Download PDF
Thromb Haemost 2014; 112(05): 876-882
DOI: 10.1160/th14-02-0167
Theme Issue Article
Schattauer GmbH

Protease-activated receptor signalling by coagulation proteases in endothelial cells

Alireza R. Rezaie
1   Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
› Author Affiliations
Further Information

Publication History

Received: 22 February 2014

Accepted after major revision: 01 May 2014

Publication Date:
20 November 2017 (online)

    Permissions and Reprints

Summary

Endothelial cells express several types of integral membrane protein receptors, which upon interaction and activation by their specific ligands, initiate a signalling network that links extracellular cues in circulation to various biological processes within a plethora of cells in the vascular system. A small family of G-protein coupled receptors, termed protease-activated receptors (PAR1–4), can be specifically activated by coagulation proteases, thereby modulating a diverse array of cellular activities under various pathophysiological conditions. Thrombin and all vitamin K-dependent coagulation proteases, with the exception of factor IXa for which no PAR signalling has been attributed, can selectively activate cell surface PARs on the vasculature. Thrombin can activate PAR1, PAR3 and PAR4, but not PAR2 which can be specifically activated by factors VIIa and Xa. The mechanistic details of the specificity of PAR signalling by coagulation proteases are the subject of extensive investigation by many research groups worldwide. However, analysis of PAR signalling data in the literature has proved to be challenging since a single coagulation protease can elicit different signalling responses through activation of the same PAR receptor in endothelial cells. This article is focused on briefly reviewing the literature with respect to determinants of the specificity of PAR signalling by coagulation proteases with special emphasis on the mechanism of PAR1 signalling by thrombin and activated protein C in endothelial cells.

