The Pleiotropic Effects of Tissue Factor: a Possible Role for Factor VIIa-induced Intracellular Signalling?

Summary

Tissue factor, a 47 kDa membrane glycoprotein, lies at the basis of the extrinsic pathway of the coagulation cascade. Interaction of TF with factor VIIa results in the formation of fibrin from fibrinogen, thereby inducing the formation of a blood clot. In addition to this well-established role in blood coagulation, TF is associated with various other physiological processes such as sepsis, inflammation, angiogenesis, metastasis and atherosclerosis. The molecular basis of the latter events is slowly emerging. It has become clear that TF-FVIIa interaction elicits a variety of intracellular signalling events that may be implicated in these actions. These events include the sequential activation of Src-like kinases, MAP kinases, small GTPases and calcium signalling. How this progress in the understanding of TF associated signal transduction may generate answers as to the mechanism through which TF exerts it pleiotropic effects will be focus of this review.

Keywords

Coagulation - inflammation - angiogenesis - tumourigenesis - atherosclerosis

• References

• 1 Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci USA 1990; 87: 6934-8.
• 2 Zioncheck TF, Roy S, Vehar GA. The cytoplasmic domain of tissue factor is phosphorylated by a protein kinase C-dependent mechanism. J Biol Chem 1992; 267: 3561-4.
• 3 Bach RR. Initiation of coagulation by tissue factor. CRC Crit Rev Biochem 1988; 23: 339-68.
• 4 Camerer E, Kolsto AB, Prydz H. Cell biology of tissue factor, the principal initiator of blood coagulation. Thromb Res 1996; 81: 1-41.
• 5 Drake TA, Morrisey JH, Edgington TS. Selective cellular expression of tissue factor in human tissues: implications for disorders of hemostasis and thrombosis. Am J Pathol 1989; 134: 1087-97.
• 6 Wilcox JN, Smith KM, Schwartz SM. Localisation of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86: 2839-43.
• 7 Fleck RA, Rao LVM, Rapaport SI, Varki N. Localisation of human tissue factor antigen by immunostaining with monospecific, polyclonal anti-human tissue factor antibody. Thromb Res 1990; 57: 765-81.
• 8 Montemurro P, Lattanzio A, Chetta G, Lupo L, Caputi-Iambrenghi L, Rubino M, Giordano D, Semeraro N. Increased in vitro and in vivo generation of procoagulant activity (tissue factor) by mononuclear phagocytes after intralipid infusion in rabbits. Blood 1985; 65: 1391-5.
• 9 Semeraro N, Triggiani R, Montemurro P, Cavallo L. G, Colucci M. Enhanced endothelial tissue factor but normal thrombomodulin in endotoxin-treated rabbits. Thromb Res 1993; 71: 479-86.
• 10 Broze GJ. Tissue Factor Pathway Inhibitor and the revised theory of coagulation. Ann Rev Med 1995; 46: 103-12.
• 11 Thiruvikraman SV, Guha A, Roboz J, Taubman MB, Nemerson Y, Fallon JT. In situ localization of tissue factor in human atherosclerotic plaques by binding of digoxigenin-labeled factors VIIa and X. Lab Invest 1996; 75: 451-61.
• 12 Weis JR, Pitas RE, Wilson BD, Rodgers GM. Oxidized low-density lipo-protein increases cultured human endothelial cell tissue factor activity and reduces protein C activation. FASEB J 1991; 5: 2459-65.
• 13 Stragliotto E, Maderna P, Bernini F, Tremoli E. Acetyl-LDL but not native and ox-LDL stimulate the expression of procoagulant activity by monocytes. Thromb Haemost 1991; 65: 1870 abstract.
• 14 Schuff-Werner P, Claus G, Armstrong VW, Kostering H, Seidel D. Enhanced procoagulatory activity (PCA) of human monocytes/macrophages after in vitro stimulation with chemically modified LDL. Atherosclerosis 1989; 78: 109-12.
