Thromb Haemost 2005; 94(06): 1122-1130
DOI: 10.1160/TH05-07-0509
Review Article
Schattauer GmbH

Structure, function and biology of tissue factor pathway inhibitor-2

Hitendra S. Chand
1   Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, and
,
Donald C. Foster
2   Zymo Genetics, Inc., Seattle, Washington, USA
,
Walter Kisiel
1   Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, and
› Author Affiliations
Further Information

Publication History

Received 02 July 2005

Accepted after revision 04 October 2005

Publication Date:
07 December 2017 (online)

Summary

Tissue factor pathway inhibitor-2 (TFPI-2) is a 32 kDa matrix-associated Kunitz-type serine proteinase inhibitor consisting of a short amino-terminal region, three tandem Kunitz-type domains and a positively charged carboxy-terminal tail. Human TFPI-2, previously designated as placental protein 5, inhibits a broad spectrum of serine proteinases almost exclusively through its first Kunitz-type domain, and is thought to play an important role in the regulation of extracellular matrix digestion and re-modeling. In this context, reduced synthesis of TFPI-2 has been related to numerous pathophysiological processes such as inflammation, angiogenesis, atherosclerosis, retinal degeneration and tumor growth/metastasis. In this review, we document current information regarding the expression of TFPI-2 by various tissues, its inhibitory activity and proteinase specificity in-vitro, and discuss possible physiological roles for this inhibitor based on in-vivo studies.

