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Gene Review

F2RL3  -  coagulation factor II (thrombin) receptor...

Homo sapiens

Synonyms: Coagulation factor II receptor-like 3, PAR-4, PAR4, Proteinase-activated receptor 4, Thrombin receptor-like 3
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Disease relevance of F2RL3

  • A partial cDNA sequence of a fourth member of this family (PAR4) was identified in an expressed sequence tag database, and the full-length cDNA clone has been isolated from a lymphoma Daudi cell cDNA library [1].
  • This was deduced from the findings that a further calcium signal could be observed in human astrocytoma cells stimulated with alpha-thrombin after SFLLRN and the PAR-4-activating peptide GYPGQV also induced a calcium response [2].
  • Further mechanistic studies on the actions of PAR-1 and PAR-4 as detrimental in experimental models of Parkinson's disease are warranted [3].
  • Here we show that at the relatively high concentration of agonist most likely found at the site of a local thrombus, dual inhibition of the P2Y12 receptor and calcium mobilization result in a complete inhibition of PAR4-induced aggregation, while having no effect on either thrombin or PAR1-mediated platelet aggregation [4].
  • Adenocarcinomas were significantly more positive than SCC for PAR-1 (17 vs. 8 cases) and PAR-4 (10 vs. 5 cases) [5].

High impact information on F2RL3


Biological context of F2RL3

  • The platelet thrombin receptors, PAR (protease-activated receptor) 1 PAR-4 and GPIb-IX-V (glycoprotein Ib-IX-V) have been described as potential contributors of thrombin-induced platelet aggregation [8].
  • For example, AYPGKF activated and desensitized PAR4 in platelets and, like thrombin, triggered phosphoinositide hydrolysis but not inhibition of adenylyl cyclase in PAR4-expressing cells [9].
  • Studies carried out in the past 12 years have established that activation of protease-activated receptor (PAR)-1 and PAR-4 by thrombin essentially drives human platelet activation [10].
  • Biotinylation of cell-surface proteins showed that PAR-4 was internalised after stimulation by thrombin [11].
  • The selective activation of each PAR by short synthetic peptides representing these sequences has demonstrated that PAR1, PAR2 and PAR4 play important roles in regulating physiological responses ranging from vasoregulation and cell growth to inflammation and nociception [12].

Anatomical context of F2RL3

  • Activation of protease-activated receptor (PAR)-1, PAR-2, and PAR-4 stimulates IL-6, IL-8, and prostaglandin E2 release from human respiratory epithelial cells [13].
  • Intracellular Ca2+ levels were assessed in A549 cells and in mouse fibroblasts expressing the human protease activated receptor (PAR)1, PAR2 or PAR4 [14].
  • The recent identification of two new thrombin receptors, PAR3 and PAR4, led us to re-examine the basis for endothelial cell responses to thrombin [15].
  • Thus, thrombin plays a dual role in modulating the motility of the oesophageal muscularis mucosae, producing contraction via PAR-1 and relaxation via PAR-4 [16].
  • Preconditioning with specific local infusion of agonist peptides for PAR-1 and PAR-4 3 days before unilateral 6-OHDA administration (10 mug into the medial forebrain bundle) was tested [3].

Associations of F2RL3 with chemical compounds

  • PAR-4 agonist AYPGKF stimulates thromboxane production by human platelets [17].
  • PAR-4-induced stimulation is also significantly inhibited by 60 micromol/L genistein [17].
  • AYPGKF was relatively specific for PAR4 in part due to the tyrosine at position 2; substitution of phenylalanine or p-fluorophenylalanine at this position produced peptides that activated both PAR1 and PAR4 [9].
  • The PAR-4-mediated relaxation was resistant to tetrodotoxin (10 microM), apamin (0.1 microM), charybdotoxin (0.1 microM), L-N(G)-nitroarginine methyl ester (100 microM), indomethacin (3 microM), propranolol (5 microM) or adenosine 3', 5'-cyclic monophosphorothioate, 8-bromo, Rp-isomer (30 microM) [16].
  • Platelet activation by thrombin, a serine protease, occurs by binding to and cleavage of the extracellular N-terminal domains of protease-activated receptors 1 and 4 (PAR1 and PAR4) [18].

