Protease-activated receptor 2 explained

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, obesity,^[1] metabolism,^[2] cancers ^{[3] [4]} and acts as a sensor for proteolytic enzymes generated during infection.^[5] 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.^[6]

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.^[7]

Mechanism of activation

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.^[8] The newly exposed N-terminus serves as tethered activation ligand, which binds a conserved region on extracellular loop 2 (ECL2) and activates the receptor.^[9] These receptors can also be activated non-protealytically, by exogenous peptide sequences that mimic the final amino acids of the tethered ligand,^[10] or by other proteases at cleavage sites that are not related to signaling and that can make them then irresponsive to further protease exposure. 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.^[11] Another PAR2 cleaving protease is tryptase, the main protease of mast cells, which by PAR2 proteolytic cleavage induces calcium signaling and proliferation.^[12] 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.^[13] PAR2 is known to transactivate TLR4^[14] and epidermal growth factor receptor^[15] in diseases.

Function

There are many studies dealing with elucidation of PAR2 function in different cells and tissues.^[16] In case of human airway and lung parenchyma PAR2 is responsible for increased fibroblasts proliferation^[17] and elevation of IL‐6, IL‐8, PGE2 and Ca2+ levels.^[18] In mice it participates on vasodilatation.^[19] Together with PAR1 its deregulation is also involved in processes of cancer cells migration and differentiation.^[20]

Agonists and antagonists

Potent and selective small molecule agonists and antagonists for PAR2 have been discovered.^{[21] [22] [23]}

Functional selectivity occurs with PAR2, several proteases cleave PAR2 at distinct sites leading to biased signalling.^[24] Synthetic small ligands also modulate biased signalling leading to different functional responses.^[25]

So far, PAR2 has been co-crystallized with two different antagonist ligands,^[26] while an agonist-bound state model of PAR2 (with the endogenous ligand SLIGKV) has been determined through mutagenesis and structure-based drug design.^[27]

See also

• Protease-activated receptor
• Protease-activated receptor 1
• Protease-activated receptor 3