• 15 Taubman MB, Marmur JD, Rosenfield CL, Guha A, Nichtberger S, Nemerson Y. Agonist-mediated tissue factor expression in cultured vascular smooth muscle cells. Role of Ca²⁺ mobilization and protein kinase C activation. J Clin Invest 1993; 91: 547-52.
• 16 Schecter AD, Giesen PL, Taby O, Rosenfield CL, Rossikhina M, Fyfe BS, Kohtz DS, Fallon JT, Nemerson Y, Taubman MB. Tissue factor expression in human arterial smooth muscle cells. TF is present in three cellular pools after growth factor stimulation. J Clin Invest 1997; 100: 2276-85.
• 17 Mach F, Schonbeck U, Sukhova GK, Bourcier T, Bonnefoy JY, Pober JS, Libby P. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells and macrophages; implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad USA 1997; 94: 1931-6.
• 18 Mach F, Schonbeck U, Bonnefoy JY, Pober JS, Libby P. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor. Circulation 1997; 96: 396-9.
• 19 Annex BH, Denning SM, Channon KM, Sketch Jr MH, Stack RS, Morrissey JH, Peters KG. Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes. Circulation 1995; 91: 619-22.
• 20 Marmur JD, Thiruvikraman SV, Fyfe BS, Guha A, Sharma SK, Ambrose JA, Fallon JT, Nemerson Y, Taubman MB. Identification of active tissue factor in human coronary atheroma. Circulation 1996; 94: 1226-32.
• 21 Toschi V, Gallo R, Lettino M, Fallon JT, Gertz SD, Fernandez-Ortiz A, Chesebro JH, Badimon L, Nemerson Y, Fuster V, Badimon JJ. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 1997; 95: 594-9.
• 22 Ardissino D, Merlini PA, Ariens R, Coppola R, Bramucci E, Mannucci PM. Tissue factor-antigen and activity in human atherosclerotic plaques. Lancet 1997; 349: 769-71.
• 23 Haskel EJ, Torr SR, Day KC, Palmier MO, Wun TC, Sobel BE, Abendschein DR. Prevention of arterial reocclusion after thrombolysis with recombinant lipoprotein-associated coagulation inhibitor. Circulation 1991; 84: 821-7.
• 24 Jang IK, Gold HK, Leinbach RC, Fallon JT, Collen D, Wilcox JN. Anti-thrombotic effect of a monoclonal antibody against tissue factor in a rabbit model of platelet-mediated arterial thrombosis. Arterioscler Thromb 1992; 12: 948-54.
• 25 Harker LA, Hanson SR, Kelly AB. Antithrombotic strategies targeting thrombin activities, thrombin receptors and thrombin generation. Thromb Haemost 1997; 78: 736-41.
• 26 Crutchley DJ, Hirsh MJ. The stable prostacyclin analog, iloprost, and pros-taglandin E1 inhibit monocyte procoagulant activity in vitro. Blood 1991; 78: 382-6.
• 27 Herbert JM, Savi P, Laplace MC, Lale A. IL-4 inhibits LPS-, IL-1 beta- and TNF alpha-induced expression of tissue factor in endothelial cells and monocytes. FEBS Lett 1992; 310: 31-3.
• 28 Osnes LT, Westvik AB, Joo GB, Okkenhaug C, Kierulf P. Inhibition of IL-1 induced tissue factor (TF) synthesis and procoagulant activity (PCA) in purified human monocytes by IL-4, IL-10 and IL-13. Cytokine 1996; 8: 822-7.
• 29 Harker LA, Kelly AB, Hanson SR, Krupski W, Bass A, Osterud B, FitzGerald GA, Goodnight SH, Connor WE. Interruption of vascular thrombus formation and vascular lesion formation by dietary n-3 fatty acids in fish oil in nonhuman primates. Circulation 1993; 87: 1017-29.
• 30 Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol 1997; 17: 265-72.
• 31 Bugge TH, Xiao Q, Kombrinck KW, Holmback K, Danton MJS, Colbert MC, Witte DP, Fujikawa K, Davie EN, Degan JL. Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of blood coagulation. Proc Natl Acad Sci USA 1996; 93: 6258-61.
