The endothelial cell protein C receptor: Cell surface conductor of cytoprotective coagulation factor signaling

Cellular and Molecular Life Sciences

Volumn 69, Issue 5, 2012, Pages 717-726

  Gleeson, Eimear M ^a   O'Donnell, James S ^a   Preston, Roger J S ^a  

^a TRINITY COLLEGE DUBLIN   (Ireland)

Author keywords

Coagulation proteases; Endothelial cell protein C receptor; Factor VII; Protein C; Sepsis

Indexed keywords

APC PROTEIN; BLOOD CLOTTING FACTOR; BLOOD CLOTTING FACTOR 7; ENDOTHELIAL PROTEIN C RECEPTOR; ENZYME PRECURSOR; PROTEIN C; PROTEINASE; PROTEINASE ACTIVATED RECEPTOR 1; PROTEINASE ACTIVATED RECEPTOR 2; RECEPTOR PROTEIN; RECOMBINANT PROTEIN; THROMBIN; UNCLASSIFIED DRUG; VITAMIN K DEPENDENT PROTEASE; VITAMIN K GROUP;

BLOOD VESSEL INJURY; CARBOXY TERMINAL SEQUENCE; CELL PROTECTION; CELL SURFACE; DISEASE SEVERITY; ENDOTHELIUM CELL; ENZYME PHOSPHORYLATION; ENZYME SYNTHESIS; HOMEOSTASIS; HUMAN; IMMUNOCOMPETENT CELL; INFLAMMATION; INNATE IMMUNITY; LIGAND BINDING; MOLECULAR BIOLOGY; NONHUMAN; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; REVIEW; SEPSIS; SIGNAL TRANSDUCTION; THROMBOSIS; TRANSCRIPTION REGULATION;

ANTIGENS, CD; BLOOD COAGULATION FACTORS; ENDOTHELIAL CELLS; HUMANS; RECEPTORS, CELL SURFACE; SEPSIS; SIGNAL TRANSDUCTION;

EID: 84857064170     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-011-0825-0     Document Type: Review

References (108)