Other interactions of F2RL3

  • This result is consistent with the presence of another thrombin receptor on human platelets, namely PAR-4 [19].
  • Whether PAR1 and PAR4 account for activation of human platelets by thrombin, or whether PAR3 or still other receptors contribute, is unknown [20].
  • The activation of human platelets by alpha-thrombin is mediated at least in part by cleavage of protease-activated G-protein-coupled receptors, PAR-1 and PAR-4 [21].

Analytical, diagnostic and therapeutic context of F2RL3

  • Thus, thrombin activates human platelets independently of PAR-1, i.e., through PAR-4, which we confirmed by PCR analysis [22].
  • RESULTS: RT-PCR showed transcripts for PAR-1 and -2 receptors, but not for PAR-4 receptors [23].
  • Globally, immunoprecipitation experiments and analysis of the cytoskeleton confirmed that GPIb translocation is powered by a contractile mechanism involving Ca2+ mobilization, actin polymerization, and myosin incorporation into the cytoskeleton and that both PAR-1 and PAR-4 can activate this process [24].


  1. Cloning and characterization of human protease-activated receptor 4. Xu, W.F., Andersen, H., Whitmore, T.E., Presnell, S.R., Yee, D.P., Ching, A., Gilbert, T., Davie, E.W., Foster, D.C. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  2. The two-receptor system PAR-1/PAR-4 mediates alpha-thrombin-induced [Ca(2+)](i) mobilization in human astrocytoma cells. Kaufmann, R., Patt, S., Zieger, M., Kraft, R., Tausch, S., Henklein, P., Nowak, G. J. Cancer Res. Clin. Oncol. (2000) [Pubmed]
  3. Protease-activated receptor-1 mediates protection elicited by thrombin preconditioning in a rat 6-hydroxydopamine model of Parkinson's disease. Cannon, J.R., Keep, R.F., Schallert, T., Hua, Y., Richardson, R.J., Xi, G. Brain Res. (2006) [Pubmed]
  4. PAR4, but not PAR1, signals human platelet aggregation via Ca2+ mobilization and synergistic P2Y12 receptor activation. Holinstat, M., Voss, B., Bilodeau, M.L., McLaughlin, J.N., Cleator, J., Hamm, H.E. J. Biol. Chem. (2006) [Pubmed]
  5. Prognostic Role of Protease-Activated Receptors 1 and 4 in Resected Stage IB Non-Small-Cell Lung Cancer. Ghio, P., Cappia, S., Selvaggi, G., Novello, S., Lausi, P., Zecchina, G., Papotti, M., Borasio, P., Scagliotti, G.V. Clinical lung cancer. (2006) [Pubmed]
  6. PAR3 is a cofactor for PAR4 activation by thrombin. Nakanishi-Matsui, M., Zheng, Y.W., Sulciner, D.J., Weiss, E.J., Ludeman, M.J., Coughlin, S.R. Nature (2000) [Pubmed]
  7. Protease-activated receptor 1 is the primary mediator of thrombin-stimulated platelet procoagulant activity. Andersen, H., Greenberg, D.L., Fujikawa, K., Xu, W., Chung, D.W., Davie, E.W. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  8. Differential involvement of thrombin receptors in Ca2+ release from two different intracellular stores in human platelets. Jardin, I., Ben Amor, N., Bartegi, A., Pariente, J.A., Salido, G.M., Rosado, J.A. Biochem. J. (2007) [Pubmed]
  9. Structure-function analysis of protease-activated receptor 4 tethered ligand peptides. Determinants of specificity and utility in assays of receptor function. Faruqi, T.R., Weiss, E.J., Shapiro, M.J., Huang, W., Coughlin, S.R. J. Biol. Chem. (2000) [Pubmed]
  10. Protease activated receptors 1 and 4 govern the responses of human platelets to thrombin. Ofosu, F.A. Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. (2003) [Pubmed]
