Endothelial cell protein C receptor: A multiliganded and multifunctional receptor

Blood

Volumn 124, Issue 10, 2014, Pages 1553-1562

  Rao, L Vijaya Mohan ^a   Esmon, Charles T ^b   Pendurthi, Usha R ^a  

^a UNIVERSITY OF TEXAS HEALTH CENTER   (United States)

^b OKLAHOMA MEDICAL RESEARCH FOUNDATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVATED PROTEIN C; BLOOD CLOTTING FACTOR 10; BLOOD CLOTTING FACTOR 7A; CD11B ANTIGEN; ENDOTHELIAL CELL PROTEIN C RECEPTOR; ERYTHROCYTE MEMBRANE PROTEIN 1; LIGAND; MYELOBLASTIN; PROTEIN C; RECEPTOR; T LYMPHOCYTE RECEPTOR DELTA CHAIN; T LYMPHOCYTE RECEPTOR GAMMA CHAIN; THROMBIN; UNCLASSIFIED DRUG; CELL SURFACE RECEPTOR; LEUKOCYTE ANTIGEN; PROCR PROTEIN, HUMAN;

BLOOD CLOTTING; CELL PROTECTION; ENDOTHELIUM CELL; HEMOSTASIS; HUMAN; INFLAMMATION; INNATE IMMUNITY; MALARIA; NEOPLASM; NONHUMAN; PATHOGENESIS; PLASMODIUM FALCIPARUM; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN STRUCTURE; REVIEW; SIGNAL TRANSDUCTION; AMINO ACID SEQUENCE; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; GENETICS; METABOLISM; MOLECULAR GENETICS; PHYSIOLOGY; PROTEIN TERTIARY STRUCTURE; SEQUENCE HOMOLOGY;

AMINO ACID SEQUENCE; ANIMALS; ANTIGENS, CD; HEMOSTASIS; HUMANS; INFLAMMATION; LIGANDS; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; PROTEIN STRUCTURE, TERTIARY; RECEPTORS, CELL SURFACE; SEQUENCE HOMOLOGY, AMINO ACID;

EID: 84907059506     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2014-05-578328     Document Type: Review

References (99)

