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Gene Review

F3  -  coagulation factor III

Mus musculus

Synonyms: AA409063, CD142, Cf-3, Cf3, Coagulation factor III, ...
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Disease relevance of F3

  • These results suggest that the induction of TF gene may increase the risk of stress-associated thrombosis in older and obese subjects and that TNF-alpha may be involved [1].
  • The role of the cytoplasmic domain of tissue factor in endotoxemia was studied in mice, which lack the cytoplasmic domain of TF (TF(deltaCT/deltaCT)) [2].
  • Tissue factor (TF) is the principal cellular initiator of coagulation and its deregulated expression has been related to thrombogenesis in sepsis, cancer, and inflammation [3].
  • Recent studies indicate that tissue factor (TF) acts in embryogenesis, metastasis, and angiogenesis [4].
  • In this study, we found that mice expressing low levels of human TF ( approximately 1% of wild-type levels) in an mTF(-/-) background had significantly shorter lifespans than wild-type mice, in part, because of spontaneous fatal hemorrhages [5].

Psychiatry related information on F3

  • The temporal and spatial pattern of TF expression during murine and human development supports the contention that TF serves as an important morphogenic factor during embryogenesis [6].

High impact information on F3

  • Tissue factor was biologically active, and was associated with fibrin generation within the thrombus [7].
  • Blood coagulation in vivo is initiated by factor VII (FVII) binding to its cellular receptor tissue factor (TF) [8].
  • Here we report that inactivation of the tissue factor gene (TF) results in abnormal circulation from yolk sac to embryo beyond embryonic day 8.5, leading to embryo wasting and death [9].
  • A genetically engineered hybrid protein consisting of the light chain of factor Xa and the first Kunitz-type inhibitor domain of LACI is shown to directly inhibit the activity of the factor VIIa-TF catalytic complex [10].
  • Tissue factor gene localized to human chromosome 1 (1pter----1p21) [11].

Chemical compound and disease context of F3

  • TF activity in the astrocytoma cells was upregulated 1.5-fold over constitutive levels by a ceramide analogue or the enzyme sphingomyelinase, however the ceramide analogue had no effect on TF activity in the primary astrocytes [12].
  • Co-administration of lipopolysaccharide (LPS, 0.5 mg/kg) with VT2 (50 ng/kg) exhibited more prominant and/or prolonged increase in not only expression of TF and PAI-1 mRNAs in the kidney and brain but also plasma levels of TAT, fibrinogen, and PAI-1 and was associated with more remarkable hemorrhage in the tissues [13].
  • CONCLUSIONS: DMSO suppresses TF expression and activity, as well as thrombus formation; in addition, it inhibits VSMC proliferation and migration [14].
  • Fluorescein-labeled F3 peptide bound to and was internalized by HL-60 cells and human MDA-MB-435 breast cancer cells, appearing initially in the cytoplasm and then in the nuclei of these cells [15].
  • F3 is a developmentally regulated adhesive glycoprotein expressed by subpopulations of central and peripheral neurons which mediates neurite growth and fasciculation via cis- and trans-interactions with cell-surface or matrix components [16].

Biological context of F3


Anatomical context of F3

  • Genetically obese mice were also hyperresponsive to restraint stress in the induction of TF gene, especially in their livers and adipose tissues [1].
  • In situ hybridization analysis of the stressed aged mice revealed that strong signals for TF mRNA were localized to renal epithelial cells, smooth muscle cells, adventitial cells, and adipocytes but not to vascular endothelial cells [1].
  • However, low-TF mice (mTF(-/-)/hTF+) have hemostatic defects in the uterus, placenta, heart, and lung [17].
  • These results indicate that deletion of the cytoplasmic domain of TF impairs the recruitment and activation of leukocytes and increases survival following endotoxin challenge [2].
  • In this study, we demonstrate that two AP-1 DNA-binding elements located 200-220 bp upstream of the transcription start site are both necessary and sufficient to confer serum inducibility to the TF gene promoter in fibroblasts [19].

