Download PDF
Thromb Haemost 2012; 107(05): 815-826
DOI: 10.1160/TH11-11-0766
Review Article
Schattauer GmbH

Is EPCR a multi-ligand receptor? Pros and cons

Ramón Montes
1   Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain
,
Cristina Puy  
1   Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain
,
Eva Molina
1   Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain
,
José Hermida
1   Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain
› Author Affiliations Financial support: The authors’ work is supported through the Unión Temporal de Empresas project CIMA and by grants from Instituto de Salud Carlos III (PI08/1349, PI10/01432 and Red Temática de Investigación RECAVA RD06/0014/0008) and Health Department, Gobierno de Navarra (15/09).
Further Information

Publication History

Received: 07 November 2011

Accepted after major revision: 05 January 2012

Publication Date:
25 November 2017 (online)

    Permissions and Reprints

Summary

In the last decade, the endothelial cell protein C/activated protein C receptor (EPCR) has received considerable attention. The role initially attributed to EPCR, i.e. the enhancement of protein C (PC) activation by the thrombin-thrombomodulin complex on the surface of the large vessels, although important, did not go beyond the haemostasis scenario. However, the discovery of the cytoprotective, anti-inflammatory and anti-apoptotic features of the activated PC (APC) and the required involvement of EPCR for APC to exert such actions did place the receptor in a privileged position in the crosstalk between coagulation and inflammation. The last five years have shown that PC/APC are not the only molecules able to interact with EPCR. Factor VII/VIIa (FVII/VIIa) and factor Xa (FXa), two other serine proteases that play a central role in haemostasis and are also involved in signalling processes influencing wound healing, tissue remodelling, inflammation or metastasis, have been reported to bind to EPCR. These observations have paved the way for an exploration of unsuspected new roles for the receptor. This review aims to offer a new image of EPCR in the light of its extended panel of ligands. A brief update of what is known about the APC-evoked EPCR-dependent cell signalling mechanisms is provided, but special care has been taken to assemble all the information available about the interaction of EPCR with FVII/VIIa and FXa.

Keywords

EPCR - protein C - factor VII - factor X - endothelium

Present address: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon, USA.


 

