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Seminars in Immunopathology

Erschienen in:

01.01.2012 | Review

Protease-activated receptor 2 signaling in inflammation

verfasst von: Andrea S. Rothmeier, Wolfram Ruf

Erschienen in: Seminars in Immunopathology | Ausgabe 1/2012

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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.

Coughlin SR (2000) Thrombin signalling and protease-activated receptors. Nature 407:258–264PubMed

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):332–343PubMed

Kahn ML, Zheng YW, Huang W, Bigornia V, Zeng DW, Moff S et al (1998) A dual thrombin receptor system for platelet activation. Nature 394:690–694PubMed

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 103:879–887PubMed

Nakanishi-Matsui M, Zheng YW, Sulciner DJ, Weiss EJ, Ludeman MJ, Coughlin SR (2000) PAR3 is a cofactor for PAR4 activation by thrombin. Nature 404:609–613PubMed

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):5662–5667PubMed

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):1880–1882PubMed

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):3109–3116PubMed

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):303–313PubMed

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):3790–3798PubMed

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 91:9208–9212PubMed

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 271:14910–14915PubMed

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 275:13502–13509PubMed

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):1014–1021PubMed

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):1930–1939PubMed

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):45–48PubMed

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):1491–1504PubMed

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):164–174PubMed

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):8884–8889PubMed

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):13532–13539PubMed

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):817–824PubMed

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):7742–7747PubMed

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 97:5255–5260PubMed

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 277:16081–16087PubMed

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 272:4043–4049PubMed

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 275:26333–26342PubMed

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):967–972PubMed

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):285–290PubMed

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):1267–1281PubMed

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):21–29PubMed

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–C123PubMed

32.

Ricks TK, Trejo J (2009) Phosphorylation of protease-activated receptor-2 differentially regulates desensitization and internalization. J Biol Chem 284(49):34444–34457PubMed

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 11:36PubMed

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):78–87PubMed

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–C357PubMed

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):34418–34426PubMed

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):55419–55424PubMed

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):221–230PubMed

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):9374–9385PubMed

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):14318–14329PubMed

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 282:20634–20646PubMed

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):31657–31666PubMed

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):8491–8496PubMed

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):741–756PubMed

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):1383–1393PubMed

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):1009–1016PubMed

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 92:9151–9155PubMed

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):53–63PubMed

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 314:1009–1016PubMed

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):535–544PubMed

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):38–45PubMed

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):380–385PubMed

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):11792–11804PubMed

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):18524–18535PubMed

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–C1329PubMed

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):16076–16087PubMed

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):28453–28466PubMed

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 271:22003–22016PubMed

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

60.

Levi M, Van der Poll T (2010) Inflammation and coagulation. Crit Care Med 38(2 Suppl):S26–S34PubMed

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):13932–13937PubMed

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):5756–5767PubMed

63.

Bazan JF (1990) Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A 87:6934–6938PubMed

64.

Carson SD, Bromberg ME (2000) Tissue factor encryption/de-encryption is not altered in the absence of the cytoplasmic domain. Thromb Haemost 84:657–663PubMed

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 266:21911–21916PubMed

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):11977–11984PubMed

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 267:3561–3564PubMed

68.

Ahamed J, Ruf W (2004) Protease-activated receptor 2-dependent phosphorylation of the tissue factor cytoplasmic domain. J Biol Chem 279(22):23038–23044PubMed

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 274:21349–21354PubMed

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):27065–27072PubMed

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):127–134PubMed

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 91:1609–1615PubMed

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):1342–1347PubMed

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):806–814PubMed

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):1028–1034PubMed

76.

Xu H, Ploplis VA, Castellino FJ (2006) A coagulation factor VII deficiency protects against acute inflammatory responses in mice. J Pathol 210(4):488–496PubMed

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):591–599PubMed

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 94:3413–3420PubMed

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):331–340PubMed

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):5251–5259PubMed

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 152:614–622PubMed

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 83:902–911PubMed

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):651–659PubMed

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):1325–1332PubMed

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):35–41PubMed

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):109–117PubMed

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):3453–3461PubMed

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):425–435PubMed

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):1817–1822PubMed

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):4440–4448PubMed

91.

Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246PubMed

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):7591–7596PubMed

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):572–577PubMed

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):513–519PubMed

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)

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):524–529PubMed

97.

Holzer P (1998) Neurogenic vasodilatation and plasma leakage in the skin. Gen Pharmacol 30(1):5–11PubMed

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 6:151–158PubMed

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):419–422PubMed

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):1083–1090PubMed

101.

