Structure–Function Relationship of the Interaction between Tissue Factor and Factor VIIa

Abstract

Interactions between tissue factor and factor VIIa are the primary initiators of coagulation in hemostasis and certain thrombotic diseases. Tissue factor, an integral membrane protein expressed extensively outside of the vasculature, is the regulatory protein cofactor for coagulation factor VIIa. Factor VIIa, a trypsin-like serine protease homologous with other blood coagulation proteases, is weakly active when free in solution and must bind its membrane-bound cofactor for physiologically relevant activity. Tissue factor allosterically activates factor VIIa by several mechanisms such as active site positioning, spatial stabilization, and direct interactions with the substrate. Protein–membrane interactions between tissue factor, factor VIIa, and substrates all play critical roles in modulating the activity of this enzyme complex. Additionally, divalent cations such as Ca²⁺ and Mg²⁺ are critical for correct protein folding, as well as protein–membrane and protein–protein interactions. The contributions of these factors toward tissue factor–factor VIIa activity are discussed in this review.

Keywords

tissue factor - factor VIIa - protein–membrane interactions - extrinsic tenase - metal ions

• References

• 1 Vadivel K, Agah S, Messer AS , et al. Structural and functional studies of γ-carboxyglutamic acid domains of factor VIIa and activated Protein C: role of magnesium at physiological calcium. J Mol Biol 2013; 425 (11) 1961-1981
• 2 Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph 1996; 14 (1) 33-38 , 27–28
• 3 Opella SJ, Marassi FM, Gesell JJ , et al. Structures of the M2 channel-lining segments from nicotinic acetylcholine and NMDA receptors by NMR spectroscopy. Nat Struct Biol 1999; 6 (4) 374-379
• 4 Mackman N. The role of tissue factor and factor VIIa in hemostasis. Anesth Analg 2009; 108 (5) 1447-1452
• 5 Morrissey JH. Tissue factor: a key molecule in hemostatic and nonhemostatic systems. Int J Hematol 2004; 79 (2) 103-108
• 6 Drake TA, Morrissey JH, Edgington TS. Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am J Pathol 1989; 134 (5) 1087-1097
• 7 Fleck RA, Rao LVM, Rapaport SI, Varki N. Localization of human tissue factor antigen by immunostaining with monospecific, polyclonal anti-human tissue factor antibody. Thromb Res 1990; 59 (2) 421-437
• 8 Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci U S A 1989; 86 (8) 2839-2843
• 9 Morrissey JH, Macik BG, Neuenschwander PF, Comp PC. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993; 81 (3) 734-744
• 10 Kondo S, Kisiel W. Regulation of factor VIIa activity in plasma: evidence that antithrombin III is the sole plasma protease inhibitor of human factor VIIa. Thromb Res 1987; 46 (2) 325-335
• 11 Seligsohn U, Kasper CK, Osterud B, Rapaport SI. Activated factor VII: presence in factor IX concentrates and persistence in the circulation after infusion. Blood 1979; 53 (5) 828-837
• 12 Lawson JH, Butenas S, Mann KG. The evaluation of complex-dependent alterations in human factor VIIa. J Biol Chem 1992; 267 (7) 4834-4843
• 13 Neuenschwander PF, Branam DE, Morrissey JH. Importance of substrate composition, pH and other variables on tissue factor enhancement of factor VIIa activity. Thromb Haemost 1993; 70 (6) 970-977
• 14 Ruf W, Rehemtulla A, Morrissey JH, Edgington TS. Phospholipid-independent and -dependent interactions required for tissue factor receptor and cofactor function. J Biol Chem 1991; 266 (4) 2158-2166
• 15 Zwaal RFA, Comfurius P, Bevers EM. Lipid-protein interactions in blood coagulation. Biochim Biophys Acta 1998; 1376 (3) 433-453