  • References

  • 1 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
  • 2 Fukudome K, Esmon CT. Molecular cloning and expression of murine and bovine endothelial cell protein C/activated protein C receptor (EPCR). The structural and functional conservation in human, bovine, and murine EPCR. J Biol Chem 1995; 270: 5571-5577.
    CrossrefPubMedGoogle Scholar
  • 3 Fukudome K. et al. The endothelial cell protein C receptor. Cell surface expression and direct ligand binding by the soluble receptor. J Biol Chem 1996; 271: 17491-17498.
    CrossrefPubMedGoogle Scholar
  • 4 Crawley JT. et al. Distribution of endothelial cell protein C/activated protein C receptor (EPCR) during mouse embryo development. Thromb Haemost 2002; 88: 259-266.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Laszik Z. et al. Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway. Circulation 1997; 96: 3633-3640.
    CrossrefPubMedGoogle Scholar
  • 6 Stearns-Kurosawa DJ. et al. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci USA 1996; 93: 10212-10216.
    CrossrefPubMedGoogle Scholar
  • 7 Bae JS. et al. Receptors of the protein C activation and activated protein C signaling pathways are colocalized in lipid rafts of endothelial cells. Proc Natl Acad Sci USA 2007; 104: 2867-2872.
    CrossrefPubMedGoogle Scholar
  • 8 Regan LM. 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
  • 9 Taylor Jr FB. et al. Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood 2001; 97: 1685-1688.
    CrossrefPubMedGoogle Scholar
  • 10 Centelles MN. et al. Blocking endothelial protein C receptor (EPCR) accelerates thrombus development in vivo. Thromb Haemost 2010; 103: 1239-1244.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Hurtado V. et al. Autoantibodies against EPCR are found in antiphospholipid syndrome and are a risk factor for fetal death. Blood 2004; 104: 1369-1374.
    CrossrefPubMedGoogle Scholar
  • 12 Montes R. et al. Autoantibodies against the endothelial receptor of protein C are associated with acute myocardial infarction in young women. J Thromb Haemost 2005; 03: 1454-1458.
    CrossrefPubMedGoogle Scholar
  • 13 van Hylckama Vlieg A. et al. Autoantibodies against endothelial protein C receptor and the risk of a first deep vein thrombosis. J Thromb Haemost 2007; 05: 1449-1454.
    CrossrefPubMedGoogle Scholar
  • 14 Castellino FJ. et al. Mice with a severe deficiency of the endothelial protein C receptor gene develop, survive, and reproduce normally, and do not present with enhanced arterial thrombosis after challenge. Thromb Haemost 2002; 88: 462-472.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Reiner AP. et al. PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study. J Thromb Haemost 2008; 06: 1625-1632.
    CrossrefPubMedGoogle Scholar
  • 16 Tang W. et al. Genome-wide association study identifies novel loci for plasma levels of protein C: the ARIC study. Blood 2010; 116: 5032-5036.
    CrossrefPubMedGoogle Scholar
  • 17 Biguzzi E. et al. A 23bp insertion in the endothelial protein C receptor (EPCR) gene impairs EPCR function. Thromb Haemost 2001; 86: 945-948.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Medina P. et al. Contribution of polymorphisms in the endothelial protein C receptor gene to soluble endothelial protein C receptor and circulating activated protein C levels, and thrombotic risk. Thromb Haemost 2004; 91: 905-911.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Saposnik B. et al. A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis. Blood 2004; 103: 1311-1318.
    PubMedGoogle Scholar
  • 20 Uitte de Willige S. et al. Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis. J Thromb Haemost 2004; 02: 1305-1310.
    CrossrefPubMedGoogle Scholar