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(42):26486-26491.
2. Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, Ferrell GL, Esmon CT. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci USA. 1996;93(19):10212-10216.
3. Oganesyan V, Oganesyan N, Terzyan S, et al. The crystal structure of the endothelial protein C receptor and a bound phospholipid. J Biol Chem. 2002;277(28):24851-24854.
4. López-Sagaseta J, Puy C, Tamayo I, et al. sPLA2-V inhibits EPCR anticoagulant and antiapoptotic properties by accommodating lysophosphatidylcholine or PAF in the hydrophobic groove. Blood. 2012;119(12):2914-2921.
5. Ghosh S, Pendurthi UR, Steinoe A, Esmon CT, Rao LV. Endothelial cell protein C receptor acts as a cellular receptor for factor VIIa on endothelium. J Biol Chem. 2007;282(16):11849-11857.
6. Preston RJ, Ajzner E, Razzari C, et al. Multifunctional specificity of the protein C/activated protein C Gla domain. J Biol Chem. 2006;281(39):28850-28857.
7. López-Sagaseta J, Montes R, Puy C, Díez N, Fukudome K, Hermida J. Binding of factor VIIa to the endothelial cell protein C receptor reduces its coagulant activity. J Thromb Haemost. 2007;5(9):1817-1824.
8. Zheng X, Li W, Gu JM, et al. Effects of membrane and soluble EPCR on the hemostatic balance and endotoxemia in mice. Blood. 2007;109(3):1003-1009.
9. Li W, Zheng X, Gu J, et al. Overexpressing endothelial cell protein C receptor alters the hemostatic balance and protects mice from endotoxin. J Thromb Haemost. 2005;3(7):1351-1359.
10. Kerschen E, Hernandez I, Zogg M, et al. Activated protein C targets CD81 dendritic cells to reduce the mortality of endotoxemia in mice. J Clin Invest. 2010;120(9):3167-3178.
11. Sen P, Clark CA, Gopalakrishnan R, et al. Factor VIIa binding to endothelial cell protein C receptor: differences between mouse and human systems. Thromb Haemost. 2012;107(5):951-961.
12. Puy C, Hermida J, Montes R. Factor X and factor VII binding to endothelial protein C receptor differs between species. J Thromb Haemost. 2011;9(6):1255-1257.
13. Laszik Z, Mitro A, Taylor FB Jr, Ferrell G, Esmon CT. 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(10):3633-3640.
14. Ye X, Fukudome K, Tsuneyoshi N, et al. The endothelial cell protein C receptor (EPCR) functions as a primary receptor for protein C activation on endothelial cells in arteries, veins, and capillaries. Biochem Biophys Res Commun. 1999;259(3):671-677.
15. Gleeson EM, O'Donnell JS, Preston RJ. The endothelial cell protein C receptor: cell surface conductor of cytoprotective coagulation factor signaling. Cell Mol Life Sci. 2012;69(5):717-726.
16. Balazs AB, Fabian AJ, Esmon CT, Mulligan RC. Endothelial protein C receptor (CD201) explicitly identifies hematopoietic stem cells in murine bone marrow. Blood. 2006;107(6):2317-2321.
17. Shipitsin M, Campbell LL, Argani P, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007;11(3):259-273.
18. Iwasaki H, Arai F, Kubota Y, Dahl M, Suda T. Endothelial protein C receptor-expressing hematopoietic stem cells reside in the perisinusoidal niche in fetal liver. Blood. 2010;116(4):544-553.
19. Park SY, Lee HE, Li H, Shipitsin M, Gelman R, Polyak K. Heterogeneity for stem cell-related markers according to tumor subtype and histologic stage in breast cancer. Clin Cancer Res. 2010;16(3):876-887.
20. Nayak RC, Sen P, Ghosh S, et al. Endothelial cell protein C receptor cellular localization and trafficking: potential functional implications. Blood. 2009;114(9):1974-1986.
21. Clark CA, Vatsyayan R, Hedner U, Esmon CT, Pendurthi UR, Rao LV. Endothelial cell protein C receptor-mediated redistribution and tissue-level accumulation of factor VIIa. J Thromb Haemost. 2012;10(11):2383-2391.
22. Nayak RC, Keshava S, Esmon CT, Pendurthi UR, Rao LV. Rab GTPases regulate endothelial cell protein C receptor-mediated endocytosis and trafficking of factor VIIa. PLoS ONE. 2013;8(3):e59304.
23. 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;8(2):379-388.