References

Further reading

• Kunzelmann K, Schreiber R, König J, Mall M . 5801308 . Ion transport induced by proteinase-activated receptors (PAR2) in colon and airways . Cell Biochemistry and Biophysics . 36 . 2–3 . 209–14 . 2003 . 12139406 . 10.1385/CBB:36:2-3:209 .
• Kawabata A . PAR-2: structure, function and relevance to human diseases of the gastric mucosa . Expert Reviews in Molecular Medicine . 4 . 16 . 1–17 . July 2002 . 14585156 . 10.1017/S1462399402004799 . 1485391 .
• Bushell T . The emergence of proteinase-activated receptor-2 as a novel target for the treatment of inflammation-related CNS disorders . The Journal of Physiology . 581 . Pt 1 . 7–16 . May 2007 . 17347265 . 2075212 . 10.1113/jphysiol.2007.129577 .
• Nystedt S, Emilsson K, Larsson AK, Strömbeck B, Sundelin J . Molecular cloning and functional expression of the gene encoding the human proteinase-activated receptor 2 . European Journal of Biochemistry . 232 . 1 . 84–9 . August 1995 . 7556175 . 10.1111/j.1432-1033.1995.tb20784.x . free .
• Santulli RJ, Derian CK, Darrow AL, Tomko KA, Eckardt AJ, Seiberg M, Scarborough RM, Andrade-Gordon P . 6 . Evidence for the presence of a protease-activated receptor distinct from the thrombin receptor in human keratinocytes . Proceedings of the National Academy of Sciences of the United States of America . 92 . 20 . 9151–5 . September 1995 . 7568091 . 40942 . 10.1073/pnas.92.20.9151 . 1995PNAS...92.9151S . free .
• Nystedt S, Emilsson K, Wahlestedt C, Sundelin J . Molecular cloning of a potential proteinase activated receptor . Proceedings of the National Academy of Sciences of the United States of America . 91 . 20 . 9208–12 . September 1994 . 7937743 . 44781 . 10.1073/pnas.91.20.9208 . 1994PNAS...91.9208N . free .
• Mirza H, Yatsula V, Bahou WF . The proteinase activated receptor-2 (PAR-2) mediates mitogenic responses in human vascular endothelial cells . The Journal of Clinical Investigation . 97 . 7 . 1705–14 . April 1996 . 8601636 . 507235 . 10.1172/JCI118597 .
• Bohm SK, Kong W, Bromme D, Smeekens SP, Anderson DC, Connolly A, Kahn M, Nelken NA, Coughlin SR, Payan DG, Bunnett NW . 6 . Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2 . The Biochemical Journal . 314 (Pt 3) . 3 . 1009–16 . March 1996 . 8615752 . 1217107 . 10.1042/bj3141009 .
• Böhm SK, Khitin LM, Grady EF, Aponte G, Payan DG, Bunnett NW . Mechanisms of desensitization and resensitization of proteinase-activated receptor-2 . The Journal of Biological Chemistry . 271 . 36 . 22003–16 . September 1996 . 8703006 . 10.1074/jbc.271.36.22003 . free .
• Kahn M, Ishii K, Kuo WL, Piper M, Connolly A, Shi YP, Wu R, Lin CC, Coughlin SR . 6 . Conserved structure and adjacent location of the thrombin receptor and protease-activated receptor 2 genes define a protease-activated receptor gene cluster . Molecular Medicine . 2 . 3 . 349–57 . May 1996 . 8784787 . 2230143 . 10.1007/BF03401632 .
• Molino M, Barnathan ES, Numerof R, Clark J, Dreyer M, Cumashi A, Hoxie JA, Schechter N, Woolkalis M, Brass LF . 6 . Interactions of mast cell tryptase with thrombin receptors and PAR-2 . The Journal of Biological Chemistry . 272 . 7 . 4043–9 . February 1997 . 9020112 . 10.1074/jbc.272.7.4043 . free .
• Howells GL, Macey MG, Chinni C, Hou L, Fox MT, Harriott P, Stone SR . Proteinase-activated receptor-2: expression by human neutrophils . Journal of Cell Science . 110 (Pt 7) . 7 . 881–7 . April 1997 . 10.1242/jcs.110.7.881 . 9133675 .
• D'Andrea MR, Derian CK, Leturcq D, Baker SM, Brunmark A, Ling P, Darrow AL, Santulli RJ, Brass LF, Andrade-Gordon P . 6 . Characterization of protease-activated receptor-2 immunoreactivity in normal human tissues . The Journal of Histochemistry and Cytochemistry . 46 . 2 . 157–64 . February 1998 . 9446822 . 10.1177/002215549804600204 . free .
• Guyonnet Dupérat V, Jacquelin B, Boisseau P, Arveiler B, Nurden AT . Protease-activated receptor genes are clustered on 5q13 . Blood . 92 . 1 . 25–31 . July 1998 . 9639495 . 10.1182/blood.V92.1.25.413k41_25_31 .
• Steinhoff M, Corvera CU, Thoma MS, Kong W, McAlpine BE, Caughey GH, Ansel JC, Bunnett NW . 6 . Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase . Experimental Dermatology . 8 . 4 . 282–94 . August 1999 . 10439226 . 10.1111/j.1600-0625.1999.tb00383.x . 8071759 .
• Takeuchi T, Harris JL, Huang W, Yan KW, Coughlin SR, Craik CS . Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates . The Journal of Biological Chemistry . 275 . 34 . 26333–42 . August 2000 . 10831593 . 10.1074/jbc.M002941200 . free .
• Loew D, Perrault C, Morales M, Moog S, Ravanat C, Schuhler S, Arcone R, Pietropaolo C, Cazenave JP, van Dorsselaer A, Lanza F . 6 . Proteolysis of the exodomain of recombinant protease-activated receptors: prediction of receptor activation or inactivation by MALDI mass spectrometry . Biochemistry . 39 . 35 . 10812–22 . September 2000 . 10978167 . 10.1021/bi0003341 .
• Knight DA, Lim S, Scaffidi AK, Roche N, Chung KF, Stewart GA, Thompson PJ . Protease-activated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma . The Journal of Allergy and Clinical Immunology . 108 . 5 . 797–803 . November 2001 . 11692107 . 10.1067/mai.2001.119025 .
• Miike S, McWilliam AS, Kita H . Trypsin induces activation and inflammatory mediator release from human eosinophils through protease-activated receptor-2 . Journal of Immunology . 167 . 11 . 6615–22 . December 2001 . 11714832 . 10.4049/jimmunol.167.11.6615 . free .
• Asokananthan N, Graham PT, Fink J, Knight DA, Bakker AJ, McWilliam AS, Thompson PJ, Stewart GA . 6 . 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 . April 2002 . 11907122 . 10.4049/jimmunol.168.7.3577 . free .
• Wong DM, Tam V, Lam R, Walsh KA, Tatarczuch L, Pagel CN, Reynolds EC, O'Brien-Simpson NM, Mackie EJ, Pike RN . 6 . Protease-activated receptor 2 has pivotal roles in cellular mechanisms involved in experimental periodontitis . Infection and Immunity . 78 . 2 . 629–38 . February 2010 . 19933835 . 2812191 . 10.1128/IAI.01019-09 .