  • 21 Medina P. et al. Influence of the 4600A/G and 4678G/C polymorphisms in the endothelial protein C receptor (EPCR) gene on the risk of venous thromboembolism in carriers of factor V Leiden. Thromb Haemost 2005; 94: 389-394.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Ireland H. et al. EPCR Ser219Gly: elevated sEPCR, prothrombin F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro. Atherosclerosis 2005; 183: 283-292.
    CrossrefPubMedGoogle Scholar
  • 23 Navarro S. et al. Haplotypes of the EPCR gene, prothrombin levels, and the risk of venous thrombosis in carriers of the prothrombin G20210A mutation. Haematologica 2008; 93: 885-891.
    CrossrefPubMedGoogle Scholar
  • 24 Medina P. et al. Endothelial protein C receptor polymorphisms and risk of myocardial infarction. Haematologica 2008; 93: 1358-63.
    CrossrefPubMedGoogle Scholar
  • 25 Pomp ER. et al. Polymorphisms in the protein C gene as risk factor for venous thrombosis. Thromb Haemost 2009; 101: 62-67.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Cochery-Nouvellon E. et al. The A6936G polymorphism of the endothelial protein C receptor gene is associated with the risk of unexplained foetal loss in Mediterranean European couples. Thromb Haemost 2009; 102: 656-667.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Yamagishi K. et al. Lack of association of soluble endothelial protein C receptor and PROCR 6936A/G polymorphism with the risk of venous thromboembolism in a prospective study. Br J Haematol 2009; 145: 221-226.
    CrossrefPubMedGoogle Scholar
  • 28 Medina P. et al. Polymorphisms in the endothelial protein C receptor gene and thrombophilia. Thromb Haemost 2007; 98: 564-569.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Navarro S. et al. The endothelial cell protein C receptor: Its role in thrombosis. Thromb Res 2011; 128: 410-416.
    CrossrefPubMedGoogle Scholar
  • 30 Bernard GR. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.
    CrossrefPubMedGoogle Scholar
  • 31 Taylor Jr FB. et al. DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage. Blood 1991; 78: 364-368.
    PubMedGoogle Scholar
  • 32 Warren BL. et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. J Am Med Assoc 2001; 286: 1869-1878.
    CrossrefPubMedGoogle Scholar
  • 33 Taylor Jr FB. et al. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 2000; 95: 1680-1686.
    PubMedGoogle Scholar
  • 34 Sarangi PP, Let al. Activated protein C action in inflammation. Br J Haematol 2010; 148: 817-833.
    CrossrefPubMedGoogle Scholar
  • 35 Neyrinck AP. et al. Protective mechanisms of activated protein C in severe inflammatory disorders. Br J Pharmacol 2009; 158: 1034-1047.
    CrossrefPubMedGoogle Scholar
  • 36 Toltl LJ. et al. Protective effects of activated protein C in sepsis. Thromb Haemost 2008; 100: 582-592.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Joyce DE. 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
  • 38 Riewald M. et al. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 2002; 296: 1880-1882.
    CrossrefPubMedGoogle Scholar
  • 39 Joyce DE, Grinnell BW. Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappa B. Crit Care Med 2002; 30: S288-293.
    CrossrefPubMedGoogle Scholar
  • 40 Cheng T. et al. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med 2003; 09: 338-42.
    CrossrefPubMedGoogle Scholar
  • 41 Franscini N. et al. Gene expression profiling of inflamed human endothelial cells and influence of activated protein C. Circulation 2004; 110: 2903-2909.
    CrossrefPubMedGoogle Scholar
  • 42 Riewald M, Ruf W. Protease-activated receptor-1 signaling by activated protein C in cytokine-perturbed endothelial cells is distinct from thrombin signaling. J Biol Chem 2005; 280: 19808-19814.
    CrossrefPubMedGoogle Scholar