• 16 Morrissey JH, Neuenschwander PF, Huang Q, McCallum CD, Su B, Johnson AE. Factor VIIa-tissue factor: functional importance of protein-membrane interactions. Thromb Haemost 1997; 78 (1) 112-116
• 17 Paborsky LR, Caras IW, Fisher KL, Gorman CM. Lipid association, but not the transmembrane domain, is required for tissue factor activity. Substitution of the transmembrane domain with a phosphatidylinositol anchor. J Biol Chem 1991; 266 (32) 21911-21916
• 18 Waters EK, Morrissey JH. Restoring full biological activity to the isolated ectodomain of an integral membrane protein. Biochemistry 2006; 45 (11) 3769-3774
• 19 Ohkubo YZ, Morrissey JH, Tajkhorshid E. Dynamical view of membrane binding and complex formation of human factor VIIa and tissue factor. J Thromb Haemost 2010; 8 (5) 1044-1053
• 20 Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A 1990; 87 (18) 6934-6938
• 21 Lhermusier T, Chap H, Payrastre B. Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome. J Thromb Haemost 2011; 9 (10) 1883-1891
• 22 Fadeel B, Xue D. The ins and outs of phospholipid asymmetry in the plasma membrane: roles in health and disease. Crit Rev Biochem Mol Biol 2009; 44 (5) 264-277
• 23 Ke K, Yuan J, Morrissey JH. Tissue factor residues that putatively interact with membrane phospholipids. PLoS One 2014; 9 (2) e88675
• 24 Al-Hashimi AA, Caldwell J, Gonzalez-Gronow M , et al. Binding of anti-GRP78 autoantibodies to cell surface GRP78 increases tissue factor procoagulant activity via the release of calcium from endoplasmic reticulum stores. J Biol Chem 2010; 285 (37) 28912-28923
• 25 Pozza LM, Austin RC. Getting a GRP on tissue factor activation. Arterioscler Thromb Vasc Biol 2005; 25 (8) 1529-1531
• 26 Butenas S. Tissue factor structure and function. Scientifica (Cairo) 2012; 2012: 964862
• 27 Chen VM, Ahamed J, Versteeg HH, Berndt MC, Ruf W, Hogg PJ. Evidence for activation of tissue factor by an allosteric disulfide bond. Biochemistry 2006; 45 (39) 12020-12028
• 28 Versteeg HH, Ruf W. Tissue factor coagulant function is enhanced by protein-disulfide isomerase independent of oxidoreductase activity. J Biol Chem 2007; 282 (35) 25416-25424
• 29 Bach RR, Monroe D. What is wrong with the allosteric disulfide bond hypothesis?. Arterioscler Thromb Vasc Biol 2009; 29 (12) 1997-1998
• 30 Persson E. Protein disulfide isomerase has no stimulatory chaperone effect on factor X activation by factor VIIa-soluble tissue factor. Thromb Res 2008; 123 (1) 171-176
• 31 Pendurthi UR, Ghosh S, Mandal SK, Rao LV. Tissue factor activation: is disulfide bond switching a regulatory mechanism?. Blood 2007; 110 (12) 3900-3908
• 32 Rao LV, Kothari H, Pendurthi UR. Tissue factor: mechanisms of decryption. Front Biosci (Elite Ed) 2012; 4: 1513-1527
• 33 Pendurthi UR, Rao LV. Role of tissue factor disulfides and lipid rafts in signaling. Thromb Res 2008; 122 (Suppl. 01) S14-S18
• 34 Butenas S, Krudysz-Amblo J. Decryption of tissue factor. Thromb Res 2012; 129 (Suppl. 02) S18-S20
• 35 Rao LV, Kothari H, Pendurthi UR. Tissue factor encryption and decryption: facts and controversies. Thromb Res 2012; 129 (Suppl. 02) S13-S17
• 36 Radcliffe R, Nemerson Y. Activation and control of factor VII by activated factor X and thrombin. Isolation and characterization of a single chain form of factor VII. J Biol Chem 1975; 250 (2) 388-395
• 37 Broze Jr GJ, Majerus PW. Purification and properties of human coagulation factor VII. J Biol Chem 1980; 255 (4) 1242-1247
• 38 Kisiel W, Davie EW. Isolation and characterization of bovine factor VII. Biochemistry 1975; 14 (22) 4928-4934
• 39 Gladhaug A, Prydz H. Purification of the coagulation factors VII and X from human serum. Some properties of factor VII. Biochim Biophys Acta 1970; 215 (1) 105-111
