Tornehave D, Gammeltoft S, Petersen LC (2003) Anti-apoptotic effect of coagulation factor VIIa. Blood 102(5):1708–1715PubMedGoogle Scholar
  178. 178.
    Wang W, Wyckoff JB, Goswami S, Wang Y, Sidani M, Segall JE et al (2007) Coordinated regulation of pathways for enhanced cell motility and chemotaxis is conserved in rat and mouse mammary tumors. Cancer Res 67(8):3505–3511PubMedGoogle Scholar
  179. 179.
    Hjortoe GM, Petersen LC, Albrektsen T, Sorensen BB, Norby PL, Mandal SK et al (2004) Tissue factor-factor VIIa specific up-regulation of IL-8 expression in MDA-MB-231 cells is mediated via PAR-2 and results in increased cell migration. Blood 103(8):3029–3037PubMedGoogle Scholar
  180. 180.
    Versteeg HH, Schaffner F, Kerver M, Petersen HH, Ahamed J, Felding-Habermann B et al (2008) Inhibition of tissue factor signaling suppresses tumor growth. Blood 111(1):190–199PubMedGoogle Scholar
  181. 181.
    Drake TA, Morrissey JH, Edgington TS (1989) Selective cellular expression of tissue factor in human tissues. Am J Pathol 134:1087–1097PubMedGoogle Scholar
  182. 182.
    Dorfleutner A, Hintermann E, Tarui T, Takada Y, Ruf W (2004) Crosstalk of integrin a3b1 and tissue factor in cell migration. Mol Biol Cell 15(10):4416–4425PubMedGoogle Scholar
  183. 183.
    Jiang X, Zhu S, Panetti TS, Bromberg ME (2008) Formation of tissue factor-factor VIIa-factor Xa complex induces activation of the mTOR pathway which regulates migration of human breast cancer cells. Thromb Haemost 100(1):127–133PubMedGoogle Scholar
  184. 184.
    Jiang X, Bailly MA, Panetti TS, Cappello M, Konigsberg WH, Bromberg ME (2004) Formation of tissue factor-factor VIIa-factor Xa complex promotes cellular signaling and migration of human breast cancer cells. J Thromb Haemost 2(1):93–101PubMedGoogle Scholar
  185. 185.
    Morris DR, Ding Y, Ricks TK, Gullapalli A, Wolfe BL, Trejo J (2006) Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration, and invasion of breast cancer cells. Cancer Res 66(1):307–314PubMedGoogle Scholar
  186. 186.
    Liu Y, Mueller BM (2006) Protease-activated receptor-2 regulates vascular endothelial growth factor expression in MDA-MB-231 cells via MAPK pathways. Biochem Biophys Res Commun 344(4):1263–1270PubMedGoogle Scholar
  187. 187.
    Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1):39–51PubMedGoogle Scholar
  188. 188.
    Gessler F, Voss V, Dutzmann S, Seifert V, Gerlach R, Kogel D (2010) Inhibition of tissue factor/protease-activated receptor-2 signaling limits proliferation, migration and invasion of malignant glioma cells. Neuroscience 165(4):1312–1322PubMedGoogle Scholar
  189. 189.
    Versteeg HH, Schaffner F, Kerver M, Ellies LG, Andrade-Gordon P, Mueller BM et al (2008) Protease activated receptor (PAR)2, but not PAR1 signaling promotes the development of mammary adenocarcinoma in PyMT mice. Cancer Res 68(17):7219–7227PubMedGoogle Scholar
  190. 190.
    Schaffner F, Versteeg HH, Schillert A, Yokota N, Petersen LC, Mueller BM et al (2010) Cooperation of tissue factor cytoplasmic domain and PAR2 signaling in breast cancer development. Blood 116(26):6106–6113PubMedGoogle Scholar
  191. 191.
    Abe K, Shoji M, Chen J, Bierhaus A, Danave I, Micko C et al (1999) Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. Proc Natl Acad Sci U S A 96(15):8663–8668PubMedGoogle Scholar
  192. 192.
    Zhang Y, Deng Y, Luther T, Müller M, Ziegler R, Waldherr R et al (1994) Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J Clin Invest 94:1320–1327PubMedGoogle Scholar
  193. 193.
    Connolly AJ, Ishihara H, Kahn ML, Farese RV Jr, Coughlin SR (1996) Role of the thrombin receptor in development and evidence for a second receptor. Nature 381:516–519PubMedGoogle Scholar
  194. 194.
    Carmeliet P, Mackman N, Moons L, Luther T, Gressens P, Van Vlaenderen I et al (1996) Role of tissue factor in embryonic blood vessel development. Nature 383:73–75PubMedGoogle Scholar
  195. 195.