1. Esmon CT (2003) Inflammation and thrombosis. J Thromb Haemost 1(7):1343-1348
2. Yang XV et al (2009) Activated protein C ligation of ApoER2 (LRP8) causes Dab1-dependent signaling in U937 cells. Proc Natl Acad Sci USA 106(1):274-279
3. Coughlin SR (1999) Protease-activated receptors and platelet function. Thromb Haemost 82(2):353-356
4. Coughlin SR (1999) How the protease thrombin talks to cells. Proc Natl Acad Sci USA 96(20):11023-11027 (Pubitemid 29487321)
5. Riewald M et al (2002) Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296(5574):1880-1882 (Pubitemid 34596276)
6. Feistritzer C, Riewald M (2005) Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 105(8):3178-3184
7. Schuepbach RA, Riewald M (2010) Coagulation factor Xa cleaves protease-activated receptor-1 and mediates signaling dependent on binding to the endothelial protein C receptor. J Thromb Haemost 8(2):379-388
8. Sen P et al (2011) Factor VIIa bound to endothelial cell protein C receptor activates protease activated receptor-1 and mediates cell signaling and barrier protection. Blood 117(11):3199-3208
9. Bae JS et al (2007) 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 110(12):3909-3916
10. Fukudome K, Esmon CT (1994) Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem 269(42):26486-26491 (Pubitemid 24328474)
11. Bretschneider E et al (2007) Human vascular smooth muscle cells express functionally active endothelial cell protein C receptor. Circ Res 100(2):255-262 (Pubitemid 46208726)
12. Feistritzer C et al (2003) Endothelial protein C receptordependent inhibition of human eosinophil chemotaxis by protein C. J Allergy Clin Immunol 112(2):375-381 (Pubitemid 36981379)
13. Sturn DH et al (2003) Expression and function of the endothelial protein C receptor in human neutrophils. Blood 102(4):1499-1505 (Pubitemid 36988062)
14. Galligan L et al (2001) Characterization of protein C receptor expression in monocytes. Br J Haematol 115(2):408-414 (Pubitemid 34203510)
15. Xue M et al (2005) Endothelial protein C receptor and proteaseactivated receptor-1 mediate induction of a wound-healing phenotype in human keratinocytes by activated protein C. J Invest Dermatol 125(6):1279-1285
16. Gorbacheva L et al (2009) Endothelial protein C receptor is expressed in rat cortical and hippocampal neurons and is necessary for protective effect of activated protein C at glutamate excitotoxicity. J Neurochem 111(4):967-975
17. Wang J et al. (2011) Activated protein C protects against myocardial ischemic/reperfusion injury through AMP-activated protein kinase signaling. J Thromb Haemost 9(7):1308-1317
18. Crawley JT et al (2002) Distribution of endothelial cell protein C/activated protein C receptor (EPCR) during mouse embryo development. Thromb Haemost 88(2):259-266 (Pubitemid 34873707)
19. Balazs AB et al (2006) Endothelial protein C receptor (CD201) explicitly identifies hematopoietic stem cells in murine bone marrow. Blood 107(6):2317-2321 (Pubitemid 43345550)
20. Iwasaki H et al (2010) Endothelial protein C receptor-expressing hematopoietic stem cells reside in the perisinusoidal niche in fetal liver. Blood 116(4):544-553
21. Simmonds RE, Lane DA (1999) Structural and functional implications of the intron/exon organization of the human endothelial cell protein C/activated protein C receptor (EPCR) gene: comparison with the structure of CD1/major histocompatibility complex alpha1 and alpha2 domains. Blood 94(2):632-641 (Pubitemid 29323877)
22. Fukudome K et al (1996) The endothelial cell protein C receptor. Cell surface expression and direct ligand binding by the soluble receptor. J Biol Chem 271(29):17491-17498 (Pubitemid 26244316)
23. Hayashi T et al (1999) Organization and chromosomal localization of the human endothelial protein C receptor gene. Gene 238(2):367-373 (Pubitemid 29447032)
24. Rance JB et al (2003) Regulation of the human endothelial cell protein C receptor gene promoter by multiple Sp1 binding sites. Blood 101(11):4393-4401 (Pubitemid 36857804)
25. Oganesyan V et al (2002) The crystal structure of the endothelial protein C receptor and a bound phospholipid. J Biol Chem 277(28):24851-24854 (Pubitemid 34951783)
26. Liaw PC et al (2001) 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 276(11):8364-8370
