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Gene Review

TFPI2  -  tissue factor pathway inhibitor 2

Homo sapiens

Synonyms: PP5, Placental protein 5, REF1, TFPI-2, Tissue factor pathway inhibitor 2
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Disease relevance of TFPI2


High impact information on TFPI2

  • In addition, TFPI-2 also reduced the activity of the gelatinases MMP-2 and MMP-9 [6].
  • We report here that the serine proteinase inhibitor tissue factor pathway inhibitor-2 (TFPI-2) can function as an MMP inhibitor [6].
  • TFPI-2 colocalized primarily with smooth muscle cells in the normal media as well as the plaque's fibrous cap [6].
  • In contrast to the "classical" tissue inhibitors of MMPs (TIMPs), TFPI-2 expression in situ correlated inversely with MMP levels in human atheroma [6].
  • PP5 stimulation by Rac provides a unique molecular mechanism for the antagonism of Rho-dependent signaling through protein kinases in many cellular processes, including metastasis, immune cell chemotaxis, and neuronal development [7].

Chemical compound and disease context of TFPI2


Biological context of TFPI2

  • The up-regulation of TFPI-2 expression by thrombin could in turn down-regulate thrombin generation and contribute to limit blood coagulation [12].
  • Of these genes, SPARC and TFPI2 showed the highest frequency of aberrant methylation in ICC specimens (86.4% for either) and together were hypermethylated in all but one ICC cases examined [13].
  • We describe the molecular cloning and expression of a full-length cDNA that encodes a molecule, designated TFPI-2, that has a similar overall domain organization and considerable primary amino acid sequence homology to TFPI [14].
  • Human tissue factor pathway inhibitor-2 (TFPI-2) is a Kunitz-type proteinase inhibitor that regulates a variety of serine proteinases involved in coagulation and fibrinolysis through their non-productive interaction with a P(1) residue (Arg-24) in its first Kunitz-type domain (KD1) [15].
  • In this study, we employed molecular modeling and mutagenesis strategies to produce several variants of human TFPI-2 KD1 in an effort to identify interactive site residues other than the P(1) Arg that contribute significantly to its inhibitory activity and specificity [15].

Anatomical context of TFPI2


Associations of TFPI2 with chemical compounds


Physical interactions of TFPI2


Regulatory relationships of TFPI2


Other interactions of TFPI2

  • Thrombin up-regulates tissue factor pathway inhibitor-2 synthesis through a cyclooxygenase-2-dependent, epidermal growth factor receptor-independent mechanism [12].
  • However, thrombin did not detectably transactivate the EGF receptor in liver myofibroblasts, and blocking the EGF receptor did not affect TFPI-2 induction [12].
  • Taken together, these data suggest that gC1qR may participate in tissue remodeling and inflammation by localizing TFPI-2 to the pericellular environment to modulate local protease activity and regulate HK activation [1].
  • Moreover, detection of TFPI-2 in close spatial proximity to plasmin/plasminogen on macrophages, on endothelial cells, and in matrix-rich areas highlighted its possible functional significance in the regulation of plasmin activity and downstream proteolytic mechanisms that occur in the atherosclerotic lesion [2].
  • CONCLUSION: With the decreased expression of TFPI-2, upregulation of MMPs in atherosclerotic plaque was disproportional to that of TIMPs, suggesting that imbalanced degradation and synthesis of extracellular matrix persists in advanced lesions, particularly in plaques with disruption [17].