24. Disse J, Petersen HH, Larsen KS, et al. The endothelial protein C receptor supports tissue factor ternary coagulation initiation complex signaling through protease-activated receptors. J Biol Chem. 2011;286(7):5756-5767.
25. Sen P, Nayak R, Clark CA, et al. Factor X binding to endothelial cell protein C receptor: comparison with factor VIIa and activated protein C. Blood. 2011;118(9):2635-2636.
26. Kurosawa S, Esmon CT, Stearns-Kurosawa DJ. The soluble endothelial protein C receptor binds to activated neutrophils: involvement of proteinase-3 and CD11b/CD18. J Immunol. 2000;165(8):4697-4703.
27. Villegas-Mendez A, Montes R, Ambrose LR, Warrens AN, Laffan M, Lane DA. Proteolysis of the endothelial cell protein C receptor by neutrophil proteinase 3. J Thromb Haemost. 2007;5(5):980-988.
28. Fink K, Busch HJ, Bourgeois N, et al. Mac-1 directly binds to the endothelial protein C-receptor: a link between the protein C anticoagulant pathway and inflammation? PLoS ONE. 2013;8(2):e53103.
29. Willcox CR, Pitard V, Netzer S, et al. Cytomegalovirus and tumor stress surveillance by binding of a human γδ T cell antigen receptor to endothelial protein C receptor. Nat Immunol. 2012;13(9):872-879.
30. Witherden DA, Havran WL. EPCR: a stress trigger for γδ T cells. Nat Immunol. 2012;13(9):812-814.
31. Turner L, Lavstsen T, Berger SS, et al. Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature. 2013;498(7455):502-505.
32. Taylor FB Jr, Peer GT, Lockhart MS, Ferrell G, Esmon CT. Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood. 2001;97(6):1685-1688.
33. Li W, Zheng X, Gu JM, et al. Extraembryonic expression of EPCR is essential for embryonic viability. Blood. 2005;106(8):2716-2722.
34. Zheng X, Li W, Song Y, et al. Non-hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia. J Thromb Haemost. 2007;5(7):1394-1400.
35. Pendurthi UR, Rao LV. Factor VIIa interaction with endothelial cells and endothelial cell protein C receptor. Thromb Res. 2010;125(Suppl 1):S19-S22.
36. Montes R, Puy C, Molina E, Hermida J. Is EPCR a multi-ligand receptor? Pros and cons. Thromb Haemost. 2012;107(5):815-826.
37. Puy C, López-Sagaseta J, Hermida J, Montes R. The endothelial cells downregulate the generation of factor VIIa through EPCR binding. Br J Haematol. 2010;149(1):111-117.
38. Pavani G, Ivanciu L, Faella A, Marcos-Contreras OA, Margaritis P. The endothelial protein C receptor enhances hemostasis of FVIIa administration in hemophilic mice in vivo. Submitted April 17, 2014; accepted June 11, 2014. Prepublished online as Blood First Edition paper June 23, 2014; DOI: 10.1182/blood-2014-04-56729.
39. Hedner U. Factor VIIa and its potential therapeutic use in bleeding-associated pathologies. Thromb Haemost. 2008;100(4):557-562.
40. Taylor FB Jr, Stearns-Kurosawa DJ, Kurosawa S, et al. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood. 2000;95(5):1680-1686.
41. Bernard GR, Vincent J-L, Laterre PF, et al; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699-709.
42. Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW. Gene expression profile of antithrombotic protein c defines new mechanisms modulating inflammation and apoptosis. J Biol Chem. 2001;276(14):11199-11203.
43. Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science. 2002;296(5574):1880-1882.
44. Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood. 2007;109(8):3161-3172.
45. Rezaie AR. Regulation of the protein C anticoagulant and antiinflammatory pathways. Curr Med Chem. 2010;17(19):2059-2069.
46. Bouwens EA, Stavenuiter F, Mosnier LO. Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway. J Thromb Haemost. 2013;11(Suppl 1):242-253.
47. Rezaie AR. The occupancy of endothelial protein C receptor by its ligand modulates the par-1 dependent signaling specificity of coagulation proteases. IUBMB Life. 2011;63(6):390-396.
48. Vu T-KH, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell. 1991;64(6):1057-1068.
49. Ludeman MJ, Kataoka H, Srinivasan Y, Esmon NL, Esmon CT, Coughlin SR. PAR1 cleavage and signaling in response to activated protein C and thrombin. J Biol Chem. 2005;280(13):13122-13128.
50. Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost. 2005;3(8):1800-1814.
51. Bae JS, Yang L, Rezaie AR. 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(8):2867-2872.
52. Russo A, Soh UJ, Paing MM, Arora P, Trejo J. Caveolae are required for protease-selective signaling by protease-activated receptor-1. Proc Natl Acad Sci USA. 2009;106(15):6393-6397.
53. 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(17):17286-17293.
54. Feistritzer C, Riewald M. Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood. 2005;105(8):3178-3184.
55. Minhas N, Xue M, Fukudome K, Jackson CJ. Activated protein C utilizes the angiopoietin/Tie2 axis to promote endothelial barrier function. FASEB J. 2010;24(3):873-881.
56. Bae JS, Yang L, Manithody C, Rezaie AR. The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells. Blood. 2007;110(12):3909-3916.
57. Bae JS, Yang L, Rezaie AR. 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(45):34803-34812.
58. Soh UJ, Trejo J. Activated protein C promotes protease-activated receptor-1 cytoprotective signaling through b-arrestin and dishevelled-2 scaffolds. Proc Natl Acad Sci USA. 2011;108(50):E1372-E1380.
59. Mosnier LO, Sinha RK, Burnier L, Bouwens EA, Griffin JH. Biased agonism of protease-activated receptor 1 by activated protein C caused by noncanonical cleavage at Arg46. Blood. 2012;120(26):5237-5246.
60. Schuepbach RA, Madon J, Ender M, Galli P, Riewald M. Protease-activated receptor-1 cleaved at R46 mediates cytoprotective effects. J Thromb Haemost. 2012;10(8):1675-1684.
61. Schuepbach RA, Feistritzer C, Brass LF, Riewald M. Activated protein C-cleaved protease activated receptor-1 is retained on the endothelial cell surface even in the presence of thrombin. Blood. 2008;111(5):2667-2673.
62. Burnier L, Mosnier LO. Novel mechanisms for activated protein C cytoprotective activities involving noncanonical activation of protease-activated receptor 3. Blood. 2013;122(5):807-816.
63. 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 signaling and barrier protection. Blood. 2011;117(11):3199-3208.
64. Sundaram J, Keshava S, Gopalakrishnan R, Esmon CT, Pendurthi UR, Rao LV. Factor VIIa binding to endothelial cell protein C receptor protects vascular barrier integrity in vivo. J Thromb Haemost. 2014;12(5):690-700.
65. Esmon CT. Protein C anticoagulant system - anti-inflammatory effects. Semin Immunopathol. 2012;34(1):127-132.
66. Iwaki T, Cruz DT, Martin JA, Castellino FJ. A cardioprotective role for the endothelial protein C receptor in lipopolysaccharide-induced endotoxemia in the mouse. Blood. 2005;105(6):2364-2371.
67. Kerschen EJ, Fernandez JA, Cooley BC, et al. Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J Exp Med. 2007;204(10):2439-2448.
68. Scaldaferri F, Sans M, Vetrano S, et al. Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. J Clin Invest. 2007;117(7):1951-1960.
69. Esmon CT. Structure and functions of the endothelial cell protein C receptor. Crit Care Med. 2004;32(5 Suppl):S298-S301.
70. Goldenberg NM, Steinberg BE, Slutsky AS, Lee WL. Broken barriers: a new take on sepsis pathogenesis. Sci Transl Med. 2011;3(88):88ps25.
71. Bae JS, Rezaie AR. Thrombin up-regulates the Angiopoietin/Tie2 Axis: EPCR occupancy prevents the thrombin mobilization of angiopoietin2 and P-selectin from Weibel-Palade bodies. J Thromb Haemost. 2010;8(5):1107-1115.
72. von Drygalski A, Furlan-Freguia C, Ruf W, Griffin JH, Mosnier LO; von DA. Organ-specific protection against lipopolysaccharide-induced vascular leak is dependent on the endothelial protein C receptor. Arterioscler Thromb Vasc Biol. 2013;33(4):769-776.
73. Beaulieu LM, Church FC. Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1. Exp Cell Res. 2007;313(4):677-687.
74. Antón I, Molina E, Luis-Ravelo D, et al. Receptor of activated protein C promotes metastasis and correlates with clinical outcome in lung adenocarcinoma. Am J Respir Crit Care Med. 2012;186(1):96-105.