27. Regan LM et al (1997) The interaction between the endothelial cell protein C receptor and protein C is dictated by the gammacarboxyglutamic acid domain of protein C. J Biol Chem 272(42):26279-26284 (Pubitemid 27458839)
28. Preston RJ et al (2006) Multifunctional specificity of the protein C/activated protein C Gla domain. J Biol Chem 281(39): 28850-28857 (Pubitemid 44507028)
29. Ghosh S et al (2007) Endothelial cell protein C receptor acts as a cellular receptor for factor VIIa on endothelium. J Biol Chem 282(16):11849-11857 (Pubitemid 47100682)
30. Lopez-Sagaseta J et al (2007) Binding of factor VIIa to the endothelial cell protein C receptor reduces its coagulant activity. J Thromb Haemost 5(9):1817-1824 (Pubitemid 47288936)
31. Disse J 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):5756-5767
32. Puy C, Hermida J, Montes R (2011) Factor X and factor VII binding to EPCR differs between species. J Thromb Haemost 9(6):1255-1257
33. Fukudome K, Esmon CT (1995) 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 270(10):5571-5577
34. Salio M, Silk JD, Cerundolo V (2010) Recent advances in processing and presentation of CD1 bound lipid antigens. Curr Opin Immunol 22(1):81-88
35. Kurosawa S, Esmon CT, Stearns-Kurosawa DJ (2000) The soluble endothelial protein C receptor binds to activated neutrophils: involvement of proteinase-3 and CD11b/CD18. J Immunol 165(8):4697-4703
36. Villegas-Mendez A et al (2007) Proteolysis of the endothelial cell protein C receptor by neutrophil proteinase 3. J Thromb Haemost 5(5):980-988 (Pubitemid 46691727)
37. Stearns-Kurosawa DJ et al (1996) The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci USA 93(19):10212-10216 (Pubitemid 26314601)
38. Fukudome K et al (1998) Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor. J Exp Med 187(7):1029-1035 (Pubitemid 28176403)
39. Bae JS, Yang L, Rezaie AR (2007) 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 104(8):2867-2872 (Pubitemid 46327971)
40. Taylor FB Jr et al (2001) Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood 97(6):1685-1688 (Pubitemid 32217234)
41. Zheng X et al (2007) Non-hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia. J Thromb Haemost 5(7):1394-1400 (Pubitemid 46965366)
42. Puy C et al (2010) The endothelial cells downregulate the generation of factor VIIa through EPCR binding. Br J Haematol 149(1):111-117
43. Gu JM et al (2002) Disruption of the endothelial cell protein C receptor gene in mice causes placental thrombosis and early embryonic lethality. J Biol Chem 277(45):43335-43343
44. Li W et al (2005) Extraembryonic expression of EPCR is essential for embryonic viability. Blood 106(8):2716-2722 (Pubitemid 41510745)
45. Iwaki T et al (2005) A cardioprotective role for the endothelial protein C receptor in lipopolysaccharide-induced endotoxemia in the mouse. Blood 105(6):2364-2371 (Pubitemid 40387032)
46. Castellino FJ et al (2002) 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 88(3):462-472 (Pubitemid 35021606)
47. Li W et al (2005) Overexpressing endothelial cell protein C receptor alters the hemostatic balance and protects mice from endotoxin. J Thromb Haemost 3(7):1351-1359 (Pubitemid 41725187)
48. Kurosawa S et al (1997) Identification of functional endothelial protein C receptor in human plasma. J Clin Invest 100(2):411-418 (Pubitemid 27349089)
49. Liaw PC et al (2000) Mechanisms by which soluble endothelial cell protein C receptor modulates protein C and activated protein C function. J Biol Chem 275(8):5447-5452 (Pubitemid 30115177)
50. Xu J et al (2000) Metalloproteolytic release of endothelial cell protein C receptor. J Biol Chem 275(8):6038-6044 (Pubitemid 30115255)
51. Qu D et al (2007) Regulated endothelial protein C receptor shedding is mediated by tumor necrosis factor-alpha converting enzyme/ADAM17. J Thromb Haemost 5(2):395-402 (Pubitemid 46139466)
52. Orhon FS et al (2010) Soluble endothelial protein C receptor levels in healthy population. J Thromb Thrombolysis 29(1):46-51
53. Regan LM et al (1996) The endothelial cell protein C receptor. Inhibition of activated protein C anticoagulant function without modulation of reaction with proteinase inhibitors. J Biol Chem 271(29):17499-17503 (Pubitemid 26244317)
54. Menschikowski M et al (2009) Regulation of endothelial protein C receptor shedding by cytokines is mediated through differential activation of MAP kinase signaling pathways. Exp Cell Res 315(15):2673-2682
