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Gene Review

F2RL1  -  coagulation factor II (thrombin) receptor...

Homo sapiens

Synonyms: Coagulation factor II receptor-like 1, G-protein coupled receptor 11, GPR11, PAR-2, PAR2, ...
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Disease relevance of F2RL1

  • Here we investigate the role of PAR-2 in the constitutive migration of a metastatic breast cancer cell line, MDA MB-231, and use small interfering RNA to determine the contribution of each beta-arrestin to this process [1].
  • However, the functional consequences of PAR-2 expression in cancer cells, especially in pancreatic cancer cells, are poorly understood [2].
  • Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis [3].
  • In normal kidneys, PAR-2 gene expression was barely detectable, whereas in IgAN biopsies the mRNA levels for this protease receptor were strikingly increased and directly correlated with the extent of interstitial fibrosis [4].
  • Thus, HAT might promote PAR-2-mediated IL-8 production to accumulate inflammatory cells in the epidermal layer of psoriasis [5].

Psychiatry related information on F2RL1

  • In this study, we report that PAR-2 was up-regulated on neurons in conjunction with neuroinflammation in brain tissue from patients with HIV-1-associated dementia [6].
  • Our data indicate that a pathogen-derived proteinase like EPa can potentially silence the function of PAR2 in the respiratory tract, thereby altering the host innate defense mechanisms and respiratory functions, and thus contributing to pathogenesis in the setting of a disease like CF [7].

High impact information on F2RL1


Chemical compound and disease context of F2RL1


Biological context of F2RL1


Anatomical context of F2RL1


Associations of F2RL1 with chemical compounds

  • We found that recombinant tryptase, human mast-cell (HMC-1) supernatant, which contains tryptase, and the PAR2-activating peptide SLIGKV exert fibroproliferative actions in human fibroblasts [22].
  • Here we report insights into this action, which after activation of PAR2 leads to increased expression of cyclooxygenase 2 (COX2), a key enzyme in the biosynthesis of prostaglandins, and consequently to enhanced prostaglandin synthesis [22].
  • The stimulatory effect of trypsin was dependent on its serine protease activity and was blocked 59% by anti-PAR2 Ab [23].
  • Treatment with trypsin, an agonist for PAR-2, and a synthetic PAR-2 agonist peptide induced intracellular Ca(2+) mobilization, and rendered cells refractory to subsequent stimulation with PR3 and vice versa [21].
  • 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 [24].

Physical interactions of F2RL1

  • Wegener autoantigen interacts with a "gateway" receptor (PAR-2) on iDCs in vitro triggering their maturation and licenses them for a T helper 1 (Th1)-type response potentially favoring granuloma formation in WG [25].

Enzymatic interactions of F2RL1

  • PR3 cleaved the peptide corresponding to the N terminus of PAR-2 with exposure of its tethered ligand [21].

Regulatory relationships of F2RL1


Other interactions of F2RL1

  • IL-8 was produced in a dose-dependent fashion when cells were stimulated with a PAR2 agonist such as trypsin or SLIGKV-amide [28].
  • Human airway trypsin-like protease (HAT), a serine protease found in the sputum of patients with chronic airway diseases, is an agonist of protease-activated receptor-2 (PAR-2) [29].
  • CONCLUSION: MT-SP1/matriptase induces release of proinflammatory cytokines in endothelial cells through activation of PAR-2 [30].
  • The production of cytokine induced by PR3 and the PAR-2 agonist peptide was completely abolished by a phospholipase C inhibitor [21].
  • Since our data indicated that keratinocytes possess a trypsin-sensitive receptor, we addressed the possibility that these cells express the human homologue of the newly described murine protease-activated receptor, PAR-2 [Nystedt, S., Emilsson, K., Wahlestedt, C. & Sundelin, J. (1994) Proc. Natl. Acad. Sci. USA 91, 9208-9212] [18].