 
  • References

  • 1 Bode W, Huber R. Structural basis of the endoproteinase-protein inhibitor interaction. Biochim Biophys Acta 2000; 1477: 241-52.
  • 2 Laskowski Jr. M, Kato I. Protein inhibitors of proteinases. Annu Rev Biochem 1980; 49: 593-626.
  • 3 Potempa J, Korzus E, Travis J. The serpin superfamily of proteinase inhibitors: structure, function, and regulation. J Biol Chem 1994; 269: 15957-60.
  • 4 Wiedow O, Schroder JM, Gregory H. et al Elafin: an elastase-specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence. J Biol Chem 1990; 265: 14791-5.
  • 5 Seppala M, Wahlstrom T, Bohn H. Circulating levels and tissue localization of placental protein five (PP5) in pregnancy and trophoblastic disease: absence of PP5 expression in the malignant trophoblast. Int J Cancer 1979; 24: 6-10.
  • 6 Butzow R, Alfthan H, Stenman UH. et al Immunofluorometric demonstration and quantification of placental protein 5 in the absence of pregnancy. Clin Chem 1988; 34: 1591-3.
  • 7 Siiteri JE, Koistinen R, Salem HT. et al Placental protein 5 is related to blood coagulation and fibrinolytic systems. Life Sci 1982; 30: 1885-91.
  • 8 Meisser A, Bischof P, Bohn H. Placental protein 5 (PP5) inhibits thrombin-induced coagulation of fibrinogen. Arch Gynecol 1985; 236: 197-201.
  • 9 Sprecher CA, Kisiel W, Mathewes S. et al Molecular cloning, expression, and partial characterization of a second human tissue-factor-pathway inhibitor. Proc Natl Acad Sci U S A 1994; 91: 3353-7.
  • 10 Kisiel W, Sprecher CA, Foster DC. Evidence that a second human tissue factor pathway inhibitor (TFPI-2) and human placental protein 5 are equivalent. Blood 1994; 84: 4384-5.
  • 11 Miyagi Y, Koshikawa N, Yasumitsu H. et al cDNA cloning and mRNA expression of a serine proteinase inhibitor secreted by cancer cells: identification as placental protein 5 and tissue factor pathway inhibitor-2. J Biochem 1994; 116: 939-42.
  • 12 Miyagi Y, Yasumitsu H, Eki T. et al Assignment of the human PP5/TFPI-2 gene to 7q22 by FISH and PCR-based human/rodent cell hybrid mapping panel analysis. Genomics 1996; 35: 267-8.
  • 13 Kamei S, Kazama Y, Kuijper JL. et al Genomic structure and promoter activity of the human tissue factor pathway inhibitor-2 gene. Biochim Biophys Acta 2001; 1517: 430-5.
  • 14 Girard TJ, Eddy R, Wesselschmidt RL. et al Structure of the human lipoprotein-associated coagulation inhibitor gene. Intro/exon gene organization and localization of the gene to chromosome 2. J Biol Chem 1991; 266: 5036-41.
  • 15 Enjyoji K, Emi M, Mukai T. et al Human tissue factor pathway inhibitor (TFPI) gene: complete genomic structure and localization on the genetic map of chromosome 2q. Genomics 1993; 17: 423-8.
  • 16 Hube F, Reverdiau P, Iochmann S. et al Characterization and functional analysis of TFPI-2 gene promoter in a human choriocarcinoma cell line. Thromb Res 2003; 109: 207-15.
  • 17 Smale ST. Transcription initiation from TATA-less promoters within eukaryotic protein-coding genes. Biochim Biophys Acta 1997; 1351: 73-88.
  • 18 Huber R, Schlessinger D, Pilia G. Multiple Sp1 sites efficiently drive transcription of the TATA-less promoter of the human glypican 3 (GPC3) gene. Gene 1998; 214: 35-44.
  • 19 Block KL, Shou Y, Thorton M. et al The regulated expression of a TATA-less, platelet-specific gene, alphaIIb. Stem Cells 1996; 14 (Suppl. 01) 38-47.
  • 20 Konduri SD, Osman FA, Rao CN. et al Minimal and inducible regulation of tissue factor pathway inhibitor-2 in human gliomas. Oncogene 2002; 21: 921-8.
  • 21 Eisenberg E, Levanon EY. Human housekeeping genes are compact. Trends Genet 2003; 19: 362-5.
  • 22 Esteller M. Aberrant DNA methylation as a cancerinducing mechanism. Annu Rev Pharmacol Toxicol 2005; 45: 629-56.
  • 23 Lewis JD, Meehan RR, Henzel WJ. et al Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 1992; 69: 905-14.