55. Gu JM et al (2000) Endotoxin and thrombin elevate rodent endothelial cell protein C receptor mRNA levels and increase receptor shedding in vivo. Blood 95(5):1687-1693
56. Kurosawa S et al (1998) 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 91(2):725-727 (Pubitemid 28053403)
57. Biguzzi E et al (2001) A 23 bp insertion in the endothelial protein C receptor (EPCR) gene impairs EPCR function. Thromb Haemost 86(4):945-948 (Pubitemid 32979129)
58. Saposnik B et al (2004) A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis. Blood 103(4):1311-1318 (Pubitemid 38168642)
59. Ireland H et al (2005) EPCR Ser219Gly: elevated sEPCR, prothrombin F1 ? 2, risk for coronary heart disease, and increased sEPCR shedding in vitro. Atherosclerosis 183(2):283-292 (Pubitemid 41579279)
60. Qu D et al (2006) The Ser219-[Gly dimorphism of the endothelial protein C receptor contributes to the higher soluble protein levels observed in individuals with the A3 haplotype. J Thromb Haemost 4(1):229-235
61. Saposnik B et al (2008) Alternative mRNA is favored by the A3 haplotype of the EPCR gene PROCR and generates a novel soluble form of EPCR in plasma. Blood 111(7):3442-3451
62. Molina E et al (2008) The functional properties of a truncated form of endothelial cell protein C receptor generated by alternative splicing. Haematologica 93(6):878-884 (Pubitemid 351821724)
63. Ireland HA et al (2009) FVII, FVIIa, and downstream markers of extrinsic pathway activation differ by EPCR Ser219Gly variant in healthy men. Arterioscler Thromb Vasc Biol 29(11): 1968-1974
64. Cheng T et al (2003) Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med 9(3):338-342 (Pubitemid 36362790)
65. Cheng T et al (2006) Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat Med 12(11): 1278-1285 (Pubitemid 44706930)
66. Isermann B et al (2007) Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med 13(11):1349-1358 (Pubitemid 350073598)
67. Bernard GR et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344(10):699-709 (Pubitemid 32204987)
68. Han MH et al (2008) Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 451(7182): 1076-1081 (Pubitemid 351317445)
69. Scaldaferri F et al (2007) Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. J Clin Invest 117(7):1951-1960 (Pubitemid 47036329)
70. Zhong Z et al (2009) Activated protein C therapy slows ALSlike disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J Clin Invest 119(11): 3437-3449
71. Riewald M et al (2003) Activated protein C signals through the thrombin receptor PAR1 in endothelial cells. J Endotoxin Res 9(5):317-321 (Pubitemid 37193040)
72. Kaneider NC et al (2007) 'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage. Nat Immunol 8(12):1303-1312 (Pubitemid 350131169)
73. Schuepbach RA et al (2009) Protection of vascular barrier integrity by activated protein C in murine models depends on protease-activated receptor-1. Thromb Haemost 101(4):724-733
74. White B et al (2000) Activated protein C inhibits lipopolysaccharide- induced nuclear translocation of nuclear factor kappaB (NF-kappaB) and tumour necrosis factor alpha (TNFalpha) production in the THP-1 monocytic cell line. Br J Haematol 110(1):130-134 (Pubitemid 30625601)
75. Stephenson DA et al (2006) Modulation of monocyte function by activated protein C, a natural anticoagulant. J Immunol 177(4):2115-2122 (Pubitemid 44200969)
76. Toltl LJ, Beaudin S, Liaw PC (2008) Activated protein C up-regulates IL-10 and inhibits tissue factor in blood monocytes. J Immunol 181(3):2165-2173
77. Mosnier LO, Griffin JH (2003) Inhibition of staurosporineinduced apoptosis of endothelial cells by activated protein C requires protease-activated receptor-1 and endothelial cell protein C receptor. Biochem J 373(Pt 1):65-70 (Pubitemid 36819502)
78. Liu D et al (2004) Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. Nat Med 10(12): 1379-1383 (Pubitemid 40022721)
79. Guo H et al (2004) Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron 41(4): 563-572 (Pubitemid 38253068)
80. Russo A et al (2009) Caveolae are required for protease-selective signaling by protease-activated receptor-1. Proc Natl Acad Sci USA 106(15):6393-6397
