Protease activated receptor 2 (PAR2) also known ascoagulation factor II (thrombin) receptor-like 1 (F2RL1) orG-protein coupled receptor 11 (GPR11) is aprotein that in humans is encoded by theF2RL1gene. 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 thestratum granulosum layer of epidermalkeratinocytes. Functional PAR2 is also expressed by several immune cells such aseosinophils,neutrophils,monocytes,macrophages,dendritic cells,mast cells andT cells.[11]
The F2RL1 gene contains twoexons and is widely expressed in human tissues. The predicted protein sequence is 83% identical to the mouse receptor sequence.[12]
PAR2 is a member of the large family of7-transmembrane receptors that couple to guanosine-nucleotide-binding proteins and also belongs to theprotease-activated receptor family. PAR2 is activated by several endogenous and exogenous proteases through proteolytic cleavage of its extracellular amino terminus between arginine and serine.[13] The newly exposedN-terminus serves as tethered activation ligand that binds to a conserved region on extracellular loop 2 (ECL2), thereby activating the receptor.[5] These receptors can also be activated non-proteolytically by exogenous peptide sequences that mimic the terminal amino acids of the tethered ligand.[14] Alternatively, cleavage by other proteases at non-signaling sites can render the receptor unresponsive 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 ofkallikreins, which have been related to various inflammatory and tumorigenic processes. In case of PAR2, particularly speaking aboutkallikrein-4,-5,-6 a-14.[17] PAR2 is known to transactivateTLR4[18] andepidermal growth factor receptor[19] in diseases.
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 increasedfibroblasts proliferation[21] and elevation ofIL‐6,IL‐8,PGE2 andCa2+ levels.[22] In mice it participates onvasodilatation.[23] Together withPAR1 its deregulation is also involved in processes of cancer cells migration and differentiation.[24]
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 throughmutagenesis andstructure-based drug design.[31]
^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.PMID19259550.
^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.PMID14976227.S2CID10806872.
^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.ISBN978-0-12-803595-5.PMID26928551.
^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.PMID18768780.S2CID3246903.
^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.PMID20873792.
Kunzelmann K, Schreiber R, König J, Mall M (2003). "Ion transport induced by proteinase-activated receptors (PAR2) in colon and airways".Cell Biochemistry and Biophysics.36 (2–3):209–14.doi:10.1385/CBB:36:2-3:209.PMID12139406.S2CID5801308.
Kawabata A (July 2002). "PAR-2: structure, function and relevance to human diseases of the gastric mucosa".Expert Reviews in Molecular Medicine.4 (16):1–17.doi:10.1017/S1462399402004799.PMID14585156.S2CID1485391.
Howells GL, Macey MG, Chinni C, Hou L, Fox MT, Harriott P, Stone SR (April 1997). "Proteinase-activated receptor-2: expression by human neutrophils".Journal of Cell Science. 110 ( Pt 7) (7):881–7.doi:10.1242/jcs.110.7.881.PMID9133675.
Guyonnet Dupérat V, Jacquelin B, Boisseau P, Arveiler B, Nurden AT (July 1998). "Protease-activated receptor genes are clustered on 5q13".Blood.92 (1):25–31.doi:10.1182/blood.V92.1.25.413k41_25_31.PMID9639495.
Steinhoff M, Corvera CU, Thoma MS, Kong W, McAlpine BE, Caughey GH, et al. (August 1999). "Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase".Experimental Dermatology.8 (4):282–94.doi:10.1111/j.1600-0625.1999.tb00383.x.PMID10439226.S2CID8071759.
Loew D, Perrault C, Morales M, Moog S, Ravanat C, Schuhler S, et al. (September 2000). "Proteolysis of the exodomain of recombinant protease-activated receptors: prediction of receptor activation or inactivation by MALDI mass spectrometry".Biochemistry.39 (35):10812–22.doi:10.1021/bi0003341.PMID10978167.
Knight DA, Lim S, Scaffidi AK, Roche N, Chung KF, Stewart GA, Thompson PJ (November 2001). "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.doi:10.1067/mai.2001.119025.PMID11692107.
"Protease-Activated Receptors: PAR2".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2016-03-03. Retrieved2008-12-09.
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