• 40 Hagen FS, Gray CL, O'Hara P , et al. Characterization of a cDNA coding for human factor VII. Proc Natl Acad Sci U S A 1986; 83 (8) 2412-2416
• 41 O'Hara PJ, Grant FJ, Haldeman BA , et al. Nucleotide sequence of the gene coding for human factor VII, a vitamin K-dependent protein participating in blood coagulation. Proc Natl Acad Sci U S A 1987; 84 (15) 5158-5162
• 42 Bloom JW, Mann KG. Metal ion induced conformational transitions of prothrombin and prothrombin fragment 1. Biochemistry 1978; 17 (21) 4430-4438
• 43 Freedman SJ, Furie BC, Furie B, Baleja JD. Structure of the metal-free gamma-carboxyglutamic acid-rich membrane binding region of factor IX by two-dimensional NMR spectroscopy. J Biol Chem 1995; 270 (14) 7980-7987
• 44 Banner DW, D'Arcy A, Chène C , et al. The crystal structure of the complex of blood coagulation factor VIIa with soluble tissue factor. Nature 1996; 380 (6569) 41-46
• 45 Schiødt J, Harrit N, Christensen U, Petersen LC. Two different Ca2+ ion binding sites in factor VIIa and in des(1-38) factor VIIa. FEBS Lett 1992; 306 (2–3) 265-268
• 46 Persson E, Nielsen LS. Ca2+ in the first epidermal growth factor-like domain of activated factor VII. Blood Coagul Fibrinolysis 1998; 9 (Suppl. 01) S79-S81
• 47 Sabharwal AK, Birktoft JJ, Gorka J, Wildgoose P, Petersen LC, Bajaj SP. High affinity Ca(2+)-binding site in the serine protease domain of human factor VIIa and its role in tissue factor binding and development of catalytic activity. J Biol Chem 1995; 270 (26) 15523-15530
• 48 Higashi S, Matsumoto N, Iwanaga S. Molecular mechanism of tissue factor-mediated acceleration of factor VIIa activity. J Biol Chem 1996; 271 (43) 26569-26574
• 49 Persson E. Macromolecular substrate affinity for free factor VIIa is independent of a buried protease domain N-terminus. Biochem Biophys Res Commun 2006; 341 (1) 28-32
• 50 Toso R, Bernardi F, Tidd T , et al. Factor VII mutant V154G models a zymogen-like form of factor VIIa. Biochem J 2003; 369 (Pt 3): 563-571
• 51 Song H, Olsen OH, Persson E, Rand KD. Sites involved in intra- and interdomain allostery associated with the activation of factor VIIa pinpointed by hydrogen-deuterium exchange and electron transfer dissociation mass spectrometry. J Biol Chem 2014; 289 (51) 35388-35396
• 52 Bajaj SP, Schmidt AE, Agah S, Bajaj MS, Padmanabhan K. High resolution structures of p-aminobenzamidine- and benzamidine-VIIa/soluble tissue factor: unpredicted conformation of the 192-193 peptide bond and mapping of Ca2+, Mg2+, Na+, and Zn2+ sites in factor VIIa. J Biol Chem 2006; 281 (34) 24873-24888
• 53 Mather T, Oganessyan V, Hof P , et al. The 2.8 A crystal structure of Gla-domainless activated protein C. EMBO J 1996; 15 (24) 6822-6831
• 54 Walker CP, Royston D. Thrombin generation and its inhibition: a review of the scientific basis and mechanism of action of anticoagulant therapies. Br J Anaesth 2002; 88 (6) 848-863
• 55 Rand KD, Jørgensen TJ, Olsen OH , et al. Allosteric activation of coagulation factor VIIa visualized by hydrogen exchange. J Biol Chem 2006; 281 (32) 23018-23024
• 56 Kirchhofer D, Eigenbrot C, Lipari MT, Moran P, Peek M, Kelley RF. The tissue factor region that interacts with factor Xa in the activation of factor VII. Biochemistry 2001; 40 (3) 675-682
• 57 Persson E, Kjalke M, Olsen OH. Rational design of coagulation factor VIIa variants with substantially increased intrinsic activity. Proc Natl Acad Sci U S A 2001; 98 (24) 13583-13588
• 58 Neuenschwander PF, Vernon JT, Morrissey JH. Tissue factor alters the pK(a) values of catalytically important factor VIIa residues. Biochemistry 2002; 41 (10) 3364-3371
• 59 McCallum CD, Hapak RC, Neuenschwander PF, Morrissey JH, Johnson AE. 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 (45) 28168-28175