  • 43 Brueckmann M. et al. Recombinant human activated protein C upregulates cyclooxygenase-2 expression in endothelial cells via binding to endothelial cell protein C receptor and activation of protease-activated receptor-1. Thromb Haemost 2005; 93: 743-750.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Brueckmann M. et al. Recombinant human activated protein C upregulates the release of soluble fractalkine from human endothelial cells. Br J Haematol 2006; 133: 550-557.
    CrossrefPubMedGoogle Scholar
  • 45 Mosnier LO. et al. The cytoprotective protein C pathway. Blood 2007; 109: 3161-3172.
    CrossrefPubMedGoogle Scholar
  • 46 Feistritzer C. et al. Protective signaling by activated protein C is mechanistically linked to protein C activation on endothelial cells. J Biol Chem 2006; 281: 20077-20084.
    CrossrefPubMedGoogle Scholar
  • 47 Vu TH. et al. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991; 64: 1-20.
    CrossrefPubMedGoogle Scholar
  • 48 Ludeman MJ. et al. PAR1 cleavage and signaling in response to activated protein C and thrombin. J Biol Chem 2005; 280: 13122-13128.
    CrossrefPubMedGoogle Scholar
  • 49 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
  • 50 Bae JS, Rezaie AR. Thrombin inhibits nuclear factor kappaB 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
  • 51 Bae JS, Rezaie AR. Thrombin and activated protein C inhibit the expression of secretory group IIA phospholipase A(2) in the TNF-alpha-activated endothelial cells by EPCR and PAR-1 dependent mechanisms. Thromb Res 2010; 125: e9-15.
    CrossrefPubMedGoogle Scholar
  • 52 Bae JS, Rezaie AR. Thrombin upregulates the angiopoietin-Tie2 Axis: endothelial protein C receptor occupancy prevents the thrombin mobilization of angiopoietin 2 and P-selectin from Weibel-Palade bodies. J Thromb Haemost 2010; 08: 1107-1115.
    PubMedGoogle Scholar
  • 53 Bae JS. et al. Thrombin down-regulates the TGF-beta-mediated synthesis of collagen and fibronectin by human proximal tubule epithelial cells through the EPCR-dependent activation of PAR-1. J Cell Physiol 2010; 225: 233-239.
    CrossrefPubMedGoogle Scholar
  • 54 Bae JS. et al. The ligand occupancy of endothelial protein C receptor switches the proteaseactivated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells. Blood 2007; 110: 3909-3916.
    CrossrefPubMedGoogle Scholar
  • 55 Bae JS, Rezaie AR. Activated protein C inhibits high mobility group box 1 signaling in endothelial cells. Blood 2011; 118: 3952-3959.
    CrossrefPubMedGoogle Scholar
  • 56 Soh UJ, Trejo J. Activated protein C promotes protease-activated receptor-1 cytoprotective signaling through ß-arrestin and dishevelled-2 scaffolds. Proc Natl Acad Sci USA. 2011 epub ahead of print.
    PubMedGoogle Scholar
  • 57 Schuepbach RA. et al. Activated protein C-cleaved protease activated receptor-1 is retained on the endothelial cell surface even in the presence of thrombin. Blood 2008; 111: 2667-2673.
    CrossrefPubMedGoogle Scholar
  • 58 Shibata M. et al. Anti-inflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke. Circulation 2001; 103: 1799-1805.
    CrossrefPubMedGoogle Scholar
  • 59 Dömötör E. et al. Activated protein C alters cytosolic calcium flux in human brain endothelium via binding to endothelial protein C receptor and activation of protease activated receptor-1. Blood 2003; 101: 4797-4801.
    CrossrefPubMedGoogle Scholar
  • 60 Zlokovic BV. et al. Functional recovery after embolic stroke in rodents by activated protein C. Ann Neurol 2005; 58: 474-477.
    CrossrefPubMedGoogle Scholar
  • 61 Liu D. et al. Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. Nat Med 2004; 10: 1379-1383.
    CrossrefPubMedGoogle Scholar
  • 62 Cheng T. et al. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat Med 2006; 12: 1278-1285.
    CrossrefPubMedGoogle Scholar
  • 63 Isermann B. et al. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med 2007; 13: 1349-1358.
    CrossrefPubMedGoogle Scholar
  • 64 Madhusudhan T. et al. Cytoprotective signaling by activated protein C requires protease activated receptor-3 in podocytes. Blood. 2011 epub ahead of print.
