Emerging Insights in Tissue Factor-Dependent Signaling Events

ABSTRACT

The complex of the cell surface receptor tissue factor (TF) and its ligand coagulation factor VIIa (FVIIa) is the primary initiator of the coagulation cascade. It is now clear the TF-initiated coagulation pathway also plays major nonhemostatic roles in inflammation, tumor growth, and angiogenesis. Direct or indirect cell signaling by TF-FVIIa or downstream coagulation proteases is an essential part of these nonhemostatic functions. The TF-FVIIa complex activates protease-activated receptor 2 and thus regulates gene transcription and protein translation, cell proliferation and survival, or cell motility and integrin activation. In this review, we relate our current understanding of direct TF signaling pathways to the emerging roles of TF in (patho)physiology.

Tissue factor - TF-FVIIa complex - coagulation - cell signaling - PAR-2 - tumor growth - angiogenesis

REFERENCES

• 1 Versteeg H H, Peppelenbosch M P, Spek C A. The pleiotropic effects of tissue factor: a possible role for factor VIIa-induced intracellular signalling?.  Thromb Haemost. 2001;  86 1353-1359
• 2 Bugge T H, Xiao Q, Kombrinck K W et al.. Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of blood coagulation.  Proc Natl Acad Sci USA. 1996;  93 6258-6261
• 3 Carmeliet P, Mackman N, Moons L et al.. Role of tissue factor in embryonic blood vessel development.  Nature. 1996;  383 73-75
• 4 Yu J L, May L, Lhotak V et al.. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis.  Blood. 2005;  105 1734-1741
• 5 Koomagi R, Volm M. Tissue-factor expression in human non-small-cell lung carcinoma measured by immunohistochemistry: correlation between tissue factor and angiogenesis.  Int J Cancer. 1998;  79 19-22
• 6 Rickles F R, Hair G A, Zeff R A, Lee E, Bona R D. Tissue factor expression in human leukocytes and tumor cells.  Thromb Haemost. 1995;  74 391-395
• 7 Zhang Y, Deng Y, Luther T et al.. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice.  J Clin Invest. 1994;  94 1320-1327
• 8 Levi M, ten Cate H, Bauer K A et al.. 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;  93 114-120
• 9 van der Poll T, Büller H R, ten Cate H et al.. Activation of coagulation after administration of tumor necrosis factor to normal subjects.  N Engl J Med. 1990;  322 1622-1627
• 10 Versteeg H H, Peppelenbosch M P, Spek C A. Tissue factor signal transduction in angiogenesis.  Carcinogenesis. 2003;  24 1009-1013
• 11 Rehemtulla A, Ruf W, Edgington T S. The integrity of the cysteine 186-cysteine 209 bond of the second disulfide loop of tissue factor is required for binding of VII.  J Biol Chem. 1991;  266 10294-10299
• 12 Bach R, Konigsberg W H, Nemerson Y. Human tissue factor contains thioester-linked palmitate and stearate on the cytoplasmic half-cystine.  Biochemistry. 1988;  27 4227-4231
• 13 Harlos K, Martin D M, O'Brien D P et al.. Crystal structure of the extracellular region of human tissue factor.  Nature. 1994;  370 662-666
• 14 Muller Y A, Ultsch M H, Kelley R F, de Vos A M. Structure of the extracellular domain of human tissue factor: location of the factor VIIa binding site.  Biochemistry. 1994;  33 10864-10870
• 15 Peppelenbosch M P, Versteeg H H, Spek C A. In silico tissue factor analysis: a bit-to-bit comparison.  Thromb Haemost. 2003;  89 592-593
• 16 Halazy S. Signal transduction: an exciting field of investigation for small molecule drug discovery.  Molecules. 2003;  8 349-358
• 17 Camerer E, Røttingen J A, Gjernes E et al.. Coagulation factors VIIa and Xa induce cell signaling leading to the upregulation of the egr-1 gene.  J Biol Chem. 1999;  274 32225-32233
• 18 Versteeg H H, Sørensen B B, Slofstra S H et al.. VIIa/tissue factor interaction results in a tissue factor cytoplasmic domain-independent activation of protein synthesis, p70, and p90 S6 kinase phosphorylation.  J Biol Chem. 2002;  277 27065-27072
