The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

F2r  -  coagulation factor II (thrombin) receptor

Mus musculus

Synonyms: AI482343, Cf2r, PAR-1, Par1, Proteinase-activated receptor 1, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of F2r


High impact information on F2r

  • Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activation [6].
  • PAR3 is a thrombin receptor that is expressed in mouse megakaryocytes [7].
  • Strikingly, tr-/- platelets respond strongly to thrombin, whereas tr-/- fibroblasts lose their ability to respond to thrombin [8].
  • We conclude that the thrombin receptor plays an unexpected role in embryonic development, suggesting a possible new function for the 'coagulation' proteases themselves [8].
  • Here we show that although disruption of the thrombin receptor (tr) gene in mice causes about half of the tr-/- embryos to die at embryonic day 9-10, half survive to become grossly normal adult mice with no bleeding diathesis [8].

Chemical compound and disease context of F2r

  • SFLLRN still induced hypotension in PAR-1(-/-) mice, but HR decrease and secondary hypertension following L-NAME were absent [2].
  • Because NMDA activity mediates hyperalgesia, we tested the hypothesis that PAR-1 receptors also regulate pain processing [9].
  • Our data suggest that PAR-1 is antinociceptive in processing of visceral pain, whereas PAR-2 expressed in the colonic luminal surface, upon activation, produces delayed sensitization of capsaicin receptors, resulting in facilitation of visceral pain and referred hyperalgesia [10].
  • We also demonstrate that pulmonary edema and TGF-beta activity are similarly reduced in Par1-/- mice following bleomycin-induced lung injury [11].
  • Intratracheal instillation of the PAR1-specific peptide TFLLRN increases lung edema during high-tidal-volume ventilation, and this effect is completely inhibited by a blocking antibody against the alpha(v)beta6 integrin [11].

Biological context of F2r


Anatomical context of F2r

  • Activated protein C (APC), a serine protease with anticoagulant and anti-inflammatory activities, exerts direct cytoprotective effects on endothelium via endothelial protein C receptor-dependent activation of protease activated receptor 1 (PAR1) [1].
  • Thus PAR1 is the major thrombin receptor in mouse endothelial cells, but PAR4 also contributes [15].
  • 5. In several instances, tissue factor-expressing epithelia were surrounded by thrombin receptor-expressing mesenchyme [12].
  • The results demonstrate that thrombin stimulates proliferation and inhibits differentiation of osteoblasts through activation of PAR-1 [16].
  • The aim of this study was to determine if PAR-1 and PAR-2 mediate gastrointestinal smooth muscle relaxation and to clarify the underlying mechanisms [17].

Associations of F2r with chemical compounds

  • Both the PAR-1-activating peptide and thrombin stimulated incorporation of 5-bromo-2'-deoxyuridine (two to four-fold, P < 0.001) and reduced alkaline phosphatase activity (approximately three-fold, P < 0.05) in cells from wild-type mice [16].
  • The reductions in crescent formation, inflammatory cell infiltration, and serum creatinine were similar in PAR-1(-/-) and hirudin-treated mice, but hirudin afforded significantly greater protection from fibrin deposition [3].
  • The enhancing and inhibiting effects were specific for thrombin (reversed with inactive diisopropyl-fluorophosphate [DFP]-thrombin) and mediated via the protease-activated receptor 1 (PAR-1) [18].
  • Thus, activation of PAR-1 sites by thrombin in the CNS appears to inhibit NMDA-mediated nociception by a pathway involving endothelin type A receptors [9].
  • Similarly, ThrR deficiency had no detectable effect in adult ThrR-/- mice on basal heart rate, arterial blood pressure, vasomotor responses to angiotensin II and acetycholine, and coagulation parameters, even though the ThrR is expressed in many cardiovascular tissue types [19].

Physical interactions of F2r

  • It is proposed that granzyme A interacts with the thrombin receptor found on platelets in a manner that is insufficient to cause aggregation, but sufficient to compete with thrombin for the receptor [20].

Enzymatic interactions of F2r

  • A synthetic peptide spanning the N-terminal thrombin receptor activation sequence was cleaved by granzyme A at the authentic thrombin cleavage site Leu-Asp-Pro-Arg-Ser [21].