External links

• Web site: Protease-Activated Receptors: PAR2 . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-12-09 . 2016-03-03 . https://web.archive.org/web/20160303170948/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=3020 . dead .

Notes and References

1. Lim J, Iyer A, Liu L, Suen JY, Lohman RJ, Seow V, Yau MK, Brown L, Fairlie DP . 6 . Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism . FASEB Journal . 27 . 12 . 4757–67 . December 2013 . 23964081 . 10.1096/fj.13-232702 . free . 30116494 .
2. Badeanlou L, Furlan-Freguia C, Yang G, Ruf W, Samad F . Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation . Nature Medicine . 17 . 11 . 1490–7 . October 2011 . 22019885 . 3210891 . 10.1038/nm.2461 .
3. Sébert M, Sola-Tapias N, Mas E, Barreau F, Ferrand A . Protease-Activated Receptors in the Intestine: Focus on Inflammation and Cancer . en . Frontiers in Endocrinology . 10 . 717 . 2019 . 31708870 . 10.3389/fendo.2019.00717 . 6821688 . free .
4. Jiang Y, Lim J, Wu KC, Xu W, Suen JY, Fairlie DP . PAR2 induces ovarian cancer cell motility by merging three signalling pathways to transactivate EGFR . British Journal of Pharmacology . November 2020 . 178 . 4 . 913–932 . 33226635 . 10.1111/bph.15332 . 227135487 . free .
5. Lee SE, Jeong SK, Lee SH . Protease and protease-activated receptor-2 signaling in the pathogenesis of atopic dermatitis . Yonsei Medical Journal . 51 . 6 . 808–22 . November 2010 . 20879045 . 2995962 . 10.3349/ymj.2010.51.6.808 .
6. Rattenholl A, Steinhoff M . Proteinase-activated receptor-2 in the skin: receptor expression, activation and function during health and disease . Drug News & Perspectives . 21 . 7 . 369–81 . September 2008 . 19259550 . 10.1358/dnp.2008.21.7.1255294 .
7. Web site: Entrez Gene: F2RL1 coagulation factor II (thrombin) receptor-like 1.
8. Guenther F, Melzig MF . Protease-activated receptors and their biological role - focused on skin inflammation . The Journal of Pharmacy and Pharmacology . 67 . 12 . 1623–33 . December 2015 . 26709036 . 10.1111/jphp.12447 . 26064678 . free .
9. Heuberger DM, Schuepbach RA . Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases . Thrombosis Journal . 17 . 1 . 4 . 2019-03-29 . 30976204 . 6440139 . 10.1186/s12959-019-0194-8 . free . Text was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
10. Kawabata A, Kanke T, Yonezawa D, Ishiki T, Saka M, Kabeya M, Sekiguchi F, Kubo S, Kuroda R, Iwaki M, Katsura K, Plevin R . 10806872 . 6 . 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 . June 2004 . 14976227 . 10.1124/jpet.103.061010 .
11. Mihara K, Ramachandran R, Saifeddine M, Hansen KK, Renaux B, Polley D, Gibson S, Vanderboor C, Hollenberg MD . 24834327 . 6 . Thrombin-Mediated Direct Activation of Proteinase-Activated Receptor-2: Another Target for Thrombin Signaling . Molecular Pharmacology . 89 . 5 . 606–14 . May 2016 . 26957205 . 10.1124/mol.115.102723 . free .
12. Akers IA, Parsons M, Hill MR, Hollenberg MD, Sanjar S, Laurent GJ, McAnulty RJ . 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 . January 2000 . 10645907 . 10.1152/ajplung.2000.278.1.l193 . 31697946 .
13. Caliendo G, Santagada V, Perissutti E, Severino B, Fiorino F, Frecentese F, Juliano L . Kallikrein protease activated receptor (PAR) axis: an attractive target for drug development . Journal of Medicinal Chemistry . 55 . 15 . 6669–86 . August 2012 . 22607152 . 10.1021/jm300407t .
14. Rayees S, Rochford I, Joshi JC, Joshi B, Banerjee S, Mehta D . Macrophage TLR4 and PAR2 Signaling: Role in Regulating Vascular Inflammatory Injury and Repair . en . Frontiers in Immunology . 11 . 2091 . 2020 . 33072072 . 10.3389/fimmu.2020.02091 . 7530636 . free .