Analytical, diagnostic and therapeutic context of F2RL1


  1. Constitutive protease-activated receptor-2-mediated migration of MDA MB-231 breast cancer cells requires both beta-arrestin-1 and -2. Ge, L., Shenoy, S.K., Lefkowitz, R.J., DeFea, K. J. Biol. Chem. (2004) [Pubmed]
  2. Signal of proteinase-activated receptor-2 contributes to highly malignant potential of human pancreatic cancer by up-regulation of interleukin-8 release. Ikeda, O., Egami, H., Ishiko, T., Ishikawa, S., Kamohara, H., Hidaka, H., Takahashi, M., Ogawa, M. Int. J. Oncol. (2006) [Pubmed]
  3. Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis. Shi, X., Gangadharan, B., Brass, L.F., Ruf, W., Mueller, B.M. Mol. Cancer Res. (2004) [Pubmed]
  4. Protease-activated receptor-2 expression in IgA nephropathy: a potential role in the pathogenesis of interstitial fibrosis. Grandaliano, G., Pontrelli, P., Cerullo, G., Monno, R., Ranieri, E., Ursi, M., Loverre, A., Gesualdo, L., Schena, F.P. J. Am. Soc. Nephrol. (2003) [Pubmed]
  5. Human airway trypsin-like protease induces PAR-2-mediated IL-8 release in psoriasis vulgaris. Iwakiri, K., Ghazizadeh, M., Jin, E., Fujiwara, M., Takemura, T., Takezaki, S., Kawana, S., Yasuoka, S., Kawanami, O. J. Invest. Dermatol. (2004) [Pubmed]
  6. Proteinase-activated receptor-2 induction by neuroinflammation prevents neuronal death during HIV infection. Noorbakhsh, F., Vergnolle, N., McArthur, J.C., Silva, C., Vodjgani, M., Andrade-Gordon, P., Hollenberg, M.D., Power, C. J. Immunol. (2005) [Pubmed]
  7. Pseudomonas aeruginosa elastase disables proteinase-activated receptor 2 in respiratory epithelial cells. Dulon, S., Leduc, D., Cottrell, G.S., D'Alayer, J., Hansen, K.K., Bunnett, N.W., Hollenberg, M.D., Pidard, D., Chignard, M. Am. J. Respir. Cell Mol. Biol. (2005) [Pubmed]
  8. A protective role for protease-activated receptors in the airways. Cocks, T.M., Fong, B., Chow, J.M., Anderson, G.P., Frauman, A.G., Goldie, R.G., Henry, P.J., Carr, M.J., Hamilton, J.R., Moffatt, J.D. Nature (1999) [Pubmed]
  9. Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis. Noorbakhsh, F., Tsutsui, S., Vergnolle, N., Boven, L.A., Shariat, N., Vodjgani, M., Warren, K.G., Andrade-Gordon, P., Hollenberg, M.D., Power, C. J. Exp. Med. (2006) [Pubmed]
  10. The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells. Wilson, S., Greer, B., Hooper, J., Zijlstra, A., Walker, B., Quigley, J., Hawthorne, S. Biochem. J. (2005) [Pubmed]
  11. Endothelial cell thrombin receptors and PAR-2. Two protease-activated receptors located in a single cellular environment. Molino, M., Woolkalis, M.J., Reavey-Cantwell, J., Praticó, D., Andrade-Gordon, P., Barnathan, E.S., Brass, L.F. J. Biol. Chem. (1997) [Pubmed]
  12. Trypsin in colorectal cancer: molecular biological mechanisms of proliferation, invasion, and metastasis. Soreide, K., Janssen, E.A., Körner, H., Baak, J.P. J. Pathol. (2006) [Pubmed]
  13. Proteinase-activated receptor-2 and human lung epithelial cells: disarming by neutrophil serine proteinases. Dulon, S., Candé, C., Bunnett, N.W., Hollenberg, M.D., Chignard, M., Pidard, D. Am. J. Respir. Cell Mol. Biol. (2003) [Pubmed]
  14. Activation of ion secretion via proteinase-activated receptor-2 in human colon. Mall, M., Gonska, T., Thomas, J., Hirtz, S., Schreiber, R., Kunzelmann, K. Am. J. Physiol. Gastrointest. Liver Physiol. (2002) [Pubmed]
  15. Jab1, a novel protease-activated receptor-2 (PAR-2)-interacting protein, is involved in PAR-2-induced activation of activator protein-1. Luo, W., Wang, Y., Hanck, T., Stricker, R., Reiser, G. J. Biol. Chem. (2006) [Pubmed]
  16. 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]