• 32 Carmeliet P, Mackman N, Moons L, Luther T, Gressens P, Van Vlaenderen I, Demunck H, Kasper M, Breier G, Evrard P, Muller M, Risau W, Edging-ton T, Collen D. Role of tissue factor in embryonic blood vessel development. Nature 1996; 383: 73-5.
• 33 Toomey JR, Kratzer KE, Lasky NM, Stanton JJ, Broze Jr GJ. Targeted disruption of the murine tissue factor gene results in embryonic lethality. Blood 1996; 88: 1583-7.
• 34 Carmeliet P, Collen D. Molecular basis of angiogenesis. Role of VEGF and VE-cadherin. Ann NY Acad Sci 2000; 902: 249-62.
• 35 Mueller BM, Reisfeld RA, Edgington TS, Ruf W. Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis. Proc Natl Acad Sci USA 1992; 89: 11832-6.
• 36 Fisher EG, Ruf W, Mueller BM. Tissue factor-initiated thrombin generation activates the signaling thrombin receptor on malignant melanoma cells. Cancer Res 1995; 55: 1629-32.
• 37 Mueller BM, Ruf W. Requirement for binding of catalytically active factor VIIa in tissue factor dependent experimental metastasis. J Clin Invest 1998; 101: 1372-8.
• 38 Zhang Y, Deng Y, Luther T, Muller M, Ziegler R, Waldherr R, Stern DM, Nawroth PP. Tissue factor controls the balance of angiogenic and anti-angiogenic properties of tumour cells in mice. J Clin Invest 1994; 94: 1320-7.
• 39 Bromberg ME, Koningsberg WH, Madison JF, Pawashe A, Garen A. Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci USA 1995; 92: 8205-9.
• 40 Abe K, Shoji M, Chen J, Bierhaus A, Danave I, Micko C, Casper K, Dillehay DL, Nawroth P, Rickles FR. Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. Proc Natl Acad Sci USA 1999; 96: 8663-8.
• 41 Ollivier V, Bentolila S, Chabbat J, Hakim J, de Prost D. Tissue factor-dependent vascular endothelial growth factor production by human fibro-blasts in response to activated factor VII. Blood 1998; 91: 2698-703.
• 42 Ollivier V, Chabbat J, Herbert JM, Hakim J, de Prost D. Vascular endothelial growth factor production by fibroblasts in response to factor VIIa binding to tissue factor involves thrombin and factor Xa. Arterioscler Thromb Vasc Biol 2000; 20: 1374-81.
• 43 Rabiet M-J, Plantier J-L, Rival Y, Genoux Y, Lampugnany M-G, Dejana E. Thrombin-induced increase in endothelial permeability is associated with changes in cell-to-cell junction organisation. Artherioscler Thromb Vasc Biol 1996; 16: 488-96.
• 44 Pendurthy UR, Allen KE, Ezban M, Rao LV. Factor VIIa and thrombin induce the expression of Cyr61 and connective tissue growth factor, extra-cellular matrix signaling proteins that could act as possible downstream mediators in Factor VIIa. tissue factor-induced signal transduction. J Biol Chem 2000; 275: 14632-41.
• 45 Kireeva ML, Lam S, Lau LF. Adhesion of human umbilical vein endothelial cells to the immediate-early gene product Cyr61 is mediated through inte-grin alphavbeta3. J Biol Chem 1998; 273: 3090-6.
• 46 Taylor Jr FB. Role of tissue factor and factor VIIa in the coagulant and inflammatory response to LD100 Escherichia coli in the baboon. Haemost 1996; 26: 83-91.
• 47 Levi M, van der Poll T, ten Cate H, van Deventer SJ. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest 1997; 27: 3-9.
• 48 Levi M, ten Cate H, Bauer KA, van der Poll T, Edgington TS, Buller HR, van Deventer SJ, Hack CE, ten Cate JW, Rosenberg RD. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest 1994; 93: 114-20.