Analytical, diagnostic and therapeutic context of TFPI2


  1. Tissue factor pathway inhibitor-2 (TFPI-2) recognizes the complement and kininogen binding protein gC1qR/p33 (gC1qR): implications for vascular inflammation. Peerschke, E.I., Petrovan, R.J., Ghebrehiwet, B., Ruf, W. Thromb. Haemost. (2004) [Pubmed]
  2. Expression and localization of tissue factor pathway inhibitor-2 in normal and atherosclerotic human vessels. Crawley, J.T., Goulding, D.A., Ferreira, V., Severs, N.J., Lupu, F. Arterioscler. Thromb. Vasc. Biol. (2002) [Pubmed]
  3. The effect of human tissue factor pathway inhibitor-2 on the growth and metastasis of fibrosarcoma tumors in athymic mice. Chand, H.S., Du, X., Ma, D., Inzunza, H.D., Kamei, S., Foster, D., Brodie, S., Kisiel, W. Blood (2004) [Pubmed]
  4. Minimal and inducible regulation of tissue factor pathway inhibitor-2 in human gliomas. Konduri, S.D., Osman, F.A., Rao, C.N., Srinivas, H., Yanamandra, N., Tasiou, A., Dinh, D.H., Olivero, W.C., Gujrati, M., Foster, D.C., Kisiel, W., Kouraklis, G., Rao, J.S. Oncogene (2002) [Pubmed]
  5. Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma. Sato, N., Parker, A.R., Fukushima, N., Miyagi, Y., Iacobuzio-Donahue, C.A., Eshleman, J.R., Goggins, M. Oncogene (2005) [Pubmed]
  6. Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis. Herman, M.P., Sukhova, G.K., Kisiel, W., Foster, D., Kehry, M.R., Libby, P., Schönbeck, U. J. Clin. Invest. (2001) [Pubmed]
  7. Rac GTPase signaling through the PP5 protein phosphatase. Gentile, S., Darden, T., Erxleben, C., Romeo, C., Russo, A., Martin, N., Rossie, S., Armstrong, D.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  8. Promoter methylation and silencing of the tissue factor pathway inhibitor-2 (TFPI-2), a gene encoding an inhibitor of matrix metalloproteinases in human glioma cells. Konduri, S.D., Srivenugopal, K.S., Yanamandra, N., Dinh, D.H., Olivero, W.C., Gujrati, M., Foster, D.C., Kisiel, W., Ali-Osman, F., Kondraganti, S., Lakka, S.S., Rao, J.S. Oncogene (2003) [Pubmed]
  9. Methylation of TFPI-2 gene is not the sole cause of its silencing. Rao, C.N., Segawa, T., Navari, J.R., Xu, L., Srivastava, S., Moul, J.W., Phillips, B. Int. J. Oncol. (2003) [Pubmed]
  10. Evidence by molecular profiling for a placental origin of infantile hemangioma. Barnés, C.M., Huang, S., Kaipainen, A., Sanoudou, D., Chen, E.J., Eichler, G.S., Guo, Y., Yu, Y., Ingber, D.E., Mulliken, J.B., Beggs, A.H., Folkman, J., Fishman, S.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  11. Prognostic value of biochemical tests in the assessment of fetal outcome in threatened abortion. Salem, H.T., Ghaneimah, S.A., Shaaban, M.M., Chard, T. British journal of obstetrics and gynaecology. (1984) [Pubmed]
  12. Thrombin up-regulates tissue factor pathway inhibitor-2 synthesis through a cyclooxygenase-2-dependent, epidermal growth factor receptor-independent mechanism. Neaud, V., Duplantier, J.G., Mazzocco, C., Kisiel, W., Rosenbaum, J. J. Biol. Chem. (2004) [Pubmed]
  13. Discovery of novel methylation biomarkers in cervical carcinoma by global demethylation and microarray analysis. Sova, P., Feng, Q., Geiss, G., Wood, T., Strauss, R., Rudolf, V., Lieber, A., Kiviat, N. Cancer Epidemiol. Biomarkers Prev. (2006) [Pubmed]
  14. Molecular cloning, expression, and partial characterization of a second human tissue-factor-pathway inhibitor. Sprecher, C.A., Kisiel, W., Mathewes, S., Foster, D.C. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  15. Structure-function analysis of the reactive site in the first Kunitz-type domain of human tissue factor pathway inhibitor-2. Chand, H.S., Schmidt, A.E., Bajaj, S.P., Kisiel, W. J. Biol. Chem. (2004) [Pubmed]
  16. Human tissue factor pathway inhibitor-2 does not bind or inhibit activated matrix metalloproteinase-1. Du, X., Chand, H.S., Kisiel, W. Biochim. Biophys. Acta (2003) [Pubmed]
  17. Altered expression balance of matrix metalloproteinases and their inhibitors in human carotid plaque disruption: results of quantitative tissue analysis using real-time RT-PCR method. Higashikata, T., Yamagishi, M., Higashi, T., Nagata, I., Iihara, K., Miyamoto, S., Ishibashi-Ueda, H., Nagaya, N., Iwase, T., Tomoike, H., Sakamoto, A. Atherosclerosis (2006) [Pubmed]
  18. Inhibitory properties of a novel human Kunitz-type protease inhibitor homologous to tissue factor pathway inhibitor. Petersen, L.C., Sprecher, C.A., Foster, D.C., Blumberg, H., Hamamoto, T., Kisiel, W. Biochemistry (1996) [Pubmed]
  19. Subcellular localization of PP5/TFPI-2 in human placenta: a possible role of PP5/TFPI-2 as an anti-coagulant on the surface of syncytiotrophoblasts. Udagawa, K., Yasumitsu, H., Esaki, M., Sawada, H., Nagashima, Y., Aoki, I., Jin, M., Miyagi, E., Nakazawa, T., Hirahara, F., Miyazaki, K., Miyagi, Y. Placenta (2002) [Pubmed]
  20. Tissue factor pathway inhibitor-2 is upregulated by vascular endothelial growth factor and suppresses growth factor-induced proliferation of endothelial cells. Xu, Z., Maiti, D., Kisiel, W., Duh, E.J. Arterioscler. Thromb. Vasc. Biol. (2006) [Pubmed]
  21. Characterization of differential gene expression in quiescent and invasive human arterial smooth muscle cells. Blindt, R., Vogt, F., Lamby, D., Zeiffer, U., Krott, N., Hilger-Eversheim, K., Hanrath, P., vom Dahl, J., Bosserhoff, A.K. J. Vasc. Res. (2002) [Pubmed]
  22. Inhibitory properties of human recombinant Arg24-->Gln type-2 tissue factor pathway inhibitor (R24Q TFPI-2). Kamei, S., Petersen, L.C., Sprecher, C.A., Foster, D.C., Kisiel, W. Thromb. Res. (1999) [Pubmed]
  23. Expression of tissue factor pathway inhibitor 2 inversely correlates during the progression of human gliomas. Rao, C.N., Lakka, S.S., Kin, Y., Konduri, S.D., Fuller, G.N., Mohanam, S., Rao, J.S. Clin. Cancer Res. (2001) [Pubmed]
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