Keywords

Protease-activated receptor - thrombin - activated protein C - signalling
 

  • References

  • 1 Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost 2005; 3: 1800-1814.
    CrossrefPubMedGoogle Scholar
  • 2 Ruf W, Dorfleutner A, Riewald M. 2003. Specificity of coagulation factor signalling. J Thromb Haemost 2003; 1: 1495-1503.
    CrossrefPubMedGoogle Scholar
  • 3 Leger AJ, Covic L, Kuliopulos A. Protease-activated receptors in cardiovascular diseases. Circulation 2006; 114: 1070-1077.
    CrossrefPubMedGoogle Scholar
  • 4 Antoniak S, Pawlinski R, Mackman N. Protease-activated receptors and myocardial infarction. IUBMB Life 2011; 63: 383-389.
    CrossrefPubMedGoogle Scholar
  • 5 Xu WF, Andersen H, Whitmore TE. et al. Cloning and characterisation of human protease-activated receptor 4. Proc Natl Acad Sci USA 1998; 95: 6642-6646.
    CrossrefPubMedGoogle Scholar
  • 6 Feistritzer C, Lenta R, Riewald M. Protease-activated receptor-1 and -2 can mediate endothelial barrier protection: role in factor Xa signalling. J Thromb Hae-most 2005; 3: 2798-2805.
    CrossrefPubMedGoogle Scholar
  • 7 Awasthi V, Mandal SK, Papanna V. et al. Modulation of tissue factor-factor VIIa signalling by lipid rafts and caveolae. Arterioscler Thromb Vasc Biol 2007; 27: 1447-1455.
    CrossrefPubMedGoogle Scholar
  • 8 Ritchie E, Saka M, MacKenzie C. et al. Cytokine upregulation of proteinase-activated receptors 2 and 4 expression mediated by p38 MAP kinase and inhibitory kappa B kinase beta in human endothelial cells. Br J Pharmacol 2007; 150: 1044-1054.
    PubMedGoogle Scholar
  • 9 McLaughlin JN, Patterson MM, Malik AB. Protease-activated receptor-3 (PAR3) regulates PAR1 signalling by receptor dimerisation. Proc Natl Acad Sci USA 2007; 104: 5662-5667.
    CrossrefPubMedGoogle Scholar
  • 10 Bae JS, Yang L, Manithody C. et al. The ligand occupancy of endothelial protein C receptor switches the PAR-1-dependent signalling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells. Blood 2007; 110: 3909-3916.
    CrossrefPubMedGoogle Scholar
  • 11 McLaughlin JN, Shen L, Holinstat M. et al. Functional selectivity of G protein signalling by agonist peptides and thrombin for the protease-activated receptor-1. J Biol Chem 2005; 280: 25048-25059.
    CrossrefPubMedGoogle Scholar
  • 12 Mosnier LO, Griffin JH. The cytoprotective protein C pathway. Blood 2007; 109: 3161-3172.
    CrossrefPubMedGoogle Scholar
  • 13 Esmon CT. Protein C anticoagulant system--anti-inflammatory effects. Semin Immunopathol 2012; 34: 127-132.
    CrossrefPubMedGoogle Scholar
  • 14 Weiler H. Multiple receptor-mediated functions of activated protein C. Hamostaseologie 2011; 31: 185-195.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Castellino FJ, Ploplis VA. The protein C pathway and pathologic processes. J Thromb Haemost 2009; 7 (Suppl. 01) 140-145.
    CrossrefPubMedGoogle Scholar
  • 16 Bernard GR, Vincent JL, Laterre PF. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Eng J Med 2001; 344: 699-709.
    CrossrefPubMedGoogle Scholar
  • 17 Mitka M. Drug for severe sepsis is withdrawn from market, fails to reduce mortality. J Am Med Assoc 2011; 306: 2439-2440.
    PubMedGoogle Scholar
  • 18 Kalil AC, LaRosa SP. Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression. Lancet Infect Dis 2012; 12: 678-686.
    CrossrefPubMedGoogle Scholar
  • 19 Lane DA, Philippou H, Huntington JA. Directing thrombin. Blood 2005; 106: 2605-2612.
    CrossrefPubMedGoogle Scholar
  • 20 Camerer E, Coughlin SR. APC signalling: tickling PAR1 for barrier protection?. Blood 2005; 105: 3004-3005.
    CrossrefPubMedGoogle Scholar
  • 21 Ossovskaya VS, Bunnett NW. Protease-activated receptors: Contribution to physiology and disease. Physiol Rev 2004; 84: 579-621.
    CrossrefPubMedGoogle Scholar
  • 22 Kaplanski G, Marin V, Fabrigoule M. et al. Thrombin-activated human endothelial cells support monocyte adhesion in vitro following expression of intra-cellular adhesion molecule-1 (ICAM-1; CD54) and vascular cell adhesion molecule-1 (VCAM-1; CD106). Blood 1998; 92: 1259-1267.