15. Jiang Y, Lim J, Wu KC, Xu W, Suen JY, Fairlie DP . PAR2 induces ovarian cancer cell motility by merging three signalling pathways to transactivate EGFR . British Journal of Pharmacology . November 2020 . 178 . 4 . 913–932 . 33226635 . 10.1111/bph.15332 . 227135487 . free .
16. Guenther F, Melzig MF . Protease-activated receptors and their biological role - focused on skin inflammation . The Journal of Pharmacy and Pharmacology . 67 . 12 . 1623–33 . December 2015 . 26709036 . 10.1111/jphp.12447 . 26064678 . free .
17. Akers IA, Parsons M, Hill MR, Hollenberg MD, Sanjar S, Laurent GJ, McAnulty RJ . 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 . January 2000 . 10645907 . 10.1152/ajplung.2000.278.1.l193 . 31697946 .
18. Asokananthan N, Graham PT, Fink J, Knight DA, Bakker AJ, McWilliam AS, Thompson PJ, Stewart GA . 6 . 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 . April 2002 . 11907122 . 10.4049/jimmunol.168.7.3577 . free .
19. Hennessey JC, McGuire JJ . Attenuated vasodilator effectiveness of protease-activated receptor 2 agonist in heterozygous par2 knockout mice . PLOS ONE . 8 . 2 . e55965 . 2013-02-07 . 23409098 . 3567012 . 10.1371/journal.pone.0055965 . 2013PLoSO...855965H . free .
20. Book: Bar-Shavit R, Maoz M, Kancharla A, Jaber M, Agranovich D, Grisaru-Granovsky S, Uziely B . Protease-activated receptors (PARs) in cancer . G Protein-Coupled Receptors - Signaling, Trafficking and Regulation . Methods in Cell Biology . 132 . 341–58 . 2016 . 26928551 . 10.1016/bs.mcb.2015.11.006 . 9780128035955 .
21. Gardell LR, Ma JN, Seitzberg JG, Knapp AE, Schiffer HH, Tabatabaei A, Davis CN, Owens M, Clemons B, Wong KK, Lund B, Nash NR, Gao Y, Lameh J, Schmelzer K, Olsson R, Burstein ES . 3246903 . 6 . Identification and characterization of novel small-molecule protease-activated receptor 2 agonists . The Journal of Pharmacology and Experimental Therapeutics . 327 . 3 . 799–808 . December 2008 . 18768780 . 10.1124/jpet.108.142570 .
22. Barry GD, Suen JY, Le GT, Cotterell A, Reid RC, Fairlie DP . Novel agonists and antagonists for human protease activated receptor 2 . Journal of Medicinal Chemistry . 53 . 20 . 7428–40 . October 2010 . 20873792 . 10.1021/jm100984y .
23. Yau MK, Liu L, Suen JY, Lim J, Lohman RJ, Jiang Y, Cotterell AJ, Barry GD, Mak JY, Vesey DA, Reid RC, Fairlie DP . 6 . PAR2 Modulators Derived from GB88 . ACS Medicinal Chemistry Letters . 7 . 12 . 1179–1184 . December 2016 . 27994760 . 5150695 . 10.1021/acsmedchemlett.6b00306 .
24. Zhao P, Metcalf M, Bunnett NW . Biased signaling of protease-activated receptors . Frontiers in Endocrinology . 5 . 67 . 2014 . 24860547 . 4026716 . 10.3389/fendo.2014.00067 . free .
25. Jiang Y, Yau MK, Kok WM, Lim J, Wu KC, Liu L, Hill TA, Suen JY, Fairlie DP . 6 . Biased Signaling by Agonists of Protease Activated Receptor 2 . ACS Chemical Biology . 12 . 5 . 1217–1226 . May 2017 . 28169521 . 10.1021/acschembio.6b01088 .
26. Cheng RK, Fiez-Vandal C, Schlenker O, Edman K, Aggeler B, Brown DG, Brown GA, Cooke RM, Dumelin CE, Doré AS, Geschwindner S, Grebner C, Hermansson NO, Jazayeri A, Johansson P, Leong L, Prihandoko R, Rappas M, Soutter H, Snijder A, Sundström L, Tehan B, Thornton P, Troast D, Wiggin G, Zhukov A, Marshall FH, Dekker N . 4461925 . 6 . Structural insight into allosteric modulation of protease-activated receptor 2 . Nature . 545 . 7652 . 112–115 . May 2017 . 28445455 . 10.1038/nature22309 . 2017Natur.545..112C .
27. Kennedy AJ, Ballante F, Johansson JR, Milligan G, Sundström L, Nordqvist A, Carlsson J . Structural Characterization of Agonist Binding to Protease-Activated Receptor 2 through Mutagenesis and Computational Modeling . ACS Pharmacology & Translational Science . 1 . 2 . 119–133 . November 2018 . 32219208 . 10.1021/acsptsci.8b00019 . 7088944 . free .