  • 24 Ng HH, Zhang Y, Hendrich B. et al MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet 1999; 23: 58-61.
  • 25 Bird AP, Wolffe AP. Methylation-induced repression– belts, braces, and chromatin. Cell 1999; 99: 451-4.
  • 26 Jain PK. Epigenetics: the role of methylation in the mechanism of action of tumor suppressor genes. Ann N Y Acad Sci 2003; 983: 71-83.
  • 27 Rao CN, Segawa T, Navari JR. et al Methylation of TFPI-2 gene is not the sole cause of its silencing. Int J Oncol 2003; 22: 843-8.
  • 28 Konduri SD, Srivenugopal KS, Yanamandra N. et al 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. Oncogene 2003; 22: 4509-16.
  • 29 Steiner FA, Hong JA, Fischette MR. et al Sequential 5-Aza 2’-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells. Oncogene 2005; 24: 2386-97.
  • 30 Saito E, Okamoto A, Saito M. et al Genes associated with the genesis of leiomyoma of the uterus in a commonly deleted chromosomal region at 7q22. Oncol Rep 2005; 13: 469-72.
  • 31 Dong JT. Chromosomal deletions and tumor suppressor genes in prostate cancer. Cancer Metastasis Rev 2001; 20: 173-93.
  • 32 Sell SM, Tullis C, Stracner D. et al Minimal interval defined on 7q in uterine leiomyoma. Cancer Genet Cytogenet 2005; 157: 67-9.
  • 33 Rollin J, Iochmann S, Blechet C. et al Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer. Br J Cancer 2005; 92: 775-83.
  • 34 Sato N, Parker AR, Fukushima N. et al Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma. Oncogene 2005; 24: 850-8.
  • 35 Ruf W, Seftor EA, Petrovan RJ. et al Differential role of tissue factor pathway inhibitors 1 and 2 in melanoma vasculogenic mimicry. Cancer Res 2003; 63: 5381-9.
  • 36 Iino M, Foster DC, Kisiel W. Quantification and characterization of human endothelial cell-derived tissue factor pathway inhibitor-2. Arterioscler Thromb Vasc Biol 1998; 18: 40-6.
  • 37 Butzow R, Lehto VP, Ritvos O. et al Regulation of the production of placental protein 5 by human endometrial stromal cells; the role of prostaglandins E2 and F2 alpha. Mol Cell Endocrinol 1988; 60: 137-43.
  • 38 Shinoda E, Yui Y, Hattori R. et al Tissue factor pathway inhibitor-2 is a novel mitogen for vascular smooth muscle cells. J Biol Chem 1999; 274: 5379-84.
  • 39 Wolter S, Mushinski JF, Saboori AM. et al Inducible expression of a constitutively active mutant of mitogen-activated protein kinase kinase 7 specifically activates c-JUN NH2-terminal protein kinase, alters expression of at least nine genes, and inhibits cell proliferation. J Biol Chem 2002; 277: 3576-84.
  • 40 Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell 2000; 103: 239-52.
  • 41 Neaud V, Duplantier JG, Mazzocco C. et al Thrombin up-regulates tissue factor pathway inhibitor-2 synthesis through a cyclooxygenase-2-dependent, epidermal growth factor receptor-independent mechanism. J Biol Chem 2004; 279: 5200-6.
  • 42 Raza SL, Cornelius LA. Matrix metalloproteinases: pro- and anti-angiogenic activities. J Investig Dermatol Symp Proc 2000; 5: 47-54.
  • 43 Galis ZS, Kranzhofer R, Fenton 2nd JW, Libby P. Thrombin promotes activation of matrix metalloproteinase-2 produced by cultured vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1997; 17: 483-9.
  • 44 Lafleur MA, Hollenberg MD, Atkinson SJ. et al Activation of pro-(matrix metalloproteinase-2) (pro-MMP-2) by thrombin is membrane-type-MMP-dependent in human umbilical vein endothelial cells and generates a distinct 63 kDa active species. Biochem J 2001; 357: 107-15.
  • 45 Rao CN, Reddy P, Liu Y. et al Extracellular matrixassociated serine protease inhibitors (Mr 33,000, 31,000, and 27,000) are single-gene products with differential glycosylation: cDNA cloning of the 33-kDa inhibitor reveals its identity to tissue factor pathway inhibitor-2. Arch Biochem Biophys 1996; 335: 82-92.
  • 46 Petersen LC, Sprecher CA, Foster DC. et al Inhibitory properties of a novel human Kunitz-type protease inhibitor homologous to tissue factor pathway inhibitor. Biochemistry 1996; 35: 266-72.