    PubMedGoogle Scholar
  • 23 Joyce DE, Gelbert L, Ciaccia A. et al. Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem 2001; 276: 11199-11203.
    CrossrefPubMedGoogle Scholar
  • 24 Finigan JH, Dudek SM, Singleton PA. et al. Activated protein C mediates novel lung endothelial barrier enhancement: Role of sphingosine 1-phosphate receptor transactivation. J Biol Chem 2005; 280: 17286-17293.
    CrossrefPubMedGoogle Scholar
  • 25 Bae JS, Rezaie AR. Thrombin inhibits nuclear factor (B and RhoA pathways in cytokine-stimulated vascular endothelial cells when EPCR is occupied by protein C. Thromb Haemost 2009; 101: 513-520.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Hoxie JA, Ahuja M, Belmonte E. et al. Internalisation and recycling of activated thrombin receptors. J Biol Chem 1993; 268: 13756-13763.
    PubMedGoogle Scholar
  • 27 Hein L, Ishii K, Coughlin SR. et al. Intracellular targeting and trafficking of thrombin receptors. A novel mechanism for resensitisation of a G protein-coupled receptor. J Biol Chem 1994; 269: 27719-27726.
    PubMedGoogle Scholar
  • 28 Busch C, Cancilla PA, DeBault LE. et al. Use of endothelium cultured on micro-carriers as a model for the microcirculation. Lab Invest 1982; 47: 498-504.
    PubMedGoogle Scholar
  • 29 Ye J, Rezaie AR, Esmon CT. Glycosaminoglycan contributions to both protein C activation and thrombin inhibition involve a common arginine-rich site in thrombin that includes residues arginine 93, 97, and 101. J Biol Chem 1994; 269: 17965-17970.
    PubMedGoogle Scholar
  • 30 Nieman MT, Schmaier AH. Interaction of thrombin with PAR1 and PAR4 at the thrombin cleavage site. Biochemistry 2007; 46: 8603-8610.
    CrossrefPubMedGoogle Scholar
  • 31 Bae JS, Yang L, Rezaie AR. Receptors of the protein C activation and activated protein C signalling pathways are colocalized in lipid rafts of endothelial cells. Proc Natl Acad Sci USA 2007; 104: 2867-2872.
    CrossrefPubMedGoogle Scholar
  • 32 Bae JS, Yang L, Rezaie AR. Lipid raft localisation regulates the cleavage specificity of protease activated receptor 1 in endothelial cells. J Thromb Haemost 2008; 6: 954-961.
    CrossrefPubMedGoogle Scholar
  • 33 Mosnier LO, Sinha RK, Burnier L. et al. Biased agonism of protease-activated receptor 1 by activated protein C caused by noncanonical cleavage at Arg46. Blood 2012; 120: 5237-5246.
    CrossrefPubMedGoogle Scholar
  • 34 Schuepbach RA, Madon J, Ender M. et al. Protease-activated receptor-1 cleaved at R46 mediates cytoprotective effects. J Thromb Haemost 2012; 10: 1675-1684.
    CrossrefPubMedGoogle Scholar
  • 35 Ludeman MJ, Kataoka H, Srinivasan Y. et al. PAR1 cleavage and signalling in response to activated protein C and thrombin. J Biol Chem 2005; 280: 13122-13128.
    CrossrefPubMedGoogle Scholar
  • 36 Toltl LJ, Swystun LL, Pepler L. et al. Protective effects of activated protein C in sepsis. Thromb Haemost 2008; 100: 582-592.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Loubele ST, Spronk HM, Ten Cate H. Activated protein C: a promising drug with multiple effects?. Mini Rev Med Chem 2009; 9: 620-626.
    CrossrefPubMedGoogle Scholar
  • 38 Fukudome K, Esmon CT. Identification, cloning and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem 1994; 269: 26486-26491.
    PubMedGoogle Scholar
  • 39 Riewald M, Petrovan RJ, Donner A. et al. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 2002; 296: 1880-1882.
    CrossrefPubMedGoogle Scholar
  • 40 Regan LM, Mollica JS, Rezaie AR. et al. The interaction between the endothelial cell protein C receptor and protein C is dictated by the gamma-carboxyglutamic acid domain of protein C. J Biol Chem 1997; 272: 26279-26284.
    CrossrefPubMedGoogle Scholar
  • 41 Feistritzer C, Schuepbach RA, Mosnier LO. et al. Protective signalling by activated protein C is mechanistically linked to protein C activation on endothelial cells. J Biol Chem 2006; 281: 20077-20084.