  11. Actin polymerisation regulates thrombin-evoked Ca(2+) signalling after activation of PAR-4 but not PAR-1 in human platelets. Harper, M.T., Sage, S.O. Platelets (2006) [Pubmed]
  12. Proteinase-mediated cell signalling: targeting proteinase-activated receptors (PARs) by kallikreins and more. Oikonomopoulou, K., Hansen, K.K., Saifeddine, M., Vergnolle, N., Tea, I., Diamandis, E.P., Hollenberg, M.D. Biol. Chem. (2006) [Pubmed]
  13. Activation of protease-activated receptor (PAR)-1, PAR-2, and PAR-4 stimulates IL-6, IL-8, and prostaglandin E2 release from human respiratory epithelial cells. Asokananthan, N., Graham, P.T., Fink, J., Knight, D.A., Bakker, A.J., McWilliam, A.S., Thompson, P.J., Stewart, G.A. J. Immunol. (2002) [Pubmed]
  14. House dust mite major allergens Der p 1 and Der p 5 activate human airway-derived epithelial cells by protease-dependent and protease-independent mechanisms. Kauffman, H.F., Tamm, M., Timmerman, J.A., Borger, P. Clinical and molecular allergy [electronic resource] : CMA. (2006) [Pubmed]
  15. Thrombin responses in human endothelial cells. Contributions from receptors other than PAR1 include the transactivation of PAR2 by thrombin-cleaved PAR1. O'Brien, P.J., Prevost, N., Molino, M., Hollinger, M.K., Woolkalis, M.J., Woulfe, D.S., Brass, L.F. J. Biol. Chem. (2000) [Pubmed]
  16. Dual modulation by thrombin of the motility of rat oesophageal muscularis mucosae via two distinct protease-activated receptors (PARs): a novel role for PAR-4 as opposed to PAR-1. Kawabata, A., Kuroda, R., Kuroki, N., Nishikawa, H., Kawai, K. Br. J. Pharmacol. (2000) [Pubmed]
  17. PAR-4 agonist AYPGKF stimulates thromboxane production by human platelets. Henriksen, R.A., Hanks, V.K. Arterioscler. Thromb. Vasc. Biol. (2002) [Pubmed]
  18. Synthesis of Novel Peptide Inhibitors of Thrombin-induced Platelet Activation. Burke, F.M., Warnock, M., Schmaier, A.H., Mosberg, H.I. Chemical biology & drug design (2006) [Pubmed]
  19. 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]
  20. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. Kahn, M.L., Nakanishi-Matsui, M., Shapiro, M.J., Ishihara, H., Coughlin, S.R. J. Clin. Invest. (1999) [Pubmed]
  21. Binding of thrombin to glycoprotein Ib accelerates the hydrolysis of Par-1 on intact platelets. De Candia, E., Hall, S.W., Rutella, S., Landolfi, R., Andrews, R.K., De Cristofaro, R. J. Biol. Chem. (2001) [Pubmed]
  22. Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor. Andrade-Gordon, P., Maryanoff, B.E., Derian, C.K., Zhang, H.C., Addo, M.F., Darrow, A.L., Eckardt, A.J., Hoekstra, W.J., McComsey, D.F., Oksenberg, D., Reynolds, E.E., Santulli, R.J., Scarborough, R.M., Smith, C.E., White, K.B. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  23. Thrombin inhibits intercellular calcium wave propagation in corneal endothelial cells by modulation of hemichannels and gap junctions. D'hondt, C., Ponsaerts, R., Srinivas, S.P., Vereecke, J., Himpens, B. Invest. Ophthalmol. Vis. Sci. (2007) [Pubmed]
  24. Redistribution of glycoprotein Ib within platelets in response to protease-activated receptors 1 and 4: roles of cytoskeleton and calcium. Han, Y., Nurden, A., Combrié, R., Pasquet, J.M. J. Thromb. Haemost. (2003) [Pubmed]
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