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Gene Review

F2R  -  coagulation factor II (thrombin) receptor

Homo sapiens

Synonyms: CF2R, Coagulation factor II receptor, HTR, PAR-1, PAR1, ...
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Disease relevance of F2R


High impact information on F2R


Chemical compound and disease context of F2R


Biological context of F2R

  • We have found that thrombin under the conditions of culture employed inhibits cell growth by both up-regulation of p21(waf/cip1) and induction of caspases via its PAR-1 receptor [14].
  • Induction of apoptosis is also PAR-1-specific, STAT1-dependent, and associated with up-regulation of caspases 1, 2, and 3 [14].
  • DNA sequence analysis indicated the presence of two SP-1-AP-2 consensus binding sequences, near or within the transcription initiation sites, and consensus binding sequences for numerous regulatory proteins that potentially modulate HTR expression [15].
  • This observation broadens our understanding of the mechanism of PAR-1 activation and its effect on cell growth, and could possibly lead to therapeutic approaches for the treatment of cancer [14].
  • To further characterize the TR gene, overlapping clones from a human genomic library were isolated [16].

Anatomical context of F2R

  • Results in fibroblasts were consistent with human platelet thrombin receptor activation [17].
  • Evidence for the presence of a protease-activated receptor distinct from the thrombin receptor in human keratinocytes [17].
  • Functional analysis of the HTR promoter was performed by transfecting human microvascular endothelial cells with HTR promoter region-luciferase constructs [15].
  • Proteolysis of the thrombin receptor, protease activated receptor-1 (PAR1), may enhance normal and pathological cellular invasion, and indirect evidence suggests that activation of PAR1 expressed by invasive extravillous trophoblasts (EVTs) influences human placentation [18].
  • The data presented in this report provide a foundation for further characterization of the HTR gene and the mechanisms that regulate its expression within the blood vessel wall [15].

Associations of F2R with chemical compounds

  • These properties of thrombin rely on its action as a serine protease, which cleaves the N-terminal region of a 7-transmembrane G protein receptor (protease-activated receptor, PAR-1), thus exposing a tethered end hexapeptide sequence capable of activating its receptor [14].
  • Several new target genes previously documented to influence bone formation were up-regulated by DHEA such as Notch 2, insulin receptor, thrombin receptor (PAR1) [19].
  • Additional studies using sense and antisense par-1 cDNA-transfected SCCHN cell lines illustrated that the presence of PAR-1 was required for the expression of involucrin, a keratinocyte differentiation marker [20].
  • Sustained stimulation of platelet thrombin receptor is associated with tyrosine dephosphorylation of a novel p67 peptide in a manner regulated by extracellular calcium [21].
  • The role of platelet glycoprotein Ib as a thrombin receptor has been often a subject of controversy [22].

Physical interactions of F2R


Enzymatic interactions of F2R


Regulatory relationships of F2R

  • The thrombin receptor (TR) and proteinase activated receptor-2 (PAR-2) may represent the prototypes of an emerging family of cell-surface receptors that effect cell activation events mediated by serine proteases generated during inflammatory, fibrinolytic or haemostatic-regulated pathways [30].
  • The thrombin receptor PAR1 has now been shown to be cleaved and activated on the tumor cell surface by stromal-derived MMP1 [31].
  • These data support a model that the N-terminal alphaN helix of the Galpha subunit is physically interposed between PAR1 and the Gbeta subunit and directly assists in transferring the signal between agonist-activated receptor and G protein [32].
  • We conclude that cross-talk from the CD36 receptor influences the responsive state of the endothelial thrombin receptor family and/or its signaling pathway [33].
  • The increase in lung microvascular permeability in response to PAR-1 activation was inhibited in TRPC4-/- mice [34].