    CrossrefPubMedGoogle Scholar
  • 42 Bae JS, Rezaie AR. Activated protein C inhibits high mobility group box 1 signalling in endothelial cells. Blood 2011; 118: 3952-3959.
    CrossrefPubMedGoogle Scholar
  • 43 Rezaie AR. The occupancy of endothelial protein C receptor by its ligand modulates the PAR1-dependent signalling specificity of coagulation proteases. IUBMB Life 2011; 63: 390-396.
    CrossrefPubMedGoogle Scholar
  • 44 Lefkowitz RJ, Rajagopal K, Whalen EJ. New roles for (-arrestins in cell signalling: Not just for seven-transmembrane receptors. Molecular Cell 2006; 24: 643-652.
    CrossrefPubMedGoogle Scholar
  • 45 Shukla AK, Xiao K, Lefkowitz RJ. Emerging paradigms of -arrestin-dependent seven transmembrane receptor signalling. Trends Biochem Sci 2011; 36: 457-469.
    CrossrefPubMedGoogle Scholar
  • 46 Soh UJ, Trejo J. Activated protein C promotes protease-activated receptor-1 cytoprotective signalling through -arrestin and dishevelled-2 scaffolds. Proc Natl Acad Sci USA 2011; 108: E1372-1380.
    CrossrefPubMedGoogle Scholar
  • 47 Bouwens EA, Stavenuiter F, Mosnier LO. Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway. J Thromb Haemost 2013; 11 (Suppl. 01) 242-253.
    CrossrefPubMedGoogle Scholar
  • 48 Schuepbach RA, Feistritzer C, Brass LF. et al. Activated protein C-cleaved pro-tease activated receptor-1 is retained on the endothelial cell surface even in the presence of thrombin. Blood 2008; 111: 2667-2673.
    CrossrefPubMedGoogle Scholar
  • 49 Versteeg HH, Schaffner F, Kerver M. et al. Inhibition of tissue factor signalling suppresses tumour growth. Blood 2008; 111: 190-199.
    CrossrefPubMedGoogle Scholar
  • 50 Lima LG, Monteiro RQ. Activation of blood coagulation in cancer: implications for tumour progression. Biosci Rep 2013; 33 pii e00064. doi: 10.1042/BSR20130057.
    PubMedGoogle Scholar
  • 51 Ahamed J, Ruf W. Protease-activated receptor 2-dependent phosphorylation of the tissue factor cytoplasmic domain. J Biol Chem 2004; 279: 23038-23044.
    CrossrefPubMedGoogle Scholar
  • 52 Ott I, Weigand B, Michl R. et al. Tissue factor cytoplasmic domain stimulates migration by activation of the GTPase Rac1 and the mitogen-activated protein kinase p38. Circulation 2005; 111: 349-355.
    CrossrefPubMedGoogle Scholar
  • 53 Ahamed J, Niessen F, Kurokawa T. et al. Regulation of macrophage procoagulant responses by the tissue factor cytoplasmic domain in endotoxemia. Blood 2007; 109: 5251-5259.
    CrossrefPubMedGoogle Scholar
  • 54 Pendurthi UR, Rao LV. Factor VIIa interaction with endothelial cells and endothelial cell protein C receptor. Thromb Res 2010; 125 (Suppl. 01) S19-22.
    CrossrefPubMedGoogle Scholar
  • 55 Ghosh S, Pendurthi UR, Steinoe A. et al. Endothelial cell protein C receptor acts as a cellular receptor for factor VIIa on endothelium. J Biol Chem 2007; 282: 11849-11857.
    CrossrefPubMedGoogle Scholar
  • 56 Sen P, Gopalakrishnan R, Kothari H. et al. Factor VIIa bound to endothelial cell protein C receptor activates protease activated receptor-1 and mediates cell signalling and barrier protection. Blood 2011; 117: 3199-3208.
    CrossrefPubMedGoogle Scholar
  • 57 Riewald M, Ruf W. Mechanistic coupling of protease signalling and initiation of coagulation by tissue factor. Proc Natl Acad Sci USA 2001; 98: 7742-7747.
    CrossrefPubMedGoogle Scholar
  • 58 Bhattacharjee G, Ahamed J, Pawlinski R. et al. Factor Xa binding to annexin 2 mediates signal transduction via protease-activated receptor 1. Circ Res 2008; 102: 457-464.
    CrossrefPubMedGoogle Scholar
  • 59 Bukowska A, Zacharias I, Weinert S. et al. Coagulation factor Xa induces an inflammatory signalling by activation of protease-activated receptors in human atrial tissue. Eur J Pharmacol 2013; 718: 114-123.
    CrossrefPubMedGoogle Scholar