Co-localisations of F2r


Regulatory relationships of F2r


Other interactions of F2r

  • By contrast, deficiencies of protease-activated receptor 1 (PAR1) or PAR2 did not provide protection [26].
  • In contrast to the thrombin receptor, prothrombin mRNA was limited to the embryonic liver and was not detected until E12.5, well after the onset of receptor expression. mRNA for tissue factor, one important trigger for thrombin generation in the adult, was detected in embryonic epithelia from E9.5-12 [12].
  • Granzyme A released upon stimulation of cytotoxic T lymphocytes activates the thrombin receptor on neuronal cells and astrocytes [21].
  • Endothelial-specific Galpha13 knockout embryos died at embryonic days 9.5-11.5 and resembled the PAR1 knockout [27].
  • We compared renal injury after 25 minutes of bilateral renal ischemia and varying periods of reperfusion in C57BL/6 mice, those expressing low levels of TF (low-TF), hirudin-treated C57BL/6, and mice lacking either PAR-1 or PAR-2 [4].

Analytical, diagnostic and therapeutic context of F2r


  1. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Guo, H., Liu, D., Gelbard, H., Cheng, T., Insalaco, R., Fernández, J.A., Griffin, J.H., Zlokovic, B.V. Neuron (2004) [Pubmed]
  2. Cardiovascular responses mediated by protease-activated receptor-2 (PAR-2) and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2 or PAR-1. Damiano, B.P., Cheung, W.M., Santulli, R.J., Fung-Leung, W.P., Ngo, K., Ye, R.D., Darrow, A.L., Derian, C.K., de Garavilla, L., Andrade-Gordon, P. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  3. Protease-activated receptor 1 mediates thrombin-dependent, cell-mediated renal inflammation in crescentic glomerulonephritis. Cunningham, M.A., Rondeau, E., Chen, X., Coughlin, S.R., Holdsworth, S.R., Tipping, P.G. J. Exp. Med. (2000) [Pubmed]
  4. Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury. Sevastos, J., Kennedy, S.E., Davis, D.R., Sam, M., Peake, P.W., Charlesworth, J.A., Mackman, N., Erlich, J.H. Blood (2007) [Pubmed]
  5. Protease-activated receptor 1 (PAR-1) is required and rate-limiting for thrombin-enhanced experimental pulmonary metastasis. Nierodzik, M.L., Chen, K., Takeshita, K., Li, J.J., Huang, Y.Q., Feng, X.S., D'Andrea, M.R., Andrade-Gordon, P., Karpatkin, S. Blood (1998) [Pubmed]
  6. Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activation. Covic, L., Misra, M., Badar, J., Singh, C., Kuliopulos, A. Nat. Med. (2002) [Pubmed]
  7. A dual thrombin receptor system for platelet activation. Kahn, M.L., Zheng, Y.W., Huang, W., Bigornia, V., Zeng, D., Moff, S., Farese, R.V., Tam, C., Coughlin, S.R. Nature (1998) [Pubmed]
  8. Role of the thrombin receptor in development and evidence for a second receptor. Connolly, A.J., Ishihara, H., Kahn, M.L., Farese, R.V., Coughlin, S.R. Nature (1996) [Pubmed]
  9. Thrombin inhibits NMDA-mediated nociceptive activity in the mouse: possible mediation by endothelin. Fang, M., Kovács, K.J., Fisher, L.L., Larson, A.A. J. Physiol. (Lond.) (2003) [Pubmed]
  10. Modulation of capsaicin-evoked visceral pain and referred hyperalgesia by protease-activated receptors 1 and 2. Kawao, N., Ikeda, H., Kitano, T., Kuroda, R., Sekiguchi, F., Kataoka, K., Kamanaka, Y., Kawabata, A. J. Pharmacol. Sci. (2004) [Pubmed]
  11. 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]
  12. Disparate temporal expression of the prothrombin and thrombin receptor genes during mouse development. Soifer, S.J., Peters, K.G., O'Keefe, J., Coughlin, S.R. Am. J. Pathol. (1994) [Pubmed]