  • 47 Kamei S, Petersen LC, Sprecher CA. et al Inhibitory properties of human recombinant Arg24–>Gln type-2 tissue factor pathway inhibitor (R24Q TFPI-2). Thromb Res 1999; 94: 147-52.
  • 48 Chand HS, Schmidt AE, Bajaj SP. et al Structurefunction analysis of the reactive site in the first Kunitztype domain of human tissue factor pathway inhibitor-2. J Biol Chem 2004; 279: 17500-7.
  • 49 Udagawa K, Yasumitsu H, Esaki M. et al 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. Placenta 2002; 23: 145-53.
  • 50 Liu Y, Stack SM, Lakka SS. et al Matrix localization of tissue factor pathway inhibitor-2/matrix-associated serine protease inhibitor (TFPI-2/MSPI) involves arginine-mediated ionic interactions with heparin and dermatan sulfate: heparin accelerates the activity of TFPI-2/MSPI toward plasmin. Arch Biochem Biophys 1999; 370: 112-8.
  • 51 Peerschke EI, Petrovan RJ, Ghebrehiwet B. et al Tissue factor pathway inhibitor-2 (TFPI-2) recognizes the complement and kininogen binding protein gC1qR/p33 (gC1qR): implications for vascular inflammation. Thromb Haemost 2004; 92: 811-9.
  • 52 Castro MJ, Anderson S. Alanine point-mutations in the reactive region of bovine pancreatic trypsin inhibitor: effects on the kinetics and thermodynamics of binding to beta-trypsin and alpha-chymotrypsin. Biochemistry 1996; 35: 11435-46.
  • 53 Grzesiak A, Helland R, Smalas AO. et al Substitutions at the P(1) position in BPTI strongly affect the association energy with serine proteinases. J Mol Biol 2000; 301: 205-17.
  • 54 Grzesiak A, Krokoszynska I, Krowarsch D. et al Inhibition of six serine proteinases of the human coagulation system by mutants of bovine pancreatic trypsin inhibitor. J Biol Chem 2000; 275: 33346-52.
  • 55 Schmidt AE, Chand HS, Cascio D. et al Crystal structure of Kunitz domain 1 of tissue factor pathway inhibitor-2 in complex with trypsin: Implications for KD1 specificity of inhibition. J Biol Chem 2005; 280: 27832-8.
  • 56 Helland R, Otlewski J, Sundheim O. et al The crystal structures of the complexes between bovine betatrypsin and ten P1 variants of BPTI. J Mol Biol 1999; 287: 923-42.
  • 57 Scheidig AJ, Hynes TR, Pelletier LA. et al Crystal structures of bovine chymotrypsin and trypsin complexed to the inhibitor domain of Alzheimer's amyloid beta-protein precursor (APPI) and basic pancreatic trypsin inhibitor (BPTI): engineering of inhibitors with altered specificities. Protein Sci 1997; 6: 1806-24.
  • 58 Wang X, Lin X, Loy JA. et al Crystal structure of the catalytic domain of human plasmin complexed with streptokinase. Science 1998; 281: 1662-5.
  • 59 Butzow R, Virtanen I, Seppala M. et al Monoclonal antibodies reacting with placental protein 5: use in radioimmunoassay, Western blot analysis, and immunohistochemistry. J Lab Clin Med 1988; 111: 249-56.
  • 60 Seppala M, Koskimies AI, Tenhunen A. et al Pregnancy proteins in seminal plasma, seminal vesicles, preovulatory follicular fluid, and ovary. Ann N Y Acad Sci 1985; 442: 212-26.
  • 61 Herman MP, Sukhova GK, Kisiel W. et al Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis. J Clin Invest 2001; 107: 1117-26.
  • 62 Ortego J, Escribano J, Coca-Prados M. Gene expression of proteases and protease inhibitors in the human ciliary epithelium and ODM-2 cells. Exp Eye Res 1997; 65: 289-99.
  • 63 Deng FM, Ding M, Lavker RM. et al Urothelial function reconsidered: a role in urinary protein secretion. Proc Natl Acad Sci U S A 2001; 98: 154-9.
  • 64 Crawley JT, Goulding DA, Ferreira V. et al Expression and localization of tissue factor pathway inhibitor-2 in normal and atherosclerotic human vessels. Arterioscler Thromb Vasc Biol 2002; 22: 218-24.
  • 65 Rao CN, Cook B, Liu Y. et al HT-1080 fibrosarcoma cell matrix degradation and invasion are inhibited by the matrix-associated serine protease inhibitor TFPI-2/33 kDa MSPI. Int J Cancer 1998; 76: 749-56.