• 60 Mutucumarana VP, Duffy EJ, Lollar P, Johnson AE. The active site of factor IXa is located far above the membrane surface and its conformation is altered upon association with factor VIIIa. A fluorescence study. J Biol Chem 1992; 267 (24) 17012-17021
• 61 Husten EJ, Esmon CT, Johnson AE. The active site of blood coagulation factor Xa. Its distance from the phospholipid surface and its conformational sensitivity to components of the prothrombinase complex. J Biol Chem 1987; 262 (27) 12953-12961
• 62 McCallum CD, Su B, Neuenschwander PF, Morrissey JH, Johnson AE. Tissue factor positions and maintains the factor VIIa active site far above the membrane surface even in the absence of the factor VIIa Gla domain. A fluorescence resonance energy transfer study. J Biol Chem 1997; 272 (48) 30160-30166
• 63 Huang X, Ding WQ, Vaught JL , et al. A soluble tissue factor-annexin V chimeric protein has both procoagulant and anticoagulant properties. Blood 2006; 107 (3) 980-986
• 64 Waters EK, Yegneswaran S, Morrissey JH. Raising the active site of factor VIIa above the membrane surface reduces its procoagulant activity but not factor VII autoactivation. J Biol Chem 2006; 281 (36) 26062-26068
• 65 Waxman E, Laws WR, Laue TM, Nemerson Y, Ross JBA. Human factor VIIa and its complex with soluble tissue factor: evaluation of asymmetry and conformational dynamics by ultracentrifugation and fluorescence anisotropy decay methods. Biochemistry 1993; 32 (12) 3005-3012
• 66 Olsen OH, Rand KD, Østergaard H, Persson E. A combined structural dynamics approach identifies a putative switch in factor VIIa employed by tissue factor to initiate blood coagulation. Protein Sci 2007; 16 (4) 671-682
• 67 Colina CM, Venkateswarlu D, Duke R, Perera L, Pedersen LG. What causes the enhancement of activity of factor VIIa by tissue factor?. J Thromb Haemost 2006; 4 (12) 2726-2729
• 68 Soejima K, Yuguchi M, Mizuguchi J , et al. The 99 and 170 loop-modified factor VIIa mutants show enhanced catalytic activity without tissue factor. J Biol Chem 2002; 277 (50) 49027-49035
• 69 Dickinson CD, Kelly CR, Ruf W. 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 (25) 14379-14384
• 70 Pike ACW, Brzozowski AM, Roberts SM, Olsen OH, Persson E. Structure of human factor VIIa and its implications for the triggering of blood coagulation. Proc Natl Acad Sci U S A 1999; 96 (16) 8925-8930
• 71 Ruf W, Miles DJ, Rehemtulla A, Edgington TS. Tissue factor residues 157-167 are required for efficient proteolytic activation of factor X and factor VII. J Biol Chem 1992; 267 (31) 22206-22210
• 72 Huang Q, Neuenschwander PF, Rezaie AR, Morrissey JH. Substrate recognition by tissue factor-factor VIIa. Evidence for interaction of residues Lys165 and Lys166 of tissue factor with the 4-carboxyglutamate-rich domain of factor X. J Biol Chem 1996; 271 (36) 21752-21757
• 73 Kirchhofer D, Lipari MT, Moran P, Eigenbrot C, Kelley RF. The tissue factor region that interacts with substrates factor IX and Factor X. Biochemistry 2000; 39 (25) 7380-7387
• 74 Roy S, Hass PE, Bourell JH, Henzel WJ, Vehar GA. Lysine residues 165 and 166 are essential for the cofactor function of tissue factor. J Biol Chem 1991; 266 (32) 22063-22066
• 75 Ruf W, Miles DJ, Rehemtulla A, Edgington TS. Cofactor residues lysine 165 and 166 are critical for protein substrate recognition by the tissue factor-factor VIIa protease complex. J Biol Chem 1992; 267 (9) 6375-6381
• 76 Morrissey JH, Fair DS, Edgington TS. Monoclonal antibody analysis of purified and cell-associated tissue factor. Thromb Res 1988; 52 (3) 247-261
• 77 Fiore MM, Neuenschwander PF, Morrissey JH. An unusual antibody that blocks tissue factor/factor VIIa function by inhibiting cleavage only of macromolecular substrates. Blood 1992; 80 (12) 3127-3134