81. Feistritzer C, Lenta R, Riewald M (2005) Protease-activated receptors-1 and-2 can mediate endothelial barrier protection: role in factor Xa signaling. J Thromb Haemost 3(12):2798-2805 (Pubitemid 41819810)
82. Bae JS, Rezaie AR (2008) 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 100(1):101-109 (Pubitemid 351948751)
83. Bae JS, Rezaie AR (2009) Thrombin inhibits nuclear factor kappaB and RhoA pathways in cytokine-stimulated vascular endothelial cells when EPCR is occupied by protein C. Thromb Haemost 101(3):513-520
84. Bae JS, Rezaie AR (2010) 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 125(1):e9-e15
85. Bae JS, Kim IS, Rezaie AR (2010) Thrombin down-regulates the TGF-beta-mediated synthesis of collagen and fibronectin by human proximal tubule epithelial cells through the EPCRdependent activation of PAR-1. J Cell Physiol 225(1):233-239
86. Bae JS, Rezaie AR (2010) 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 8(5):1107-1115
87. Bae JS et al (2009) Concentration dependent dual effect of thrombin in endothelial cells via Par-1 and PI3 Kinase. J Cell Physiol 219(3):744-751
88. Niessen F et al (2008) Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation. Nature 452(7187):654-658 (Pubitemid 351483355)
89. Kerschen EJ et al (2007) Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J Exp Med 204(10):2439-2448 (Pubitemid 47529328)
90. Bae JS, Yang L, Rezaie AR (2010) 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 285(45):34803-34812
91. Nayak RC et al (2009) Endothelial cell protein C receptor cellular localization and trafficking: potential functional implications. Blood 114(9):1974-1986
92. Taylor FB Jr et al (2000) The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 95(5):1680-1686 (Pubitemid 30120829)
93. Kerschen E et al (2010) Activated protein C targets CD8 ? dendritic cells to reduce the mortality of endotoxemia in mice. J Clin Invest 120(9):3167-3178
94. van Hylckama Vlieg A et al (2007) Autoantibodies against endothelial protein C receptor and the risk of a first deep vein thrombosis. J Thromb Haemost 5(7):1449-1454 (Pubitemid 46965374)
95. Montes R et al (2005) Autoantibodies against the endothelial receptor of protein C are associated with acute myocardial infarction in young women. J Thromb Haemost 3(7):1454-1458 (Pubitemid 41725203)
96. Hurtado V et al (2004) Autoantibodies against EPCR are found in antiphospholipid syndrome and are a risk factor for fetal death. Blood 104(5):1369-1374 (Pubitemid 39166513)
97. Zlokovic BV, Griffin JH (2011) Cytoprotective protein C pathways and implications for stroke and neurological disorders. Trends Neurosci 34(4):198-209
98. Domotor E et al (2003) 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 101(12):4797-4801 (Pubitemid 36857737)
99. Uchiba M et al (2004) Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo. Circ Res 95(1):34-41 (Pubitemid 38931833)
100. Thiyagarajan M et al (2008) Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1. J Neurosci 28(48):12788-12797
101. Petraglia AL et al (2010) Activated protein C is neuroprotective and mediates new blood vessel formation and neurogenesis after controlled cortical impact. Neurosurgery 66(1):165-171 discussion 171-2
102. Shibata M et al (2001) Anti-inflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke. Circulation 103(13):1799-1805 (Pubitemid 32291419)
103. Gorbacheva L et al (2010) Activated protein C prevents glutamate-and thrombin-induced activation of nuclear factor-kappaB in cultured hippocampal neurons. Neuroscience 165(4):1138-1146
104. Deane R et al (2009) Endothelial protein C receptor-assisted transport of activated protein C across the mouse blood-brain barrier. J Cereb Blood Flow Metab 29(1):25-33
105. Zlokovic BV et al (2005) Functional recovery after embolic stroke in rodents by activated protein C. Ann Neurol 58(3):474-477 (Pubitemid 41266637)
106. Tsuneyoshi N et al (2001) Expression and anticoagulant function of the endothelial cell protein C receptor (EPCR) in cancer cell lines. Thromb Haemost 85(2):356-361 (Pubitemid 32140584)
107. Beaulieu LM, Church FC (2007) Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1. Exp Cell Res 313(4):677-687 (Pubitemid 46198814)
108. Bezuhly M et al (2009) Role of activated protein C and its receptor in inhibition of tumor metastasis. Blood 113(14):3371-3374