F2RL1
Identifiers
AliasesF2RL1, GPR11, PAR2, Protease activated receptor 2, F2R like trypsin receptor 1
External IDsOMIM: 600933 MGI: 101910 HomoloGene: 21087 GeneCards: F2RL1
Orthologs
SpeciesHumanMouse
Entrez

2150

14063

Ensembl

ENSG00000164251

ENSMUSG00000021678

UniProt

P55085

P55086

RefSeq (mRNA)

NM_005242

NM_007974

RefSeq (protein)

NP_005233

NP_032000

Location (UCSC)Chr 5: 76.82 – 76.84 MbChr 13: 95.65 – 95.66 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Protease activated receptor 2 (PAR2) also known as coagulation factor II (thrombin) receptor-like 1 (F2RL1) or G-protein coupled receptor 11 (GPR11) is a protein that in humans is encoded by the F2RL1 gene. PAR2 modulates inflammatory responses,[5] obesity,[6] metabolism,[7] cancers [8][9] and acts as a sensor for proteolytic enzymes generated during infection.[10] In humans, we can find PAR2 in the stratum granulosum layer of epidermal keratinocytes. Functional PAR2 is also expressed by several immune cells such as eosinophils, neutrophils, monocytes, macrophages, dendritic cells, mast cells and T cells.[11]

Gene

The F2RL1 gene contains two exons and is widely expressed in human tissues. The predicted protein sequence is 83% identical to the mouse receptor sequence.[12]

Mechanism of activation

Activation vs silencing of PAR

PAR2 is a member of the large family of 7-transmembrane receptors that couple to guanosine-nucleotide-binding proteins. PAR2 is also a member of the protease-activated receptor family. PAR2 is activated by several different endogenous and exogenous proteases. It is activated by proteolytic cleavage of its extracellular amino terminus between arginine and serine.[13] The newly exposed N-terminus serves as tethered activation ligand, which binds a conserved region on extracellular loop 2 (ECL2) and activates the receptor.[5] These receptors can also be activated non-protealytically, by exogenous peptide sequences that mimic the final amino acids of the tethered ligand,[14] or by other proteases at cleavage sites that are not related to signaling and that can make them then irresponsive to further protease exposure.[5] Trypsin is the major PAR2 cleaving protease that initiates inflammatory signaling. It was found that even thrombin in high concentrations is able to cleave PAR2.[15] Another PAR2 cleaving protease is tryptase, the main protease of mast cells, which by PAR2 proteolytic cleavage induces calcium signaling and proliferation.[16] PARs have been identified as substrates of kallikreins, which have been related to various inflammatory and tumorigenic processes. In case of PAR2, particularly speaking about kallikrein-4, -5, -6 a -14.[17] PAR2 is known to transactivate TLR4[18] and epidermal growth factor receptor[19] in diseases.

Function

There are many studies dealing with elucidation of PAR2 function in different cells and tissues.[20] In case of human airway and lung parenchyma PAR2 is responsible for increased fibroblasts proliferation[21] and elevation of IL‐6, IL‐8, PGE2 and Ca2+ levels.[22] In mice it participates on vasodilatation.[23] Together with PAR1 its deregulation is also involved in processes of cancer cells migration and differentiation.[24]

Agonists and antagonists

Potent and selective small molecule agonists and antagonists for PAR2 have been discovered.[25][26][27]

Functional selectivity occurs with PAR2, several proteases cleave PAR2 at distinct sites leading to biased signalling.[28] Synthetic small ligands also modulate biased signalling leading to different functional responses.[29]

So far, PAR2 has been co-crystallized with two different antagonist ligands,[30] while an agonist-bound state model of PAR2 (with the endogenous ligand SLIGKV) has been determined through mutagenesis and structure-based drug design.[31]