• 78 Ruf W, Edgington TS. An anti-tissue factor monoclonal antibody which inhibits TF.VIIa complex is a potent anticoagulant in plasma. Thromb Haemost 1991; 66 (5) 529-533
• 79 Huang M, Syed R, Stura EA , et al. The mechanism of an inhibitory antibody on TF-initiated blood coagulation revealed by the crystal structures of human tissue factor, Fab 5G9 and TF.G9 complex. J Mol Biol 1998; 275 (5) 873-894
• 80 Kirchhofer D, Moran P, Chiang N , et al. Epitope location on tissue factor determines the anticoagulant potency of monoclonal anti-tissue factor antibodies. Thromb Haemost 2000; 84 (6) 1072-1081
• 81 Versteeg HH, Schaffner F, Kerver M , et al. Inhibition of tissue factor signaling suppresses tumor growth. Blood 2008; 111 (1) 190-199
• 82 Contreras FX, Sánchez-Magraner L, Alonso A, Goñi FM. Transbilayer (flip-flop) lipid motion and lipid scrambling in membranes. FEBS Lett 2010; 584 (9) 1779-1786
• 83 McDonald JF, Shah AM, Schwalbe RA, Kisiel W, Dahlbäck B, Nelsestuen GL. Comparison of naturally occurring vitamin K-dependent proteins: correlation of amino acid sequences and membrane binding properties suggests a membrane contact site. Biochemistry 1997; 36 (17) 5120-5127
• 84 Nelsestuen GL, Kisiel W, Di Scipio RG. Interaction of vitamin K dependent proteins with membranes. Biochemistry 1978; 17 (11) 2134-2138
• 85 Tavoosi N, Smith SA, Davis-Harrison RL, Morrissey JH. Factor VII and protein C are phosphatidic acid-binding proteins. Biochemistry 2013; 52 (33) 5545-5552
• 86 Neuenschwander PF, Morrissey JH. Roles of the membrane-interactive regions of factor VIIa and tissue factor. The factor VIIa Gla domain is dispensable for binding to tissue factor but important for activation of factor X. J Biol Chem 1994; 269 (11) 8007-8013
• 87 Hedner U. Mechanism of action, development and clinical experience of recombinant FVIIa. J Biotechnol 2006; 124 (4) 747-757
• 88 Feng D, Whinna H, Monroe D, Stafford DW. FVIIa as used pharmacologically is not TF dependent in hemophilia B mice. Blood 2014; 123 (11) 1764-1766
• 89 Tavoosi N, Davis-Harrison RL, Pogorelov TV , et al. Molecular determinants of phospholipid synergy in blood clotting. J Biol Chem 2011; 286 (26) 23247-23253
• 90 Kay JG, Koivusalo M, Ma X, Wohland T, Grinstein S. Phosphatidylserine dynamics in cellular membranes. Mol Biol Cell 2012; 23 (11) 2198-2212
• 91 Huang M, Rigby AC, Morelli X , et al. Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins. Nat Struct Biol 2003; 10 (9) 751-756
• 92 Sunnerhagen M, Forsén S, Hoffrén AM, Drakenberg T, Teleman O, Stenflo J. Structure of the Ca(2+)-free Gla domain sheds light on membrane binding of blood coagulation proteins. Nat Struct Biol 1995; 2 (6) 504-509
• 93 Persson E, Petersen LC. Structurally and functionally distinct Ca2+ binding sites in the gamma-carboxyglutamic acid-containing domain of factor VIIa. Eur J Biochem 1995; 234 (1) 293-300
• 94 de Courcy B, Pedersen LG, Parisel O , et al. Understanding selectivity of hard and soft metal cations within biological systems using the subvalence concept. I. Application to blood coagulation: direct cation-protein electronic effects vs. indirect interactions through water networks. J Chem Theory Comput 2010; 6 (4) 1048-1063
• 95 Tavoosi N, Morrissey JH. Influence of membrane composition on the enhancement of factor VIIa/tissue factor activity by magnesium ions. Thromb Haemost 2014; 111 (4) 770-772
• 96 Sekiya F, Yoshida M, Yamashita T, Morita T. Magnesium(II) is a crucial constituent of the blood coagulation cascade. Potentiation of coagulant activities of factor IX by Mg2+ ions. J Biol Chem 1996; 271 (15) 8541-8544