Other interactions of F2R


Analytical, diagnostic and therapeutic context of F2R


  1. Role and regulation of the thrombin receptor (PAR-1) in human melanoma. Tellez, C., Bar-Eli, M. Oncogene (2003) [Pubmed]
  2. Comparison of the effects of PAR1 antagonists, PAR4 antagonists, and their combinations on thrombin-induced human platelet activation. Wu, C.C., Teng, C.M. Eur. J. Pharmacol. (2006) [Pubmed]
  3. Expression of functional protease-activated receptor 1 in human prostate cancer cell lines. Liu, J., Bastian, M., Kohlschein, P., Schuff-Werner, P., Steiner, M. Urol. Res. (2003) [Pubmed]
  4. Ligation of protease-activated receptor 1 enhances alpha(v)beta6 integrin-dependent TGF-beta activation and promotes acute lung injury. Jenkins, R.G., Su, X., Su, G., Scotton, C.J., Camerer, E., Laurent, G.J., Davis, G.E., Chambers, R.C., Matthay, M.A., Sheppard, D. J. Clin. Invest. (2006) [Pubmed]
  5. Chromosomal assignment of the human thrombin receptor gene: localization to region q13 of chromosome 5. Bahou, W.F., Nierman, W.C., Durkin, A.S., Potter, C.L., Demetrick, D.J. Blood (1993) [Pubmed]
  6. Thrombin receptor ligation and activated Rac uncap actin filament barbed ends through phosphoinositide synthesis in permeabilized human platelets. Hartwig, J.H., Bokoch, G.M., Carpenter, C.L., Janmey, P.A., Taylor, L.A., Toker, A., Stossel, T.P. Cell (1995) [Pubmed]
  7. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Vu, T.K., Hung, D.T., Wheaton, V.I., Coughlin, S.R. Cell (1991) [Pubmed]
  8. Hypersensitivity of platelets to thrombin: formation of stable thrombin-receptor complexes and the role of shape change. Bennett, W.F., Glenn, K.C. Cell (1980) [Pubmed]
  9. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Cheng, T., Liu, D., Griffin, J.H., Fernández, J.A., Castellino, F., Rosen, E.D., Fukudome, K., Zlokovic, B.V. Nat. Med. (2003) [Pubmed]
  10. PGE2 and PAR-1 in pulmonary fibrosis: a case of biting the hand that feeds you? Remillard, C.V., Yuan, J.X. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  11. Different levels of platelet activation in preeclamptic, normotensive pregnant, and nonpregnant women. Holthe, M.R., Staff, A.C., Berge, L.N., Lyberg, T. Am. J. Obstet. Gynecol. (2004) [Pubmed]
  12. A novel PAR-1-type thrombin receptor signaling pathway: cyclic AMP-independent activation of PKA in SNB-19 glioblastoma cells. Zieger, M., Tausch, S., Henklein, P., Nowak, G., Kaufmann, R. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  13. Comparative neurovirulence in lentiviral infections: The roles of viral molecular diversity and select proteases. Power, C., Zhang, K., van Marle, G. J. Neurovirol. (2004) [Pubmed]
  14. Thrombin inhibits tumor cell growth in association with up-regulation of p21(waf/cip1) and caspases via a p53-independent, STAT-1-dependent pathway. Huang, Y.Q., Li, J.J., Karpatkin, S. J. Biol. Chem. (2000) [Pubmed]
  15. Cloning and identification of regulatory sequences of the human thrombin receptor gene. Li, F., Baykal, D., Horaist, C., Yan, C.N., Carr, B.N., Rao, G.N., Runge, M.S. J. Biol. Chem. (1996) [Pubmed]
  16. Genomic cloning and characterization of the human thrombin receptor gene. Structural similarity to the proteinase activated receptor-2 gene. Schmidt, V.A., Vitale, E., Bahou, W.F. J. Biol. Chem. (1996) [Pubmed]
  17. Evidence for the presence of a protease-activated receptor distinct from the thrombin receptor in human keratinocytes. Santulli, R.J., Derian, C.K., Darrow, A.L., Tomko, K.A., Eckardt, A.J., Seiberg, M., Scarborough, R.M., Andrade-Gordon, P. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  18. Thrombin receptors and protease-activated receptor-2 in human placentation: receptor activation mediates extravillous trophoblast invasion in vitro. O'Brien, P.J., Koi, H., Parry, S., Brass, L.F., Strauss, J.F., Wang, L.P., Tomaszewski, J.E., Christenson, L.K. Am. J. Pathol. (2003) [Pubmed]
  19. The effects of dexamethasone and dehydroepiandrosterone (DHEA) on cytokines and receptor expression in a human osteoblastic cell line: Potential steroid-sparing role for DHEA. Harding, G., Mak, Y.T., Evans, B., Cheung, J., Macdonald, D., Hampson, G. Cytokine (2006) [Pubmed]
  20. Correlation of protease-activated receptor-1 with differentiation markers in squamous cell carcinoma of the head and neck and its implication in lymph node metastasis. Zhang, X., Hunt, J.L., Landsittel, D.P., Muller, S., Adler-Storthz, K., Ferris, R.L., Shin, D.M., Chen, Z.G. Clin. Cancer Res. (2004) [Pubmed]