    Nierodzik ML, Karpatkin S (2006) Thrombin induces tumor growth, metastasis, and angiogenesis: Evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell 10(5):355–362PubMedGoogle Scholar
  196. 196.
    Uusitalo-Jarvinen H, Kurokawa T, Mueller BM, Andrade-Gordon P, Friedlander M, Ruf W (2007) Role of protease activated receptor 1 and 2 signaling in hypoxia-induced angiogenesis. Arterioscler Thromb Vasc Biol 27(6):1456–1462PubMedGoogle Scholar
  197. 197.
    Belting M, Dorrell MI, Sandgren S, Aguilar E, Ahamed J, Dorfleutner A et al (2004) Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nature Med 10(5):502–509PubMedGoogle Scholar
  198. 198.
    Zhu T, Sennlaub F, Beauchamp MH, Fan L, Joyal JS, Checchin D et al (2006) Proangiogenic effects of protease-activated receptor 2 are tumor necrosis factor-{alpha} and consecutively Tie2 dependent. Arterioscler Thromb Vasc Biol 26(4):744–750PubMedGoogle Scholar
  199. 199.
    Milia AF, Salis MB, Stacca T, Pinna A, Madeddu P, Trevisani M et al (2002) Protease-activated receptor-2 stimulates angiogenesis and accelerates hemodynamic recovery in a mouse model of hindlimb ischemia. Circ Res 91(4):346–352PubMedGoogle Scholar
  200. 200.
    van den Berg YW, van den Hengel LG, Myers HR, Ayachi O, Jordanova E, Ruf W et al (2009) Alternatively spliced tissue factor induces angiogenesis through integrin ligation. Proc Natl Acad Sci U S A 106(46):19497–19502PubMedGoogle Scholar
  201. 201.
    Signaevsky M, Hobbs J, Doll J, Liu N, Soff GA (2008) Role of alternatively spliced tissue factor in pancreatic cancer growth and angiogenesis. Semin Thromb Hemost 34(2):161–169PubMedGoogle Scholar
  202. 202.
    Srinivasan R, Ozhegov E, van den Berg YW, Aronow BJ, Franco RS, Palascak MB et al (2011) Splice variants of tissue factor promote monocyte-endothelial interactions by triggering the expression of cell adhesion molecules via integrin-mediated signaling. J Thromb Haemost. Aug 3. doi: 10.1111/j.1538-7836.2011.04454.x
  203. 203.
    Napoli C, Cicala C, Wallace JL, de Nigris F, Santagada V, Caliendo G et al (2000) Protease-activated receptor-2 modulates myocardial ischemia-reperfusion injury in the rat heart. Proc Natl Acad Sci U S A 97:3678–3683PubMedGoogle Scholar
  204. 204.
    Gardell LR, Ma JN, Seitzberg JG, Knapp AE, Schiffer HH, Tabatabaei A et al (2008) Identification and characterization of novel small-molecule protease-activated receptor 2 agonists. J Pharmacol Exp Ther 327(3):799–808PubMedGoogle Scholar
  205. 205.
    Kelso EB, Lockhart JC, Hembrough T, Dunning L, Plevin R, Hollenberg MD et al (2006) Therapeutic promise of proteinase-activated receptor-2 antagonism in joint inflammation. J Pharmacol Exp Ther 316(3):1017–1024PubMedGoogle Scholar
  206. 206.
    Goh FG, Ng PY, Nilsson M, Kanke T, Plevin R (2009) Dual effect of the novel peptide antagonist K-14585 on proteinase-activated receptor-2-mediated signalling. Br J Pharmacol 158(7):1695–1704PubMedGoogle Scholar
  207. 207.
    Kanke T, Kabeya M, Kubo S, Kondo S, Yasuoka K, Tagashira J et al (2009) Novel antagonists for proteinase-activated receptor 2: inhibition of cellular and vascular responses in vitro and in vivo. Br J Pharmacol 158(1):361–371PubMedGoogle Scholar
  208. 208.
    Barry GD, Suen JY, Le GT, Cotterell A, Reid RC, Fairlie DP (2010) Novel agonists and antagonists for human protease activated receptor 2. J Med Chem 53(20):7428–7440PubMedGoogle Scholar
  209. 209.
    Suen JY, Barry GD, Lohman RJ, Halili MA, Cotterell AJ, Le GT et al (2011) Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110). Br J Pharmacol 10–5381Google Scholar
  210. 210.
    Larsen KS, Ostergaard H, Olsen OH, Bjelke JR, Ruf W, Petersen LC (2010) Engineering of substrate selectivity for tissue factor-factor VIIa complex signaling through protease activated receptor 2. J Biol Chem 285(26):19959–19966PubMedGoogle Scholar

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© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Immunology and Microbial ScienceThe Scripps Research InstituteLa JollaUSA

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