    PubMedGoogle Scholar
  • 65 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
  • 66 Finigan JH. 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
  • 67 Minhas N. et al. Activated protein C utilizes the angiopoietin/Tie2 axis to promote endothelial barrier function. FASEB J 2010; 24: 873-881.
    CrossrefPubMedGoogle Scholar
  • 68 Schuepbach RA. et al. Protection of vascular barrier integrity by activated protein C in murine models depends on protease-activated receptor-1. Thromb Haemost 2009; 101: 724-733.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 69 Bezuhly M. et al. Role of activated protein C and its receptor in inhibition of tumor metastasis. Blood 2009; 113: 3371-3374.
    CrossrefPubMedGoogle Scholar
  • 70 Van Sluis GL. et al. Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1-mediated vascular endothelial barrier enhancement. Blood 2009; 114: 1968-73.
    CrossrefPubMedGoogle Scholar
  • 71 Nold MF. et al. Activated protein C downregulates p38 mitogen-activated protein kinase and improves clinical parameters in an in-vivo model of septic shock. Thromb Haemost 2007; 98: 1118-1126.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 72 Schouten M. et al. Recombinant activated protein C attenuates coagulopathy and inflammation when administered early in murine pneumococcal pneumonia. Thromb Haemost 2011; 106: 1189-1196.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 73 Xu J. et al. Endogenous activated protein C signaling is critical to protection of mice from lipopolysaccaride-induced septic shock. J Thromb Haemost 2009; 07: 851-856.
    CrossrefPubMedGoogle Scholar
  • 74 Frommhold D. et al. Protein C concentrate controls leukocyte recruitment during inflammation and improves survival during endotoxemia after efficient in vivo activation. Am J Pathol. 2011 epub ahead of print.
    PubMedGoogle Scholar
  • 75 Zheng X. et al. Non-hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia. J Thromb Haemost 2007; 05: 1394-1400.
    CrossrefPubMedGoogle Scholar
  • 76 Iwaki T. et al. A cardioprotective role for the endothelial protein C receptor in lipo-polysaccharide-induced endotoxemia in the mouse. Blood 2005; 105: 2364-2371.
    CrossrefPubMedGoogle Scholar
  • 77 Zheng X. et al. Effects of membrane and soluble EPCR on the hemostatic balance and endotoxemia in mice. Blood 2007; 109: 1003-1009.
    PubMedGoogle Scholar
  • 78 Scaldaferri F. et al. Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. J Clin Invest 2007; 117: 1951-1960.
    CrossrefPubMedGoogle Scholar
  • 79 Cabello-Gutiérrez C. et al. Modification of the cytoprotective protein C pathway during Dengue virus infection of human endothelial vascular cells. Thromb Haemost 2009; 101: 916-928.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 80 Lichtnekert J. et al. Activated Protein C Attenuates Systemic Lupus Erythematosus and Lupus Nephritis in MRL-Fas(lpr) Mice. J Immunol 2011; 187: 3413-3421.
    CrossrefPubMedGoogle Scholar
  • 81 Martí-Carvajal AJ. et al. Human recombinant activated protein C for severe sepsis. Cochrane Database Syst Rev 2011; 04: CD004388.
    PubMedGoogle Scholar
  • 82 Mosnier LO. et al. Activated protein C variants with normal cytoprotective but reduced anticoagulant activity. Blood 2004; 104: 1740-1744.
    CrossrefPubMedGoogle Scholar
  • 83 Bae JS. et al. Engineering a disulfide bond to stabilize the calcium-binding loop of activated protein C eliminates its anticoagulant but not its protective signaling properties. J Biol Chem 2007; 282: 9251-9259.
    CrossrefPubMedGoogle Scholar
  • 84 Yang L. et al. Identification of a specific exosite on activated protein C for interaction with protease-activated receptor 1. J Biol Chem 2007; 282: 25493-25500.
    CrossrefPubMedGoogle Scholar
  • 85 Kerschen EJ. et al. Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J Exp Med 2007; 204: 2439-2448.