Associations of F3 with chemical compounds

  • Following i.p injection with 0.5 mg of lipopolysaccharide (LPS), TF(deltaCT/deltaCT) mice showed significantly greater survival at 24 hours compared to the wt mice (TF(+/+)) [2].
  • Tissue factor (TF) is a small-molecular-weight glycoprotein that initiates the extrinsic coagulation pathway but may have important noncoagulation vascular functions as well [20].
  • Taken together, these observations suggest that the induction of PAI-1 and TF gene expression plays and important role in the formation and persistence of extracellular fibrin in bleomycin injured murine lungs [21].
  • These results suggest that LACI serves as a cofactor for heparin and thus greatly enhances the inhibition of TF-induced coagulation [22].
  • Since phosphatidylserine (PS) is exposed on activated cells at sites of vascular injury, we cloned the cDNA for a chimeric protein consisting of the extracellular domain of TF (called soluble TF or sTF) and annexin V, a human PS-binding protein [23].

Physical interactions of F3

  • These results are consistent with the concept that TF interacting with P-selectin may play a significant role in the pathophysiology of trauma [24].
  • A region of the TF promoter required for constitutive expression exhibited 85% identity in DNA sequence and included two conserved binding sites for Sp1 [25].
  • F3/Contactin is a neuronal glycoprotein which mediates axonal growth control via complex interactions with a number of cell surface or matrix components [26].

Regulatory relationships of F3

  • In conclusion, anxA5 down-regulates surface-expressed TF by activating the novel portal of cell entry [18].
  • Tissue factor gene transcription in serum-stimulated fibroblasts is mediated by recruitment of c-Fos into specific AP-1 DNA-binding complexes [19].
  • Identification of the mechanism by which Grp78 regulates TF function may advance insight into the pathobiology of atherosclerosis and associated arterial thrombosis [27].
  • Tissue factor pathway inhibitor (TFPI) is the protease inhibitor that regulates the extrinsic coagulation pathway initiated by the factor VIIa/TF complex [28].
  • The objective was to investigate whether TF haploinsufficiency reduces endotoxin-induced cytokine production in murine cells or in mice [29].

Other interactions of F3

  • Conversely, a decrease in TFPI levels dose-dependently prolonged the survival of low-TF mice and rescued the hemorrhagic defects in the lung and placenta but not in the heart or uterus [17].
  • We furthermore show that THP-1 cells produce and externalize anxA5 that cause the internalization of TF in an autocrine type of mechanism [18].
  • Importantly, overexpression of JunD and c-Fos abrogates the requirement for serum in the stimulation of TF promoter activity in fibroblasts [19].
  • To characterize this function, we analyzed the effect of Grp78 on TF-mediated procoagulant activity on murine brain endothelial cells (bEND.3) and macrophage-like (RAW) cells, which are relevant in mediation of atherothrombosis [27].
  • METHODS AND RESULTS: We determined the effect of a 50% reduction of TF levels in all cells on atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice [30].

Analytical, diagnostic and therapeutic context of F3

  • Intervention studies blocking tissue factor (TF) driven coagulation show beneficial effects on survival in endotoxemia models by reducing cytokine production [29].
  • In addition to identifying tissue expression of endothelial TF in the sickle lung, these studies implicate reperfusion injury physiology in its expression and suggest a rationale for use of statins in sickle disease [31].
  • Transplantation of low-TF marrow into wild-type mice did not suppress arterial or venous thrombus formation [32].
  • In contrast, expression of the physiological ligand for TF, factor VII, was not detectable during early stages of human embryogenesis using immunohistochemistry [6].
  • Thus, our findings support the contention that ligation of cellular TF may be involved in morphogenic processes such as adhesion and spreading by an association to cytoskeletal structures [33].