  21. Sustained stimulation of platelet thrombin receptor is associated with tyrosine dephosphorylation of a novel p67 peptide in a manner regulated by extracellular calcium. Karim, Z.A., Mukhopadhyay, S., Ramars, A.S., Dash, D. Biochim. Biophys. Acta (2004) [Pubmed]
  22. Efficient tyrosine phosphorylation of proteins after activation of platelets with thrombin depends on intact glycoprotein Ib. Diaz-Ricart, M., Fuste, B., Estebanell, E., Tonda, R., Lozano, M., Escolar, G., Jamieson, G., Ordinas, A. Platelets (2005) [Pubmed]
  23. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. Esmon, C.T. FASEB J. (1995) [Pubmed]
  24. Coupling of the thrombin receptor to G12 may account for selective effects of thrombin on gene expression and DNA synthesis in 1321N1 astrocytoma cells. Post, G.R., Collins, L.R., Kennedy, E.D., Moskowitz, S.A., Aragay, A.M., Goldstein, D., Brown, J.H. Mol. Biol. Cell (1996) [Pubmed]
  25. Distinct pathways mediate transcriptional regulation of platelet-derived growth factor B/c-sis expression. Daniel, T.O., Fen, Z. J. Biol. Chem. (1988) [Pubmed]
  26. Shc adaptor proteins are key transducers of mitogenic signaling mediated by the G protein-coupled thrombin receptor. Chen, Y., Grall, D., Salcini, A.E., Pelicci, P.G., Pouysségur, J., Van Obberghen-Schilling, E. EMBO J. (1996) [Pubmed]
  27. Interactions of mast cell tryptase with thrombin receptors and PAR-2. Molino, M., Barnathan, E.S., Numerof, R., Clark, J., Dreyer, M., Cumashi, A., Hoxie, J.A., Schechter, N., Woolkalis, M., Brass, L.F. J. Biol. Chem. (1997) [Pubmed]
  28. Gene structure of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for thrombin-catalyzed activation of protein C. Suzuki, K. Nippon Ketsueki Gakkai Zasshi (1988) [Pubmed]
  29. Bradykinin and its metabolite, Arg-Pro-Pro-Gly-Phe, are selective inhibitors of alpha-thrombin-induced platelet activation. Hasan, A.A., Amenta, S., Schmaier, A.H. Circulation (1996) [Pubmed]
  30. The human thrombin receptor and proteinase activated receptor-2 genes are tightly linked on chromosome 5q13. Schmidt, V.A., Nierman, W.C., Feldblyum, T.V., Maglott, D.R., Bahou, W.F. Br. J. Haematol. (1997) [Pubmed]
  31. Matrix metalloproteinases target protease-activated receptors on the tumor cell surface. Pei, D. Cancer Cell (2005) [Pubmed]
  32. PAR1 thrombin receptor-G protein interactions. Separation of binding and coupling determinants in the galpha subunit. Swift, S., Sheridan, P.J., Covic, L., Kuliopulos, A. J. Biol. Chem. (2000) [Pubmed]
  33. Thrombin-stimulated calcium mobilization is inhibited by thrombospondin via CD36. Enenstein, J., Gupta, K., Vercellotti, G.M., Hebbel, R.P. Exp. Cell Res. (1998) [Pubmed]
  34. Ca2+ Signaling, TRP Channels, and Endothelial Permeability. Tiruppathi, C., Ahmmed, G.U., Vogel, S.M., Malik, A.B. Microcirculation (New York, N.Y. : 1994) (2006) [Pubmed]
  35. Protease-activated receptor genes are clustered on 5q13. Guyonnet Dupérat, V., Jacquelin, B., Boisseau, P., Arveiler, B., Nurden, A.T. Blood (1998) [Pubmed]
  36. Endothelial protein C receptor and protease-activated receptor-1 mediate induction of a wound-healing phenotype in human keratinocytes by activated protein C. Xue, M., Campbell, D., Sambrook, P.N., Fukudome, K., Jackson, C.J. J. Invest. Dermatol. (2005) [Pubmed]
  37. Intravenous recombinant soluble human thrombomodulin prevents venous thrombosis in a rat model. Solis, M.M., Cook, C., Cook, J., Glaser, C., Light, D., Morser, J., Yu, S.C., Fink, L., Eidt, J.F. J. Vasc. Surg. (1991) [Pubmed]
  38. Discovery of potent peptide-mimetic antagonists for the human thrombin receptor, protease-activated receptor-1 (PAR-1). Maryanoff, B.E., Zhang, H.C., Andrade-Gordon, P., Derian, C.K. Current medicinal chemistry. Cardiovascular and hematological agents. (2003) [Pubmed]
  39. Direct vascular effects of protease-activated receptor type 1 agonism in vivo in humans. Gudmundsd??ttir, I.J., Megson, I.L., Kell, J.S., Ludlam, C.A., Fox, K.A., Webb, D.J., Newby, D.E. Circulation (2006) [Pubmed]
  40. Solid tumor cells express functional "tethered ligand" thrombin receptor. Wojtukiewicz, M.Z., Tang, D.G., Ben-Josef, E., Renaud, C., Walz, D.A., Honn, K.V. Cancer Res. (1995) [Pubmed]
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