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000164251 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021678 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 Heuberger DM, Schuepbach RA (2019-03-29). "Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases". Thrombosis Journal. 17 (1): 4. doi:10.1186/s12959-019-0194-8. PMC 6440139. PMID 30976204. Text was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
  6. ↑ Lim J, Iyer A, Liu L, Suen JY, Lohman RJ, Seow V, et al. (December 2013). "Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism". FASEB Journal. 27 (12): 4757–67. doi:10.1096/fj.13-232702. PMID 23964081. S2CID 30116494.
  7. ↑ Badeanlou L, Furlan-Freguia C, Yang G, Ruf W, Samad F (October 2011). "Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation". Nature Medicine. 17 (11): 1490–7. doi:10.1038/nm.2461. PMC 3210891. PMID 22019885.
  8. ↑ Sébert M, Sola-Tapias N, Mas E, Barreau F, Ferrand A (2019). "Protease-Activated Receptors in the Intestine: Focus on Inflammation and Cancer". Frontiers in Endocrinology. 10: 717. doi:10.3389/fendo.2019.00717. PMC 6821688. PMID 31708870.
  9. ↑ Jiang Y, Lim J, Wu KC, Xu W, Suen JY, Fairlie DP (November 2020). "PAR2 induces ovarian cancer cell motility by merging three signalling pathways to transactivate EGFR". British Journal of Pharmacology. 178 (4): 913–932. doi:10.1111/bph.15332. PMID 33226635. S2CID 227135487.
  10. ↑ Lee SE, Jeong SK, Lee SH (November 2010). "Protease and protease-activated receptor-2 signaling in the pathogenesis of atopic dermatitis". Yonsei Medical Journal. 51 (6): 808–22. doi:10.3349/ymj.2010.51.6.808. PMC 2995962. PMID 20879045.
  11. ↑ Rattenholl A, Steinhoff M (September 2008). "Proteinase-activated receptor-2 in the skin: receptor expression, activation and function during health and disease". Drug News & Perspectives. 21 (7): 369–81. doi:10.1358/dnp.2008.21.7.1255294. PMID 19259550.
  12. ↑ "Entrez Gene: F2RL1 coagulation factor II (thrombin) receptor-like 1".
  13. ↑ Guenther F, Melzig MF (December 2015). "Protease-activated receptors and their biological role - focused on skin inflammation". The Journal of Pharmacy and Pharmacology. 67 (12): 1623–33. doi:10.1111/jphp.12447. PMID 26709036. S2CID 26064678.
  14. ↑ Kawabata A, Kanke T, Yonezawa D, Ishiki T, Saka M, Kabeya M, et al. (June 2004). "Potent and metabolically stable agonists for protease-activated receptor-2: evaluation of activity in multiple assay systems in vitro and in vivo". The Journal of Pharmacology and Experimental Therapeutics. 309 (3): 1098–107. doi:10.1124/jpet.103.061010. PMID 14976227. S2CID 10806872.
  15. ↑ Mihara K, Ramachandran R, Saifeddine M, Hansen KK, Renaux B, Polley D, et al. (May 2016). "Thrombin-Mediated Direct Activation of Proteinase-Activated Receptor-2: Another Target for Thrombin Signaling". Molecular Pharmacology. 89 (5): 606–14. doi:10.1124/mol.115.102723. PMID 26957205. S2CID 24834327.
  16. ↑ Akers IA, Parsons M, Hill MR, Hollenberg MD, Sanjar S, Laurent GJ, McAnulty RJ (January 2000). "Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2". American Journal of Physiology. Lung Cellular and Molecular Physiology. 278 (1): L193-201. doi:10.1152/ajplung.2000.278.1.l193. PMID 10645907. S2CID 31697946.
  17. ↑ Caliendo G, Santagada V, Perissutti E, Severino B, Fiorino F, Frecentese F, Juliano L (August 2012). "Kallikrein protease activated receptor (PAR) axis: an attractive target for drug development". Journal of Medicinal Chemistry. 55 (15): 6669–86. doi:10.1021/jm300407t. PMID 22607152.
  18. ↑ Rayees S, Rochford I, Joshi JC, Joshi B, Banerjee S, Mehta D (2020). "Macrophage TLR4 and PAR2 Signaling: Role in Regulating Vascular Inflammatory Injury and Repair". Frontiers in Immunology. 11: 2091. doi:10.3389/fimmu.2020.02091. PMC 7530636. PMID 33072072.