  • 60 Daubie V, Cauwenberghs S, Senden NH. et al. Factor Xa and thrombin evoke additive calcium and proinflammatory responses in endothelial cells subjected to coagulation. Biochim Biophys Acta 2006; 1763: 860-869.
    CrossrefPubMedGoogle Scholar
  • 61 Senden NH, Jeunhomme TM, Heemskerk JW. et al. Factor Xa induces cytokine production and expression of adhesion molecules by human umbilical vein endothelial cells. J Immunol 1998; 161: 4318-4824.
    PubMedGoogle Scholar
  • 62 Rana S, Yang L, Hassanian SM. et al. Determinants of the specificity of protease-activated receptors 1 and 2 signalling by factor Xa and thrombin. J Cell Biochem 2012; 113: 977-984.
    CrossrefPubMedGoogle Scholar
  • 63 Manithody C, Yang L, Rezaie AR. Identification of exosite residues of factor Xa involved in recognition of PAR-2 on endothelial cells. Biochemistry 2012; 51: 2551-2557.
    CrossrefPubMedGoogle Scholar
  • 64 Ambrosini G, Plescia J, Chu KC. et al. Activation-dependent exposure of the inter-EGF sequence Leu83-Leu88 in factor Xa mediates ligand binding to effector cell protease receptor-1. J Biol Chem 1997; 272: 8340-8345.
    CrossrefPubMedGoogle Scholar
  • 65 Bae JS, Yang L, Rezaie AR. Factor X/Xa elicits protective signalling responses in endothelial cells directly via PAR-2 and indirectly via endothelial protein C receptor-dependent recruitment of PAR-1. J Biol Chem 2010; 285: 34803-34812.
    CrossrefPubMedGoogle Scholar
  • 66 Bae JS, Rezaie AR. Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand. Thromb Haemost 2008; 100: 101-109.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 67 Slofstra SH, Bijlsma MF, Groot AP. et al. Protease-activated receptor-4 inhibition protects from multiorgan failure in a murine model of systemic inflammation. Blood 2007; 110: 3176-3182.
    CrossrefPubMedGoogle Scholar
  • 68 Feistritzer C, Riewald M.. Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 2005; 105: 3178-3184.
    CrossrefPubMedGoogle Scholar
  • 69 Minhas N, Xue M, Fukudome K. et al. Activated protein C utilizes the angiopoietin/Tie2 axis to promote endothelial barrier function. FASEB J 2010; 24: 873-881.
    CrossrefPubMedGoogle Scholar
  • 70 Bae JS, Rezaie AR. Thrombin upregulates the angiopoietin-Tie2 Axis: endothelial protein C receptor occupancy prevents the thrombin mobilisation of angiopoietin 2 and P-selectin from Weibel-Palade bodies. J Thromb Haemost 2010; 8: 1107-1115.
    PubMedGoogle Scholar
  • 71 Yang XV, Banerjee Y, Fernández JA. et al. Activated protein C ligation of ApoER2 (LRP8) causes Dab1-dependent signalling in U937 cells. Proc Natl Acad Sci USA 2009; 106: 274-279.
    CrossrefPubMedGoogle Scholar
  • 72 Cao C, Gao Y, Li Y. et al. The efficacy of activated protein C in murine endotoxemia is dependent on integrin CD11b. J Clin Invest 2010; 120: 1971-1980.
    CrossrefPubMedGoogle Scholar
  • 73 Niessen F, Schaffner F, Furlan-Freguia C. et al. Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation. Nature 2008; 452: 654-658.
    CrossrefPubMedGoogle Scholar
  • 74 Guo H, Liu D, Gelbard H. et al. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron 2004; 41: 563-572.
    CrossrefPubMedGoogle Scholar
  • 75 Bock F, Shahzad K, Wang H. et al. Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc. Proc Natl Acad Sci USA 2013; 110: 648-653.
    CrossrefPubMedGoogle Scholar
  • 76 Burnier L, Mosnier LO. Novel mechanisms for activated protein C cytoprotective activities involving noncanonical activation of protease-activated receptor 3. Blood 2013; 122: 807-816.
    CrossrefPubMedGoogle Scholar
  • 77 Arachiche A, Mumaw MM, de la Fuente M. et al. Protease-activated receptor 1 (PAR1) and PAR4 heterodimers are required for PAR1-enhanced cleavage of PAR4 by [/acute]-thrombin. J Biol Chem 2013; 288: 32553-32562.
    CrossrefPubMedGoogle Scholar
  • 78 Hassanian SM, Dinarvand P, Rezaie AR. Adenosine Regulates the Proinflamma-tory Signalling Function of Thrombin in Endothelial Cells. J Cell Physiol. 2014 Epub ahead of print.
    PubMedGoogle Scholar