    CrossrefPubMedGoogle Scholar
  • 86 Kerschen E. et al. Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice. J Clin Invest 2010; 120: 3167-3178.
    CrossrefPubMedGoogle Scholar
  • 87 Bir N. et al. Cytoprotective-selective Activated Protein C Attenuates P. aeruginosa-induced Lung Injury in Mice. Am J Respir Cell Mol Biol 2011; 45: 632-641.
    CrossrefPubMedGoogle Scholar
  • 88 Guo H. et al. Neuroprotective activities of activated protein C mutant with reduced anticoagulant activity. Eur J Neurosci 2009; 29: 1119-1130.
    CrossrefPubMedGoogle Scholar
  • 89 Guo H. et al. Species-dependent neuroprotection by activated protein C mutants with reduced anticoagulant activity. J Neurochem 2009; 109: 116-124.
    CrossrefPubMedGoogle Scholar
  • 90 Deane R. et al. Endothelial protein C receptor-assisted transport of activated protein C across the mouse blood-brain barrier. J Cereb Blood Flow Metab 2009; 29: 25-33.
    CrossrefPubMedGoogle Scholar
  • 91 Wildhagen KC. et al. The structure-function relationship of activated protein C. Lessons from natural and engineered mutations. Thromb Haemost 2011; 106: 1034-1045.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 92 Nayak RC. et al. Endothelial cell protein C receptor cellular localization and trafficking: potential functional implications. Blood 2009; 114: 1974-1986.
    CrossrefPubMedGoogle Scholar
  • 93 Stephenson DA. et al. Modulation of monocyte function by activated protein C, a natural anticoagulant. J Immunol 2006; 177: 2115-2122.
    CrossrefPubMedGoogle Scholar
  • 94 Xue M. et al. Endothelial protein C receptor is overexpressed in rheumatoid arthritic (RA) synovium and mediates the anti-inflammatory effects of activated protein C in RA monocytes. Ann Rheum Dis 2007; 66: 1574-1580.
    CrossrefPubMedGoogle Scholar
  • 95 Toltl LJ. et al. Canadian Critical Care Translational Biology Group. Activated protein C upregulates IL-10 and inhibits tissue factor in blood monocytes. J Immunol 2008; 181: 2165-2173.
    CrossrefPubMedGoogle Scholar
  • 96 Feistritzer C. et al. Endothelial protein C receptor-dependent inhibition of migration of human lymphocytes by protein C involves epidermal growth factor receptor. J Immunol 2006; 176: 1019-1025.
    CrossrefPubMedGoogle Scholar
  • 97 Sturn DH. et al. Expression and function of the endothelial protein C receptor in human neutrophils. Blood 2003; 102: 1499-1505.
    CrossrefPubMedGoogle Scholar
  • 98 Nakamura M. et al. Anti-inflammatory effect of activated protein C in gastric epithelial cells. J Thromb Haemost 2005; 03: 2721-2729.
    CrossrefPubMedGoogle Scholar
  • 99 Xue M. et al. Endothelial protein C receptor and protease-activated receptor-1 mediate induction of a wound-healing phenotype in human keratinocytes by activated protein C. J Invest Dermatol 2005; 125: 1279-1285.
    CrossrefPubMedGoogle Scholar
  • 100 Xue M. et al. Protein C is an autocrine growth factor for human skin keratinocytes. J Biol Chem 2007; 282: 13610-6.
    CrossrefPubMedGoogle Scholar
  • 101 Xue M. et al. Activated protein C enhances human keratinocyte barrier integrity via sequential activation of epidermal growth factor receptor and Tie2. J Biol Chem 2011; 286: 6742-6750.
    CrossrefPubMedGoogle Scholar
  • 102 Julovi SM. et al. Protease Activated Receptor-2 Mediates Activated Protein C-Induced Cutaneous Wound Healing via Inhibition of p38. Am J Pathol. 2011 epub ahead of print.
    PubMedGoogle Scholar
  • 103 Xue M. et al. Activated protein C mediates a healing phenotype in cultured tenocytes. J Cell Mol Med 2009; 13: 749-757.
    CrossrefPubMedGoogle Scholar
  • 104 Jackson MT. et al. Activation of cartilage matrix metalloproteinases by activated protein C. Arthritis Rheum 2009; 60: 780-791.
    CrossrefPubMedGoogle Scholar
  • 105 Kurata T. et al. Activated protein C stimulates osteoblast proliferation via endothelial protein C receptor. Thromb Res 2010; 125: 184-191.