  1. Aging and obesity augment the stress-induced expression of tissue factor gene in the mouse. Yamamoto, K., Shimokawa, T., Yi, H., Isobe, K., Kojima, T., Loskutoff, D.J., Saito, H. Blood (2002) [Pubmed]
  2. The cytoplasmic domain of tissue factor contributes to leukocyte recruitment and death in endotoxemia. Sharma, L., Melis, E., Hickey, M.J., Clyne, C.D., Erlich, J., Khachigian, L.M., Davenport, P., Morand, E., Carmeliet, P., Tipping, P.G. Am. J. Pathol. (2004) [Pubmed]
  3. Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system. Carmeliet, P., Moons, L., Dewerchin, M., Mackman, N., Luther, T., Breier, G., Ploplis, V., Müller, M., Nagy, A., Plow, E., Gerard, R., Edgington, T., Risau, W., Collen, D. Ann. N. Y. Acad. Sci. (1997) [Pubmed]
  4. Mouse embryogenesis requires the tissue factor extracellular domain but not the cytoplasmic domain. Parry, G.C., Mackman, N. J. Clin. Invest. (2000) [Pubmed]
  5. Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction. Pawlinski, R., Fernandes, A., Kehrle, B., Pedersen, B., Parry, G., Erlich, J., Pyo, R., Gutstein, D., Zhang, J., Castellino, F., Melis, E., Carmeliet, P., Baretton, G., Luther, T., Taubman, M., Rosen, E., Mackman, N. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  6. Tissue factor expression during human and mouse development. Luther, T., Flössel, C., Mackman, N., Bierhaus, A., Kasper, M., Albrecht, S., Sage, E.H., Iruela-Arispe, L., Grossmann, H., Ströhlein, A., Zhang, Y., Nawroth, P.P., Carmeliet, P., Loskutoff, D.J., Müller, M. Am. J. Pathol. (1996) [Pubmed]
  7. Real-time in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse. Falati, S., Gross, P., Merrill-Skoloff, G., Furie, B.C., Furie, B. Nat. Med. (2002) [Pubmed]
  8. Mice lacking factor VII develop normally but suffer fatal perinatal bleeding. Rosen, E.D., Chan, J.C., Idusogie, E., Clotman, F., Vlasuk, G., Luther, T., Jalbert, L.R., Albrecht, S., Zhong, L., Lissens, A., Schoonjans, L., Moons, L., Collen, D., Castellino, F.J., Carmeliet, P. Nature (1997) [Pubmed]
  9. Role of tissue factor in embryonic blood vessel development. Carmeliet, P., Mackman, N., Moons, L., Luther, T., Gressens, P., Van Vlaenderen, I., Demunck, H., Kasper, M., Breier, G., Evrard, P., Müller, M., Risau, W., Edgington, T., Collen, D. Nature (1996) [Pubmed]
  10. Inhibition of factor VIIa-tissue factor coagulation activity by a hybrid protein. Girard, T.J., MacPhail, L.A., Likert, K.M., Novotny, W.F., Miletich, J.P., Broze, G.J. Science (1990) [Pubmed]
  11. Tissue factor gene localized to human chromosome 1 (1pter----1p21). Carson, S.D., Henry, W.M., Shows, T.B. Science (1985) [Pubmed]
  12. Cytokine and intracellular signaling regulation of tissue factor expression in astrocytes. Klein, B.D., White, H.S., Callahan, K.S. Neurochem. Int. (2000) [Pubmed]
  13. Activation of coagulation in C57BL/6 mice given verotoxin 2 (VT2) and the effect of co-administration of LPS with VT2. Sugatani, J., Igarashi, T., Munakata, M., Komiyama, Y., Takahashi, H., Komiyama, N., Maeda, T., Takeda, T., Miwa, M. Thromb. Res. (2000) [Pubmed]
  14. Dimethyl sulfoxide inhibits tissue factor expression, thrombus formation, and vascular smooth muscle cell activation: a potential treatment strategy for drug-eluting stents. Camici, G.G., Steffel, J., Akhmedov, A., Schafer, N., Baldinger, J., Schulz, U., Shojaati, K., Matter, C.M., Yang, Z., L??scher, T.F., Tanner, F.C. Circulation (2006) [Pubmed]
  15. A fragment of the HMGN2 protein homes to the nuclei of tumor cells and tumor endothelial cells in vivo. Porkka, K., Laakkonen, P., Hoffman, J.A., Bernasconi, M., Ruoslahti, E. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  16. Functional organization of the promoter region of the mouse F3 axonal glycoprotein gene. Cangiano, G., Ambrosini, M., Patruno, A., Tino, A., Buttiglione, M., Gennarini, G. Brain Res. Mol. Brain Res. (1997) [Pubmed]