• 49 Biemond BJ, Levi M, ten Cate H, Soule HR, Morris LD, Foster DL, Bogowitz CA, van der Poll T, Buller HR, ten Cate JW. Complete inhibition of endotoxin-induced coagulation activation in chimpanzees with a monoclonal Fab fragment against factor VII/VIIa. Thromb Haemost 1995; 73: 223-30.
• 50 Van der Poll T, Buller HR, ten Cate H, Wortel CH, Bauer KA, van Deventer SJ, Hack CE, Sauerwein HP, Rosenberg RD, ten Cate JW. Activation of coagulation after administration of tumour necrosis factor to normal subjects. N Engl J Med 1990; 322: 1622-7.
• 51 Van der Poll T, Levi M, van Deventer SJ, ten Cate H, Haagmans BL, Biemond BJ, Buller HR, Hack CE, ten Cate JW. Differential effects of anti-tumour necrosis factor monoclonal antibodies on systemic inflammatory responses in experimental endotoxemia in chimpanzees. Blood 1994; 83: 446-51.
• 52 Van der Poll T, Coyle SM, Levi M, Jansen PM, Dentener M, Barbosa K, Buurman WA, Hack CE, ten Cate JW, Agosti JM, Lowry SF. Effect of a recombinant dimeric tumour necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans. Blood 1997; 89: 3727-34.
• 53 DeLa Cadena RA, Majluf-Cruz A, Stadnicki A, Tropea M, Reda D, Agosti JM, Colman RW, Suffredini AF. Recombinant tumour necrosis factor receptor p75 fusion protein (TNFR:Fc) alters endotoxin-induced activation of the kinin, fibrinolytic, and coagulation systems in normal humans. Thromb Haemost 1998; 80: 114-8.
• 54 Van der Poll T, Levi M, Hack CE, Ten Cate H, Van Deventer SJH, Eerenberg AJM, De Groot ER, Jansen J, Gallati H, Buller HR, Ten Cate JW, Aarden LA. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 1994; 179: 1253-9.
• 55 Boermeester MA, van Leeuwen PA, Coyle SM, Wolbink GJ, Hack CE, Lowry SF. Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch Surg 1995; 130: 739-48.
• 56 Taylor Jr FB, Chang AC, Ruf W, Morrissey JH, Hinshaw LB, Blick KE, Edgington TS. Lethal septic shock is prevented by blocking tissue factor. Circ Shock 1991; 33: 127-34.
• 57 Creasey AA, Chang AC, Fiegen L, Wun T-C, Taylor Jr FB, Hinshaw LB. Tissue factor pathway inhibitor (TFPI) reduces mortality from Escherichia coli septic shock. J Clin Invest 1993; 91: 2850-6.
• 58 Park CT, Creasey AA, Wright SD. Tissue factor pathway inhibitor blocks cellular effects of endotoxin and interfering with transfer to CD14. Blood 1997; 89: 4268-74.
• 59 Taylor Jr FB, Chang AC, Peer G, Li A, Ezban M, Hedner U. Active site inhibited Factor VIIa (DEGR VIIa) attenuates the coagulant and inter-leukin-6 and -8, but not tumour necrosis factor, responses of the baboon to LD100 Escherichia coli. Blood 1998; 91: 1609-15.
• 60 Randolph GJ, Luther T, Albrecht A, Magdolen V, Muller WA. Role of tissue factor in adhesion of mononuclear phagocytes to and trafficking through endothelium in vitro. Blood 1998; 92: 4167-77.
• 61 Cunningham MA, Romas P, Hutchinson P, Holdsworth SR, Tipping PG. Tissue factor and factor VIIa receptor/ligand interactions induce proinflammatory effects in macrophages. Blood 1999; 94: 3413-20.
• 62 Pendurthy UR, Alok D, Rao LV. Binding of factor VIIa to tissue factor induces alterations in gene expression in human fibroblast cells: upregulation of poly(A) polymerase. Proc Natl Acad Sci USA 1997; 94: 12598-603.