    CrossrefPubMedGoogle Scholar
  • 106 Wang J. et al. Activated protein C protects against myocardial ischemic/reperfusion injury through AMP-activated protein kinase signaling. J Thromb Haemost 2011; 09: 1308-1317.
    CrossrefPubMedGoogle Scholar
  • 107 Bretschneider E. et al. Human vascular smooth muscle cells express functionally active endothelial cell protein C receptor. Circ Res 2007; 100: 255-262.
    CrossrefPubMedGoogle Scholar
  • 108 Oganesyan V. et al. The crystal structure of the endothelial protein C receptor and a bound phospholipid. J Biol Chem 2002; 277: 24851-24854.
    CrossrefPubMedGoogle Scholar
  • 109 López-Sagaseta J. et al. Binding of factor VIIa to the endothelial cell protein C receptor reduces its coagulant activity. J Thromb Haemost 2007; 05: 1817-1824.
    CrossrefPubMedGoogle Scholar
  • 110 Liaw PC. et al. Identification of the protein C/activated protein C binding sites on the endothelial cell protein C receptor. Implications for a novel mode of ligand recognition by a major histocompatibility complex class 1-type receptor. J Biol Chem 2001; 276: 8364-8370.
    CrossrefPubMedGoogle Scholar
  • 111 López-Sagaseta J. et al. Recombinant expression of biologically active murine soluble EPCR. Protein Expr Purif 2009; 64: 194-197.
    CrossrefPubMedGoogle Scholar
  • 112 Li W. et al. Extraembryonic expression of EPCR is essential for embryonic viability. Blood 2005; 106: 2716-2722.
    CrossrefPubMedGoogle Scholar
  • 113 Schouten M. et al. Therapeutic recombinant murine activated protein C attenuates pulmonary coagulopathy and improves survival in murine pneumococcal pneumonia. J Infect Dis 2010; 202: 1600-1607.
    CrossrefPubMedGoogle Scholar
  • 114 Preston RJ. et al. Multifunctional specificity of the protein C/activated protein C Gla domain. J Biol Chem 2006; 281: 28850-28857.
    CrossrefPubMedGoogle Scholar
  • 115 Ghosh S. 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
  • 116 Hedner U, Erhardtsen E. Potential role for rFVIIa in transfusion medicine. Transfusion 2002; 42: 114-124.
    CrossrefPubMedGoogle Scholar
  • 117 Kenet G. et al. A new approach to treatment of bleeding episodes in young hemophilia patients: a single bolus megadose of recombinant activated factor VII (NovoSeven). J Thromb Haemost 2003; 01: 450-455.
    CrossrefPubMedGoogle Scholar
  • 118 Butenas S, Mann KG. Kinetics of human factor VII activation. Biochemistry 1996; 35: 1904-1910.
    CrossrefPubMedGoogle Scholar
  • 119 Puy C. et al. The endothelial cells downregulate the generation of factor VIIa through EPCR binding. Br J Haematol 2010; 149: 111-117.
    CrossrefPubMedGoogle Scholar
  • 120 Morrissey JH. Tissue factor: a key molecule in hemostatic and nonhemostatic systems. Int J Hematol 2004; 79: 103-108.
    CrossrefPubMedGoogle Scholar
  • 121 Dickinson CD. et al. Identification of surface residues mediating tissue factor binding and catalytic function of the serine protease factor VIIa. Proc Natl Acad Sci U S A 1996; 93: 14379-14384.
    CrossrefPubMedGoogle Scholar
  • 122 Kurosawa S. et al. Identification of functional endothelial protein C receptor in human plasma. J Clin Invest 1997; 100: 411-418.
    CrossrefPubMedGoogle Scholar
  • 123 Qu D. et al. Regulated endothelial protein C receptor shedding is mediated by tumor necrosis factor-alpha converting enzyme/ADAM17. J Thromb Haemost 2007; 05: 395-402.
    CrossrefPubMedGoogle Scholar
  • 124 Saposnik B. et al. Alternative mRNA is favored by the A3 haplotype of the EPCR gene PROCR and generates a novel soluble form of EPCR in plasma. Blood 2008; 111: 3442-3451.
    CrossrefPubMedGoogle Scholar
  • 125 Molina E. et al. The functional properties of a truncated form of endothelial cell protein C receptor generated by alternative splicing. Haematologica 2008; 93: 878-884.