  17. A balance between tissue factor and tissue factor pathway inhibitor is required for embryonic development and hemostasis in adult mice. Pedersen, B., Holscher, T., Sato, Y., Pawlinski, R., Mackman, N. Blood (2005) [Pubmed]
  18. Annexin A5 down-regulates surface expression of tissue factor: a novel mechanism of regulating the membrane receptor repertoir. Ravassa, S., Bennaghmouch, A., Kenis, H., Lindhout, T., Hackeng, T., Narula, J., Hofstra, L., Reutelingsperger, C. J. Biol. Chem. (2005) [Pubmed]
  19. Tissue factor gene transcription in serum-stimulated fibroblasts is mediated by recruitment of c-Fos into specific AP-1 DNA-binding complexes. Felts, S.J., Stoflet, E.S., Eggers, C.T., Getz, M.J. Biochemistry (1995) [Pubmed]
  20. Tissue factor pathway inhibitor deficiency enhances neointimal proliferation and formation in a murine model of vascular remodelling. Singh, R., Pan, S., Mueske, C.S., Witt, T.A., Kleppe, L.S., Peterson, T.E., Caplice, N.M., Simari, R.D. Thromb. Haemost. (2003) [Pubmed]
  21. Changes in procoagulant and fibrinolytic gene expression during bleomycin-induced lung injury in the mouse. Olman, M.A., Mackman, N., Gladson, C.L., Moser, K.M., Loskutoff, D.J. J. Clin. Invest. (1995) [Pubmed]
  22. Lipoprotein-associated coagulation inhibitor (LACI) is a cofactor for heparin: synergistic anticoagulant action between LACI and sulfated polysaccharides. Wun, T.C. Blood (1992) [Pubmed]
  23. A soluble tissue factor-annexin V chimeric protein has both procoagulant and anticoagulant properties. Huang, X., Ding, W.Q., Vaught, J.L., Wolf, R.F., Morrissey, J.H., Harrison, R.G., Lind, S.E. Blood (2006) [Pubmed]
  24. Pulmonary tissue factor mRNA expression during murine traumatic shock: effect of P-selectin blockade. Armstead, V.E., Minchenko, A.G., Scalla, R., Lefer, A.M. Shock (2001) [Pubmed]
  25. Structure of the murine tissue factor gene. Chromosome location and conservation of regulatory elements in the promoter. Mackman, N., Imes, S., Maske, W.H., Taylor, B., Lusis, A.J., Drake, T.A. Arterioscler. Thromb. (1992) [Pubmed]
  26. Alternative promoters drive the expression of the gene encoding the mouse axonal glycoprotein F3/contactin. De Benedictis, L., Polizzi, A., Cangiano, G., Buttiglione, M., Arbia, S., Storlazzi, C.T., Rocchi, M., Gennarini, G. Brain Res. Mol. Brain Res. (2001) [Pubmed]
  27. Regulation of tissue factor--mediated initiation of the coagulation cascade by cell surface grp78. Bhattacharjee, G., Ahamed, J., Pedersen, B., El-Sheikh, A., Mackman, N., Ruf, W., Liu, C., Edgington, T.S. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  28. Down-regulation of murine tissue factor pathway inhibitor mRNA by endotoxin and tumor necrosis factor-alpha in vitro and in vivo. Shimokawa, T., Yamamoto, K., Kojima, T., Saito, H. Thromb. Res. (2000) [Pubmed]
  29. Tissue factor haploinsufficiency during endotoxin induced coagulation and inflammation in mice. Schoenmakers, S.H., Versteeg, H.H., Groot, A.P., Reitsma, P.H., Spek, C.A. J. Thromb. Haemost. (2004) [Pubmed]
  30. Atherosclerosis in mice is not affected by a reduction in tissue factor expression. Tilley, R.E., Pedersen, B., Pawlinski, R., Sato, Y., Erlich, J.H., Shen, Y., Day, S., Huang, Y., Eitzman, D.T., Boisvert, W.A., Curtiss, L.K., Fay, W.P., Mackman, N. Arterioscler. Thromb. Vasc. Biol. (2006) [Pubmed]
  31. Endothelial cell expression of tissue factor in sickle mice is augmented by hypoxia/reoxygenation and inhibited by lovastatin. Solovey, A., Kollander, R., Shet, A., Milbauer, L.C., Choong, S., Panoskaltsis-Mortari, A., Blazar, B.R., Kelm, R.J., Hebbel, R.P. Blood (2004) [Pubmed]
  32. Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall. Day, S.M., Reeve, J.L., Pedersen, B., Farris, D.M., Myers, D.D., Im, M., Wakefield, T.W., Mackman, N., Fay, W.P. Blood (2005) [Pubmed]
  33. Localization of tissue factor in actin-filament-rich membrane areas of epithelial cells. Müller, M., Albrecht, S., Gölfert, F., Hofer, A., Funk, R.H., Magdolen, V., Flössel, C., Luther, T. Exp. Cell Res. (1999) [Pubmed]
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