75. Uchiba M, Okajima K, Oike Y, et al. Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo. Circ Res. 2004;95(1):34-41.
76. Gramling MW, Beaulieu LM, Church FC. Activated protein C enhances cell motility of endothelial cells and MDA-MB-231 breast cancer cells by intracellular signal transduction. Exp Cell Res. 2010;316(3):314-328.
77. Van Sluis GL, Niers TM, Esmon CT, et al. Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1-mediated vascular endothelial barrier enhancement. Blood. 2009;114(9):1968-1973.
78. Bezuhly M, Cullen R, Esmon CT, et al. Role of activated protein C and its receptor in inhibition of tumor metastasis. Blood. 2009;113(14):3371-3374.
79. van Sluis GL, Brüggemann LW, Esmon CT, et al. Endogenous activated protein C is essential for immune-mediated cancer cell elimination from the circulation. Cancer Lett. 2011;306(1):106-110.
80. Schaffner F, Yokota N, Carneiro-Lobo T, et al. Endothelial protein C receptor function in murine and human breast cancer development. PLoS ONE. 2013;8(4):e61071.
81. Keshava S, Kothari H, Rao LV, Pendurthi UR. Influence of endothelial cell protein C receptor on breast cancer development. J Thromb Haemost. 2013;11(11):2062-2065.
82. Keshava S, Sahoo S, Tucker TA, Idell S, Rao LV, Pendurthi UR. Endothelial cell protein C receptor opposes mesothelioma growth driven by tissue factor. Cancer Res. 2013;73(13):3963-3973.
83. Born W, Cady C, Jones-Carson J, Mukasa A, Lahn M, O'Brien R. Immunoregulatory functions of gamma delta T cells. Adv Immunol. 1999;71:77-144.
84. Tsuneyoshi N, Fukudome K, Horiguchi S, et al. Expression and anticoagulant function of the endothelial cell protein C receptor (EPCR) in cancer cell lines. Thromb Haemost. 2001;85(2):356-361.
85. Heng W, Mu CY, Chen C, Huang JA, Wang ZY. Endothelial cell protein C receptor (EPCR) is expressed by lung carcinoma and correlated with clinical parameters. Clin Lab. 2013;59(3-4):375-380.
86. Ducros E, Mirshahi S, Azzazene D, et al. Endothelial protein C receptor expressed by ovarian cancer cells as a possible biomarker of cancer onset. Int J Oncol. 2012;41(2):433-440.
87. Menschikowski M, Hagelgans A, Tiebel O, Klinsmann L, Eisenhofer G, Siegert G. Expression and shedding of endothelial protein C receptor in prostate cancer cells. Cancer Cell Int. 2011;11:4.
88. Scheffer GL, Flens MJ, Hageman S, Izquierdo MA, Shoemaker RH, Scheper RJ. Expression of the vascular endothelial cell protein C receptor in epithelial tumour cells. Eur J Cancer. 2002;38(11):1535-1542.
89. Kraemer SM, Smith JD. A family affair: var genes, PfEMP1 binding, and malaria disease. Curr Opin Microbiol. 2006;9(4):374-380.
90. Lavstsen T, Turner L, Saguti F, et al. Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children. Proc Natl Acad Sci USA. 2012;109(26):E1791-E1800.
91. Moxon CA, Wassmer SC, Milner DA Jr, et al. Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children. Blood. 2013;122(5):842-851.
92. van der Poll T. The endothelial protein C receptor and malaria. Blood. 2013;122(5):624-625.
93. Aird WC, Mosnier LO, Fairhurst RM. Plasmodium falciparum picks (on) EPCR. Blood. 2014;123(2):163-167.
94. Ho M. EPCR: holy grail of malaria cytoadhesion? Blood. 2014;123(2):157-159.
95. Naka I, Patarapotikul J, Hananantachai H, Imai H, Ohashi J. Association of the endothelial protein C receptor (PROCR) rs867186-G allele with protection from severe malaria. Malar J. 2014;13(1):105.
96. Rénia L, Potter SM, Mauduit M, et al. Pathogenic T cells in cerebral malaria. Int J Parasitol. 2006;36(5):547-554.
97. Costa G, Loizon S, Guenot M, et al. Control of Plasmodium falciparum erythrocytic cycle: γδ T cells target the red blood cell-invasive merozoites. Blood. 2011;118(26):6952-6962.
98. López-Sagaseta J, Montes R, Hermida J. Recombinant expression of biologically active murine soluble EPCR. Protein Expr Purif. 2009;64(2):194-197.
99. Liaw PC, Mather T, Oganesyan N, Ferrell GL, Esmon CT. 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(11):8364-8370.