  19. ↑ Jiang Y, Lim J, Wu KC, Xu W, Suen JY, Fairlie DP (November 2020). "PAR2 induces ovarian cancer cell motility by merging three signalling pathways to transactivate EGFR". British Journal of Pharmacology. 178 (4): 913–932. doi:10.1111/bph.15332. PMID 33226635. S2CID 227135487.
  20. ↑ Guenther F, Melzig MF (December 2015). "Protease-activated receptors and their biological role - focused on skin inflammation". The Journal of Pharmacy and Pharmacology. 67 (12): 1623–33. doi:10.1111/jphp.12447. PMID 26709036. S2CID 26064678.
  21. ↑ Akers IA, Parsons M, Hill MR, Hollenberg MD, Sanjar S, Laurent GJ, McAnulty RJ (January 2000). "Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2". American Journal of Physiology. Lung Cellular and Molecular Physiology. 278 (1): L193-201. doi:10.1152/ajplung.2000.278.1.l193. PMID 10645907. S2CID 31697946.
  22. ↑ Asokananthan N, Graham PT, Fink J, Knight DA, Bakker AJ, McWilliam AS, et al. (April 2002). "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". Journal of Immunology. 168 (7): 3577–85. doi:10.4049/jimmunol.168.7.3577. PMID 11907122.
  23. ↑ Hennessey JC, McGuire JJ (2013-02-07). "Attenuated vasodilator effectiveness of protease-activated receptor 2 agonist in heterozygous par2 knockout mice". PLOS ONE. 8 (2): e55965. Bibcode:2013PLoSO...855965H. doi:10.1371/journal.pone.0055965. PMC 3567012. PMID 23409098.
  24. ↑ Bar-Shavit R, Maoz M, Kancharla A, Jaber M, Agranovich D, Grisaru-Granovsky S, Uziely B (2016). "Protease-activated receptors (PARs) in cancer". G Protein-Coupled Receptors - Signaling, Trafficking and Regulation. Methods in Cell Biology. Vol. 132. pp. 341–58. doi:10.1016/bs.mcb.2015.11.006. ISBN 9780128035955. PMID 26928551.
  25. ↑ Gardell LR, Ma JN, Seitzberg JG, Knapp AE, Schiffer HH, Tabatabaei A, et al. (December 2008). "Identification and characterization of novel small-molecule protease-activated receptor 2 agonists". The Journal of Pharmacology and Experimental Therapeutics. 327 (3): 799–808. doi:10.1124/jpet.108.142570. PMID 18768780. S2CID 3246903.
  26. ↑ Barry GD, Suen JY, Le GT, Cotterell A, Reid RC, Fairlie DP (October 2010). "Novel agonists and antagonists for human protease activated receptor 2". Journal of Medicinal Chemistry. 53 (20): 7428–40. doi:10.1021/jm100984y. PMID 20873792.
  27. ↑ Yau MK, Liu L, Suen JY, Lim J, Lohman RJ, Jiang Y, et al. (December 2016). "PAR2 Modulators Derived from GB88". ACS Medicinal Chemistry Letters. 7 (12): 1179–1184. doi:10.1021/acsmedchemlett.6b00306. PMC 5150695. PMID 27994760.
  28. ↑ Zhao P, Metcalf M, Bunnett NW (2014). "Biased signaling of protease-activated receptors". Frontiers in Endocrinology. 5: 67. doi:10.3389/fendo.2014.00067. PMC 4026716. PMID 24860547.
  29. ↑ Jiang Y, Yau MK, Kok WM, Lim J, Wu KC, Liu L, et al. (May 2017). "Biased Signaling by Agonists of Protease Activated Receptor 2" (PDF). ACS Chemical Biology. 12 (5): 1217–1226. doi:10.1021/acschembio.6b01088. PMID 28169521.
  30. ↑ Cheng RK, Fiez-Vandal C, Schlenker O, Edman K, Aggeler B, Brown DG, et al. (May 2017). "Structural insight into allosteric modulation of protease-activated receptor 2". Nature. 545 (7652): 112–115. Bibcode:2017Natur.545..112C. doi:10.1038/nature22309. PMID 28445455. S2CID 4461925.
  31. ↑ Kennedy AJ, Ballante F, Johansson JR, Milligan G, Sundström L, Nordqvist A, Carlsson J (November 2018). "Structural Characterization of Agonist Binding to Protease-Activated Receptor 2 through Mutagenesis and Computational Modeling". ACS Pharmacology & Translational Science. 1 (2): 119–133. doi:10.1021/acsptsci.8b00019. PMC 7088944. PMID 32219208.

Further reading

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