• 63 Masuda M, Nakamura S, Murakami T, Komiyama Y, Takahashi H. Association of tissue factor with a g chain homodimer of the IgE receptor type I in cultured human monocytes. Eur J Immunol 1996; 26: 2529-32.
• 64 Røttingen JA, Enden T, Camerer E, Iversen JG, Prydz H. Binding of human factor VIIa to tissue factor induces cytosolic Ca²⁺ signals in J82 cells, transfected Cos-1 cells, Madin Darby Canine Kidney cells and in human endothelial cells, induced to synthesize tissue factor. J Biol Chem 1995; 270: 4650-60.
• 65 Camerer E, Røttingen JA, Iversen JG, Prydz H. Coagulation factors VII and X induce Ca²⁺ oscillations in Madin-Darby Canine Kidney cells only when proteolytically active. J Biol Chem 1996; 271: 29034-42.
• 66 Poulsen LK, Jacobsen N, Sørensen BB, Bergenhem N, Kelly JD, Foster DC, Thastrup O, Ezban M, Petersen LC. Signal Transduction via the Mitogen Activated Protein Kinase pathway induced by binding of coagulation factor VIIa to tissue factor. J Biol Chem 1998; 273: 6228-32.
• 67 Sørensen BB, Freskgård PO, Nielsen LS, Rao LV, Ezban M, Petersen LC. Factor VIIa-induced p42/44 Mitogen-Activated Protein Kinase activation requires the proteolytic activity of Factor VIIa and is independent of the tissue factor cytoplasmic domain. J Biol Chem 1999; 274: 21349-54.
• 68 Camerer E, Røttingen JA, Gjernes E, Larsen K, Skartlien AH, Iversen JG, Prydz H. Coagulation factors VIIa and Xa induce cell signaling leading to the upregulation of the egr-1 gene. J Biol Chem 1999; 274: 32225-33.
• 69 Versteeg HH, Hoedemaeker I, Diks SH, Stam JC, Spaargaren M, Van Bergen en Henegouwen PM, Van Deventer SJ, Peppelenbosch MP. Factor VIIa/tissue factor-induced signaling via activation of Src-like kinases, Phosphatidylinositol 3-kinase, and Rac. J Biol Chem 2000; 275: 28750-6.
• 70 Harlos K, Martin DM, O’Brien DP, Jones EY, Stuart DI, Polikarpov I, Miller A, Tuddenham EG, Boys CW. Crystal structure of the extracellular region of human tissue factor. Nature 1994; 370: 662-6.
• 71 Muller YA, Ultsch MH, Kelley RF, de Vos AM. Structure of the extra-cellular domain of human tissue factor: location of the factor VIIa binding site. Biochemistry 1994; 33: 10864-70.
• 72 Ott I, Fischer E, Miyagi Y, Mueller BM, Ruf W. A role for tissue factor in cell adhesion and migration mediated by interaction with Actin-binding Protein 280. J Cell Biol 1998; 140: 1241-53.
• 73 Camerer E, Huang W, Coughlin SR. Tissue factor and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci USA 2000; 97: 5255-60.
• 74 Petersen LC, Thastrup O, Hagel G, Sorensen BB, Freskgard PO, Rao LV, Ezban M. Exclusion of known protease-activated receptors in factor VIIa-induced signal transduction. Thromb Haemost 2000; 83: 571-6.
• 75 Camerer E, Gjernes E, Wiiger M, Pringle S, Prydz H. Binding of factor VIIa to tissue factor on keratinocytes induces gene expression. J Biol Chem 2000; 275: 6580-5.
• 76 Heine H, Ulmer AJ, Flad HD, Hauschildt S. Lipopolysaccharide-induced change of phosphorylation of two cytosolic proteins in human monocytes is prevented by inhibitors of ADP-ribosylation. J Immunol 1995; 155: 4899-908.
• 77 Beyaert R, Cuenda A, Vanden Berghe W, Plaisance S, Lee JC, Haegeman G, Cohen P, Fiers W. The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis response to tumour necrosis factor. EMBO J 1996; 15: 1914-23.