  13. Genetic evidence that protease-activated receptors mediate factor Xa signaling in endothelial cells. Camerer, E., Kataoka, H., Kahn, M., Lease, K., Coughlin, S.R. J. Biol. Chem. (2002) [Pubmed]
  14. Conserved structure and adjacent location of the thrombin receptor and protease-activated receptor 2 genes define a protease-activated receptor gene cluster. Kahn, M., Ishii, K., Kuo, W.L., Piper, M., Connolly, A., Shi, Y.P., Wu, R., Lin, C.C., Coughlin, S.R. Mol. Med. (1996) [Pubmed]
  15. Protease-activated receptors 1 and 4 mediate thrombin signaling in endothelial cells. Kataoka, H., Hamilton, J.R., McKemy, D.D., Camerer, E., Zheng, Y.W., Cheng, A., Griffin, C., Coughlin, S.R. Blood (2003) [Pubmed]
  16. Studies on the receptors mediating responses of osteoblasts to thrombin. Song, S.J., Pagel, C.N., Pike, R.N., Mackie, E.J. Int. J. Biochem. Cell Biol. (2005) [Pubmed]
  17. Protease-activated receptors mediate apamin-sensitive relaxation of mouse and guinea pig gastrointestinal smooth muscle. Cocks, T.M., Sozzi, V., Moffatt, J.D., Selemidis, S. Gastroenterology (1999) [Pubmed]
  18. Concentration-dependent dual effect of thrombin on impaired growth/apoptosis or mitogenesis in tumor cells. Zain, J., Huang, Y.Q., Feng, X., Nierodzik, M.L., Li, J.J., Karpatkin, S. Blood (2000) [Pubmed]
  19. Biological consequences of thrombin receptor deficiency in mice. Darrow, A.L., Fung-Leung, W.P., Ye, R.D., Santulli, R.J., Cheung, W.M., Derian, C.K., Burns, C.L., Damiano, B.P., Zhou, L., Keenan, C.M., Peterson, P.A., Andrade-Gordon, P. Thromb. Haemost. (1996) [Pubmed]
  20. The serine protease granzyme A does not induce platelet aggregation but inhibits responses triggered by thrombin. Suidan, H.S., Clemetson, K.J., Brown-Luedi, M., Niclou, S.P., Clemetson, J.M., Tschopp, J., Monard, D. Biochem. J. (1996) [Pubmed]
  21. Granzyme A released upon stimulation of cytotoxic T lymphocytes activates the thrombin receptor on neuronal cells and astrocytes. Suidan, H.S., Bouvier, J., Schaerer, E., Stone, S.R., Monard, D., Tschopp, J. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  22. Activation of proteinase-activated receptor-1 inhibits neurally evoked chloride secretion in the mouse colon in vitro. Buresi, M.C., Vergnolle, N., Sharkey, K.A., Keenan, C.M., Andrade-Gordon, P., Cirino, G., Cirillo, D., Hollenberg, M.D., MacNaughton, W.K. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  23. Receptor-activating peptides distinguish thrombin receptor (PAR-1) and protease activated receptor 2 (PAR-2) mediated hemodynamic responses in vivo. Cheung, W.M., Andrade-Gordon, P., Derian, C.K., Damiano, B.P. Can. J. Physiol. Pharmacol. (1998) [Pubmed]
  24. Tissue factor-initiated thrombin generation activates the signaling thrombin receptor on malignant melanoma cells. Fischer, E.G., Ruf, W., Mueller, B.M. Cancer Res. (1995) [Pubmed]
  25. Thrombin induces mast cell adhesion to fibronectin: evidence for involvement of protease-activated receptor-1. Vliagoftis, H. J. Immunol. (2002) [Pubmed]
  26. Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Camerer, E., Qazi, A.A., Duong, D.N., Cornelissen, I., Advincula, R., Coughlin, S.R. Blood (2004) [Pubmed]
  27. Essential role for Galpha13 in endothelial cells during embryonic development. Ruppel, K.M., Willison, D., Kataoka, H., Wang, A., Zheng, Y.W., Cornelissen, I., Yin, L., Xu, S.M., Coughlin, S.R. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  28. The proteinase activated receptor-2 (PAR-2) mediates mitogenic responses in human vascular endothelial cells. Mirza, H., Yatsula, V., Bahou, W.F. J. Clin. Invest. (1996) [Pubmed]
WikiGenes - Universities