• 19 Sørensen B B, Rao L V, Tornehave D, Gammeltoft S, Petersen L C. Antiapoptotic effect of coagulation factor VIIa.  Blood. 2003;  102 1708-1715
• 20 Versteeg H H, Spek C A, Richel D J, Peppelenbosch M P. Coagulation factors VIIa and Xa inhibit apoptosis and anoikis.  Oncogene. 2004;  15 410-417
• 21 Versteeg H H, Hoedemaeker I, Diks S H et al.. Factor VIIa/tissue factor-induced signaling via activation of Src-like kinases, phosphatidylinositol 3-kinase, and Rac.  J Biol Chem. 2000;  275 28750-28756
• 22 Rottingen J A, Enden T, Camerer E, Iversen J G, 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 4650-4660
• 23 Camerer E, Rottingen J A, Iversen J G, 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 29034-29042
• 24 Poulsen L K, Jacobsen N, Sørensen B B et al.. Signal transduction via the mitogen activated protein kinase pathway induced by binding of coagulation factor VIIa to tissue factor.  J Biol Chem. 1998;  273 6228-6232
• 25 Riewald M, Ruf W. Orchestration of coagulation protease signaling by tissue factor.  Trends Cardiovasc Med. 2002;  12 149-154
• 26 Camerer E, Kataoka H, Kahn M, Lease K, Coughlin S R. Genetic evidence that protease-activated receptors mediate factor Xa signaling in endothelial cells.  J Biol Chem. 2002;  277 16081-16087
• 27 Riewald M, Petrovan R J, Donner A, Mueller B M, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway.  Science. 2002;  296 1880-1882
• 28 Kuliopulos A, Covic L, Seeley S K et al.. Plasmin desensitization of the PAR1 thrombin receptor: kinetics, sites of truncation, and implications for thrombolytic therapy.  Biochemistry. 1999;  38 4572-4585
• 29 Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells.  Cell. 2005;  120 303-313
• 30 Nystedt S, Emilsson K, Wahlestedt C, Sundelin J. Molecular cloning of a potential proteinase activated receptor.  Proc Natl Acad Sci USA. 1994;  91 9208-9212
• 31 Steinhoff M, Corvera C U, Thoma M S et al.. Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase.  Exp Dermatol. 1999;  8 282-294
• 32 Camerer E, Huang W, Coughlin S R. Tissue factor and factor X-dependent activation of protease-activated receptor 2 by factor VIIa.  Proc Natl Acad Sci USA. 2000;  97 5255-5260
• 33 Ishihara H, Connolly A J, Zeng D et al.. Protease-activated receptor 3 is a second thrombin receptor in humans.  Nature. 1997;  386 502-506
• 34 Kahn M L, Zheng Y W, Huang W et al.. A dual thrombin receptor system for platelet activation.  Nature. 1998;  394 690-694
• 35 Petersen L C, Thastrup O, Hagel G et al.. Exclusion of known protease-activated receptors in factor VIIa-induced signal transduction.  Thromb Haemost. 2000;  83 571-576
• 36 Ott I, Weigand B, Michl R et al.. Tissue factor cytoplasmic domain stimulates migration by activation of the GTPase Rac1 and the mitogen-activated protein kinase p38.  Circulation. 2005;  111 349-355
• 37 Ahamed J, Ruf W. Protease-activated receptor 2-dependent phosphorylation of the tissue factor cytoplasmic domain.  J Biol Chem. 2004;  279 23038-23044
• 38 Ahamed J, Belting M, Ruf W. Regulation of tissue factor-induced signaling by endogenous and recombinant tissue factor pathway inhibitor 1.  Blood. 2005;  105 2384-2391
• 39 Riewald M, Ruf W. Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor.  Proc Natl Acad Sci USA. 2001;  98 7742-7747
• 40 Fan L, Yotov W V, Zhu T et al.. Tissue factor enhances protease-activated receptor-2-mediated factor VIIa cell proliferative properties.  J Thromb Haemost. 2005;  3 1056-1063
• 41 Hjortoe G M, Petersen L C, Albrektsen T et al.. Tissue factor-factor VIIa-specific up-regulation of IL-8 expression in MDA-MB-231 cells is mediated by PAR-2 and results in increased cell migration.  Blood. 2004;  103 3029-3037
• 42 Dorfleutner A, Ruf W. Regulation of tissue factor cytoplasmic domain phosphorylation by palmitoylation.  Blood. 2003;  102 3998-4005
• 43 Belting M, Dorrell M I, Sandgren S et al.. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling.  Nat Med. 2004;  10 502-509