• 97 Persson E, Olsen OH, Østergaard A, Nielsen LS. Ca2+ binding to the first epidermal growth factor-like domain of factor VIIa increases amidolytic activity and tissue factor affinity. J Biol Chem 1997; 272 (32) 19919-19924
• 98 Petersen LC, Olsen OH, Nielsen LS, Freskgård PO, Persson E. Binding of Zn2+ to a Ca2+ loop allosterically attenuates the activity of factor VIIa and reduces its affinity for tissue factor. Protein Sci 2000; 9 (5) 859-866
• 99 Prendergast FG, Mann KG. Differentiation of metal ion-induced transitions of prothrombin fragment 1. J Biol Chem 1977; 252 (3) 840-850
• 100 Persson E, Björk I, Stenflo J. Protein structural requirements for Ca2+ binding to the light chain of factor X. Studies using isolated intact fragments containing the gamma-carboxyglutamic acid region and/or the epidermal growth factor-like domains. J Biol Chem 1991; 266 (4) 2444-2452
• 101 Persson E, Østergaard A. Mg(2+) binding to the Gla domain of factor X influences the interaction with tissue factor. J Thromb Haemost 2007; 5 (9) 1977-1978
• 102 Bromberg ME, Konigsberg WH, Madison JF, Pawashe A, Garen A. Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci U S A 1995; 92 (18) 8205-8209
• 103 Hjortoe GM, Petersen LC, 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 (8) 3029-3037
• 104 Hembrough TA, Swartz GM, Papathanassiu A , et al. Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism. Cancer Res 2003; 63 (11) 2997-3000
• 105 Bluff JE, Brown NJ, Reed MW, Staton CA. Tissue factor, angiogenesis and tumour progression. Breast Cancer Res 2008; 10 (2) 204
• 106 Ueno T, Toi M, Koike M, Nakamura S, Tominaga T. Tissue factor expression in breast cancer tissues: its correlation with prognosis and plasma concentration. Br J Cancer 2000; 83 (2) 164-170
• 107 Shoji M, Hancock WW, Abe K , et al. Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer. Am J Pathol 1998; 152 (2) 399-411
• 108 Dorfleutner A, Ruf W. Regulation of tissue factor cytoplasmic domain phosphorylation by palmitoylation. Blood 2003; 102 (12) 3998-4005
• 109 Ahamed J, Ruf W. Protease-activated receptor 2-dependent phosphorylation of the tissue factor cytoplasmic domain. J Biol Chem 2004; 279 (22) 23038-23044
• 110 Belting M, Dorrell MI, Sandgren S , et al. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nat Med 2004; 10 (5) 502-509
• 111 Rydén L, Grabau D, Schaffner F, Jönsson PE, Ruf W, Belting M. Evidence for tissue factor phosphorylation and its correlation with protease-activated receptor expression and the prognosis of primary breast cancer. Int J Cancer 2010; 126 (10) 2330-2340
• 112 Sørensen BB, Freskgård PO, Nielsen LS, Rao LV, Ezban M, Petersen LC. Factor VIIa-induced p44/42 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 (30) 21349-21354
• 113 Camerer E, Rottingen 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 (46) 29034-29042
• 114 Åberg M, Siegbahn A. Tissue factor non-coagulant signaling - molecular mechanisms and biological consequences with a focus on cell migration and apoptosis. J Thromb Haemost 2013; 11 (5) 817-825
• 115 de Jonge E, Friederich PW, Vlasuk GP , et al. Activation of coagulation by administration of recombinant factor VIIa elicits interleukin 6 (IL-6) and IL-8 release in healthy human subjects. Clin Diagn Lab Immunol 2003; 10 (3) 495-497
• 116 Versteeg HH, Spek CA, Slofstra SH, Diks SH, Richel DJ, Peppelenbosch MP. FVIIa:TF induces cell survival via G12/G13-dependent Jak/STAT activation and BclXL production. Circ Res 2004; 94 (8) 1032-1040
• 117 Versteeg HH, Sørensen BB, Slofstra SH , 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 (30) 27065-27072
• 118 Kasthuri RS, Taubman MB, Mackman N. Role of tissue factor in cancer. J Clin Oncol 2009; 27 (29) 4834-4838
• 119 Rao LV, Pendurthi UR. Tissue factor-factor VIIa signaling. Arterioscler Thromb Vasc Biol 2005; 25 (1) 47-56