  17. Protease-activated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma. Knight, D.A., Lim, S., Scaffidi, A.K., Roche, N., Chung, K.F., Stewart, G.A., Thompson, P.J. J. Allergy Clin. Immunol. (2001) [Pubmed]
  18. 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]
  19. Differential expression and regulation of protease-activated receptors in human peripheral monocytes and monocyte-derived antigen-presenting cells. Colognato, R., Slupsky, J.R., Jendrach, M., Burysek, L., Syrovets, T., Simmet, T. Blood (2003) [Pubmed]
  20. 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]
  21. Activation of human oral epithelial cells by neutrophil proteinase 3 through protease-activated receptor-2. Uehara, A., Sugawara, S., Muramoto, K., Takada, H. J. Immunol. (2002) [Pubmed]
  22. Proliferative action of mast-cell tryptase is mediated by PAR2, COX2, prostaglandins, and PPARgamma : Possible relevance to human fibrotic disorders. Frungieri, M.B., Weidinger, S., Meineke, V., Köhn, F.M., Mayerhofer, A. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  23. Trypsin induces activation and inflammatory mediator release from human eosinophils through protease-activated receptor-2. Miike, S., McWilliam, A.S., Kita, H. J. Immunol. (2001) [Pubmed]
  24. 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]
  25. Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway. Csernok, E., Ai, M., Gross, W.L., Wicklein, D., Petersen, A., Lindner, B., Lamprecht, P., Holle, J.U., Hellmich, B. Blood (2006) [Pubmed]
  26. Activation of protease-activated receptor 2 stimulates proliferation and interleukin (IL)-6 and IL-8 secretion of endometriotic stromal cells. Hirota, Y., Osuga, Y., Hirata, T., Harada, M., Morimoto, C., Yoshino, O., Koga, K., Yano, T., Tsutsumi, O., Taketani, Y. Hum. Reprod. (2005) [Pubmed]
  27. German cockroach proteases regulate matrix metalloproteinase-9 in human bronchial epithelial cells. Page, K., Hughes, V.S., Bennett, G.W., Wong, H.R. Allergy (2006) [Pubmed]
  28. Interleukin-8 production via protease-activated receptor 2 in human esophageal epithelial cells. Yoshida, N., Katada, K., Handa, O., Takagi, T., Kokura, S., Naito, Y., Mukaida, N., Soma, T., Shimada, Y., Yoshikawa, T., Okanoue, T. Int. J. Mol. Med. (2007) [Pubmed]
  29. Human airway trypsin-like protease induces amphiregulin release through a mechanism involving protease-activated receptor-2-mediated ERK activation and TNF alpha-converting enzyme activity in airway epithelial cells. Chokki, M., Eguchi, H., Hamamura, I., Mitsuhashi, H., Kamimura, T. FEBS J. (2005) [Pubmed]
  30. Membrane-type serine protease-1/matriptase induces interleukin-6 and -8 in endothelial cells by activation of protease-activated receptor-2: potential implications in atherosclerosis. Seitz, I., Hess, S., Schulz, H., Eckl, R., Busch, G., Montens, H.P., Brandl, R., Seidl, S., Schömig, A., Ott, I. Arterioscler. Thromb. Vasc. Biol. (2007) [Pubmed]
  31. Protease-activated receptor genes are clustered on 5q13. Guyonnet Dupérat, V., Jacquelin, B., Boisseau, P., Arveiler, B., Nurden, A.T. Blood (1998) [Pubmed]
  32. Expression of protease-activated receptor-1, -2, -3, and -4 in control and experimentally inflamed mouse bladder. D'Andrea, M.R., Saban, M.R., Nguyen, N.B., Andrade-Gordon, P., Saban, R. Am. J. Pathol. (2003) [Pubmed]
  33. Effect of acute and chronic inflammatory stimuli on expression of protease-activated receptors 1 and 2 in alveolar macrophages. Roche, N., Stirling, R.G., Lim, S., Oliver, B.G., Oates, T., Jazrawi, E., Caramori, G., Chung, K.F. J. Allergy Clin. Immunol. (2003) [Pubmed]
  34. Phospholipid metabolite production in human urothelial cells after protease-activated receptor cleavage. Rickard, A., McHowat, J. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
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