    CrossrefPubMedGoogle Scholar
  • 126 Stearns-Kurosawa DJ. et al. Bimodal distribution of soluble endothelial protein C receptor levels in healthy populations. J Thromb Haemost 2003; 01: 855-856.
    CrossrefPubMedGoogle Scholar
  • 127 Kurosawa S. et al. Plasma levels of endothelial cell protein C receptor are elevated in patients with sepsis and systemic lupus erythematosus: lack of correlation with thrombomodulin suggests involvement of different pathological processes. Blood 1998; 91: 725-727.
    PubMedGoogle Scholar
  • 128 Sesin CA. et al. Shedding of endothelial protein C receptor contributes to vasculopathy and renal injury in lupus: in vivo and in vitro evidence. Kidney Int 2005; 68: 110-120.
    CrossrefPubMedGoogle Scholar
  • 129 Medina P. et al. Contribution of polymorphisms in the endothelial protein C receptor gene to soluble endothelial protein C receptor and circulating activated protein C levels, and thrombotic risk. Thromb Haemost 2004; 91: 905-911.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 130 Saposnik B. et al. A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis. Blood 2004; 103: 1311-1318.
    PubMedGoogle Scholar
  • 131 Smith NL. et al. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation 2010; 121: 1382-1392.
    CrossrefPubMedGoogle Scholar
  • 132 Ireland HA. et al. FVII, FVIIa and downstream markers of extrinsic pathway activation differ by EPCR Ser219Gly variant in healthy men. Arterioscler Thromb Vasc Biol 2009; 29: 1968-1974.
    CrossrefPubMedGoogle Scholar
  • 133 Sen P. et al. Factor VIIa bound to endothelial cell protein C receptor activates protease activated receptor-1 and mediates cell signaling and barrier protection. Blood 2011; 117: 3199-3208.
    CrossrefPubMedGoogle Scholar
  • 134 Puy C. et al. Factor X and factor VII binding to endothelial protein C receptor differs between species. J Thromb Haemost 2011; 09: 1255-1257.
    CrossrefPubMedGoogle Scholar
  • 135 Disse J. et al. The endothelial protein C receptor supports tissue factor ternary coagulation initiation complex signaling through protease-activated receptors. J Biol Chem 2011; 286: 5756-5767.
    CrossrefPubMedGoogle Scholar
  • 136 Schuepbach RA, Riewald M. Coagulation factor Xa cleaves protease-activated receptor-1 and mediates signaling dependent on binding to the endothelial protein C receptor. J Thromb Haemost 2010; 08: 379-388.
    CrossrefPubMedGoogle Scholar
  • 137 Sen P. et al. Factor X binding to endothelial cell protein C receptor: comparison with factor VIIa and activated protein C. Blood 2011; 118: 2635-2636.
    CrossrefPubMedGoogle Scholar
  • 138 Bhattacharjee G. et al. Factor Xa binding to annexin 2 mediates signal transduction via protease-activated receptor 1. Circ Res 2008; 102: 457-464.
    CrossrefPubMedGoogle Scholar
  • 139 Bae JS. et al. Factor X/Xa elicits protective signaling 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
  • 140 Disse J, Ruf W. The endothelial protein C receptor is required for tissue factor ternary complex signaling in the mouse. J Thromb Haemost. 2011 epub ahead of print.
    PubMedGoogle Scholar
  • 141 McCallum CD. et al. The location of the active site of blood coagulation factor VIIa above the membrane surface and its reorientation upon association with tissue factor. A fluorescence energy transfer study. J Biol Chem 1996; 271: 28168-28175.
    CrossrefPubMedGoogle Scholar
  • 142 Riewald M, Ruf W. Orchestration of coagulation protease signaling by tissue factor. Trends Cardiovasc Med 2002; 12: 149-154.
    CrossrefPubMedGoogle Scholar
  • 143 Mackman N. The many faces of tissue factor. J Thromb Haemost 2009; 07 (Suppl. 01) 136-9.
    CrossrefPubMedGoogle Scholar
  • 144 Schaffner F, Ruf W. Tissue factor and PAR2 signaling in the tumor microenvironment. Arterioscler Thromb Vasc Biol 2009; 29: 1999-2004.
    CrossrefPubMedGoogle Scholar