  • 66 Konduri SD, Tasiou A, Chandrasekar N. et al Role of tissue factor pathway inhibitor-2 (TFPI-2) in amelanotic melanoma (C-32) invasion. Clin Exp Metastasis 2000; 18: 303-8.
  • 67 Lakka SS, Konduri SD, Mohanam S. et al In vitro modulation of human lung cancer cell line invasiveness by antisense cDNA of tissue factor pathway inhibitor-2. Clin Exp Metastasis 2000; 18: 239-44.
  • 68 Konduri SD, Rao CN, Chandrasekar N. et al A novel function of tissue factor pathway inhibitor-2 (TFPI-2) in human glioma invasion. Oncogene 2001; 20: 6938-45.
  • 69 Konduri SD, Tasiou A, Chandrasekar N. et al Overexpression of tissue factor pathway inhibitor-2 (TFPI-2), decreases the invasiveness of prostate cancer cells in vitro. Int J Oncol 2001; 18: 127-31.
  • 70 Rao CN, Lakka SS, Kin Y. et al Expression of tissue factor pathway inhibitor 2 inversely correlates during the progression of human gliomas. Clin Cancer Res 2001; 7: 570-6.
  • 71 Chand HS, Du X, Ma D. et al The effect of human tissue factor pathway inhibitor-2 on the growth and metastasis of fibrosarcoma tumors in athymic mice. Blood 2004; 103: 1069-77.
  • 72 Yanamandra N, Kondraganti S, Gondi CS. et al Recombinant adeno-associated virus (rAAV) expressing TFPI-2 inhibits invasion, angiogenesis and tumor growth in a human glioblastoma cell line. Int J Cancer 2005; 115: 998-1005.
  • 73 Wojtukiewicz MZ, Sierko E, Zimnoch L. et al Immunohistochemical localization of tissue factor pathway inhibitor-2 in human tumor tissue. Thromb Haemost 2003; 90: 140-6.
  • 74 Neaud V, Hisaka T, Monvoisin A. et al Paradoxical pro-invasive effect of the serine proteinase inhibitor tissue factor pathway inhibitor-2 on human hepatocellular carcinoma cells. J Biol Chem 2000; 275: 35565-9.
  • 75 Fischer EG, Riewald M, Huang HY. et al Tumor cell adhesion and migration supported by interaction of a receptor-protease complex with its inhibitor. J Clin Invest 1999; 104: 1213-21.
  • 76 Garcia-Touchard A, Henry TD, Sangiorgi G. et al Extracellular proteases in atherosclerosis and restenosis. Arterioscler Thromb Vasc Biol 2005; 25: 1119-27.
  • 77 Kong D, Ma D, Bai H. et al Expression and characterization of the first kunitz domain of human tissue factor pathway inhibitor-2. Biochem Biophys Res Commun 2004; 324: 1179-85.
  • 78 Du X, Chand HS, Kisiel W. Human tissue factor pathway inhibitor-2 does not bind or inhibit activated matrix metalloproteinase-1. Biochim Biophys Acta 2003; 1621: 242-5.
  • 79 Rao CN, Mohanam S, Puppala A. et al Regulation of ProMMP-1 and ProMMP-3 activation by tissue factor pathway inhibitor-2/matrix-associated serine protease inhibitor. Biochem Biophys Res Commun 1999; 255: 94-8.
  • 80 Tarui T, Majumdar M, Miles LA. et al Plasmin-induced migration of endothelial cells. A potential target for the anti-angiogenic action of angiostatin. J Biol Chem 2002; 277: 33564-70.
  • 81 Miyagi Y, Yasumitsu H, Mizushima H. et al Cloning of the cDNA encoding mouse PP5/TFPI-2 and mapping of the gene to chromosome 6. DNA Cell Biol 1996; 15: 947-54.
  • 82 Kazama Y, Kamei S, Kuijper JL. et al Nucleotide sequence of the gene encoding murine tissue factor pathway inhibitor-2. Thromb Haemost 2000; 83: 141-7.
  • 83 Girard TJ, Warren LA, Novotny WF. et al Functional significance of the Kunitz-type inhibitory domains of lipoprotein-associated coagulation inhibitor. Nature 1989; 338: 518-20.
  • 84 Hisaka T, Lardeux B, Lamireau T. et al Expression of tissue factor pathway inhibitor-2 in murine and human liver regulation during inflammation. Thromb Haemost 2004; 91: 569-75.
  • 85 Hisaka T, Kisiel W, Rosenbaum J. cDNA cloning and tissue distribution of the rat ortholog of tissue factor pathway inhibitor-2. Thromb Haemost 2002; 88: 356-7.
  • 86 Du X, Deng FM, Chand HS. et al Molecular cloning, expression, and characterization of bovine tissue factor pathway inhibitor-2. Arch Biochem Biophys 2003; 417: 96-104.