• 44 Dorfleutner A, Hintermann E, Tarui T, Takada Y, Ruf W. Cross-talk of integrin alpha3beta1 and tissue factor in cell migration.  Mol Biol Cell. 2004;  15 4416-4425
• 45 Sorensen B B, Freskgard P O, Nielsen L S et al.. Factor VIIa-induced p42/p44 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 21349-21354
• 46 Hansen C B, Pyke C, Petersen L C, Rao L V. Tissue factor-mediated endocytosis, recycling and degradation of factor VIIa by a clathrin-independent mechanism not requiring the cytoplasmic tail of tissue factor.  Blood. 2001;  97 1712-1720
• 47 Ott I, Fischer E G, Miyagi Y, Mueller B M, 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 1241-1253
• 48 Cunningham M A, Romas P, Hutchinson P, Holdsworth S R, Tipping P G. Tissue factor and VIIa receptor/ligand interactions induce proinflammatory effects in macrophages.  Blood. 1999;  94 3413-3420
• 49 Wiiger M T, Prydz H. The epidermal growth factor receptor (EGFR) and proline rich tyrosine kinase 2 (PYK2) are involved in tissue factor dependent factor VIIa signalling in HaCaT cells.  Thromb Haemost. 2004;  92 13-22
• 50 Versteeg H H, Spek C A, Slofstra S H et al.. FVIIa:TF induces cell survival via G12/G13-dependent Jak/STAT activation and BclXL production.  Circ Res. 2004;  94 1032-1040
• 51 Versteeg H H, Bresser H L, Spek C A et al.. Regulation of the p21Ras-MAP kinase pathway by factor VIIa.  J Thromb Haemost. 2003;  1 1012-1018
• 52 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 6580-6585
• 53 Pendurthi U R, Alok D, Rao L V. Binding of factor VIIa to tissue factor induces alterations in gene expression in human fibroblast cells: up-regulation of poly(A) polymerase.  Proc Natl Acad Sci USA. 1997;  94 12598-12603
• 54 Pendurthi U R, Allen K E, Ezban M, Rao L V. Factor VIIa and thrombin induce the expression of Cyr61 and connective tissue growth factor, extracellular matrix signaling proteins that could act as possible downstream mediators in factor VIIa x tissue factor-induced signal transduction.  J Biol Chem. 2000;  275 14632-14641
• 55 Riewald M, Kravchenko V V, Petrovan R J et al.. Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor-1.  Blood. 2001;  97 3109-3116
• 56 Wang X, Gjernes E, Prydz H. Factor VIIa induces tissue factor-dependent up-regulation of interleukin-8 in a human keratinocyte line.  J Biol Chem. 2002;  277 23620-23626
• 57 Contrino J, Hair G, Kreutzer D L, Rickles F R. In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease.  Nat Med. 1996;  2 209-215
• 58 Hamada K, Kuratsu J, Saitoh Y et al.. Expression of tissue factor correlates with grade of malignancy in human glioma.  Cancer. 1996;  77 1877-1883
• 59 Sorensen B B, Persson E, Freskgard P O et al.. Incorporation of an active site inhibitor in factor VIIa alters the affinity for tissue factor.  J Biol Chem. 1997;  272 11863-11868
• 60 Versteeg H H, Richel D J, Peppelenbosch M P, Spek C A. Concerted action of coagulation factors on cell survival.  J Thromb Haemost. 2004;  2 673-674
• 61 Muller M, Albrecht S, Golfert F et al.. Localization of tissue factor in actin-filament-rich membrane areas of epithelial cells.  Exp Cell Res. 1999;  248 136-147
• 62 Ge L, Shenoy S K, Lefkowitz R J, DeFea K. Constitutive protease-activated receptor-2-mediated migration of MDA MB-231 breast cancer cells requires both beta-arrestin-1 and -2.  J Biol Chem. 2004;  279 55419-55424
• 63 Siegbahn A, Johnell M, Rorsman C et al.. Binding of factor VIIa to tissue factor on human fibroblasts leads to activation of phospholipase C and enhanced PDGF-BB-stimulated chemotaxis.  Blood. 2000;  96 3452-3458
• 64 Sato Y, Asada Y, Marutsuka K, Hatakeyama K, Sumiyoshi A. Tissue factor induces migration of cultured aortic smooth muscle cells.  Thromb Haemost. 1996;  75 389-392
• 65 Kennedy S G, Wagner A J, Conzen S D et al.. The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal.  Genes Dev. 1997;  11 701-713
• 66 Kurada P, White K. Ras promotes cell survival in Drosophila by downregulating hid expression.  Cell. 1998;  95 319-329