Suckow SK, Caudle RM (2008) Identification and immunohistochemical characterization of colospinal afferent neurons in the rat. Neuroscience 153(3):803–813PubMed

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):920–927PubMed

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):4296–4300PubMed

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 7:821–826PubMed

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):4293–4299PubMed

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):4300–4312PubMed

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):555–571PubMed

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):937–946PubMed

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):715–733PubMed

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):643–650PubMed

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):300–307PubMed

112.

Lam DK, Schmidt BL (2010) Serine proteases and protease-activated receptor 2-dependent allodynia: a novel cancer pain pathway. Pain 149(2):263–272PubMed

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):1979–1987PubMed

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–G42PubMed

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):157–164PubMed

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):261–269PubMed

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–S240PubMed

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):950–957PubMed

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):20703–20712PubMed

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 129:1808–1814PubMed

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):958–964PubMed

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–G395PubMed

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):636–647PubMed

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):1903–1915PubMed

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):847–852PubMed

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):8363–8368PubMed

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):1222–1229PubMed

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):913–925PubMed

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):31936–31948PubMed

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):118–124PubMed

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):1330–1335PubMed

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):57–65PubMed

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):4200–4205PubMed

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 165:6504–6510PubMed

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):699–709PubMed

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):1595–1601PubMed

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):2634–2643PubMed

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):3238–3246PubMed

139.

Chung WO, Hansen SR, Rao D, Dale BA (2004) Protease-activated receptor signaling increases epithelial antimicrobial peptide expression. J Immunol 173(8):5165–5170PubMed

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):4326–4333PubMed

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):156–160PubMed

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):7795–7802PubMed

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):5315–5321PubMed

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):99–102PubMed

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):6708–6716PubMed

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):156–168PubMed

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):325–346PubMed

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):2015–2022PubMed

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):32941–32945PubMed

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):25–38PubMed

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):2653–2663PubMed

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):676–683PubMed

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):444–449PubMed

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):32095–32112PubMed

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):1135–1147PubMed

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):2736–2742PubMed

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):161PubMed

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):259–266PubMed

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 270:66–72PubMed

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 275:6580–6585PubMed

161.

Xu Z, Xu H, Ploplis VA, Castellino FJ (2010) Factor VII deficiency impairs cutaneous wound healing in mice. Mol Med 16(5–6):167–176PubMed

162.

Ruf W, Mueller BM (2006) Thrombin generation and the pathogenesis of cancer. Semin Thromb Hemost 32(Suppl 1):61–68PubMed

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):397–401PubMed

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):395–402PubMed

165.

Schaffner F, Ruf W (2009) Tissue factor and PAR2 signaling in the tumor microenvironment. Arterioscler Thromb Vasc Biol 29(12):1999–2004PubMed

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):1734–1741PubMed

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):10068–10076PubMed

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):1089–1096PubMed

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):7067–7074PubMed

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):2540–2549PubMed

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):1406–1413PubMed

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):9453–9460PubMed

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):815–818PubMed

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):2330–2340PubMed

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 5:1588–1597PubMed

176.

Versteeg HH, Spek CA, Richel DJ, Peppelenbosch MP (2004) Coagulation factors VIIa and Xa inhibit apoptosis and anoikis. Oncogene 23(2):410–417PubMed

177.

Sorensen BB, Rao LVM, Tornehave D, Gammeltoft S, Petersen LC (2003) Anti-apoptotic effect of coagulation factor VIIa. Blood 102(5):1708–1715PubMed

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):3505–3511PubMed

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):3029–3037PubMed

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):190–199PubMed

181.

Drake TA, Morrissey JH, Edgington TS (1989) Selective cellular expression of tissue factor in human tissues. Am J Pathol 134:1087–1097PubMed

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):4416–4425PubMed

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):127–133PubMed

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):93–101PubMed

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):307–314PubMed

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):1263–1270PubMed

187.

Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1):39–51PubMed

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):1312–1322PubMed

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):7219–7227PubMed

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):6106–6113PubMed

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):8663–8668PubMed

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 94:1320–1327PubMed

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 381:516–519PubMed

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 383:73–75PubMed

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):355–362PubMed

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):1456–1462PubMed

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):502–509PubMed

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):744–750PubMed

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):346–352PubMed

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):19497–19502PubMed

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):161–169PubMed

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.

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 97:3678–3683PubMed

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):799–808PubMed

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):1017–1024PubMed

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):1695–1704PubMed

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):361–371PubMed

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):7428–7440PubMed

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 10–5381

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):19959–19966PubMed

Titel: Protease-activated receptor 2 signaling in inflammation
verfasst von: Andrea S. Rothmeier
Wolfram Ruf
Publikationsdatum: 01.01.2012
Verlag: Springer-Verlag
Erschienen in: Seminars in Immunopathology / Ausgabe 1/2012
Print ISSN: 1863-2297
Elektronische ISSN: 1863-2300
DOI: https://doi.org/10.1007/s00281-011-0289-1

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