Protease-activated receptor 2

Last updated
F2RL1
Identifiers
Aliases F2RL1 , GPR11, PAR2, Protease activated receptor 2, F2R like trypsin receptor 1
External IDs OMIM: 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 Mb Chr 13: 95.65 – 95.66 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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]

Contents

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 Activation vs silencing of PAR.png
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

Related Research Articles

Protease-activated receptors (PAR) are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain. They are highly expressed in platelets, and also on endothelial cells, fibroblasts, immune cells, myocytes, neurons, and tissues that line the gastrointestinal tract.

<span class="mw-page-title-main">Tryptase</span> Class of enzymes

Tryptase is the most abundant secretory granule-derived serine proteinase contained in mast cells and has been used as a marker for mast cell activation. Club cells contain tryptase, which is believed to be responsible for cleaving the hemagglutinin surface protein of influenza A virus, thereby activating it and causing the symptoms of flu.

<span class="mw-page-title-main">Complement component 5a</span> Protein fragment

C5a is a protein fragment released from cleavage of complement component C5 by protease C5-convertase into C5a and C5b fragments. C5b is important in late events of the complement cascade, an orderly series of reactions which coordinates several basic defense mechanisms, including formation of the membrane attack complex (MAC), one of the most basic weapons of the innate immune system, formed as an automatic response to intrusions from foreign particles and microbial invaders. It essentially pokes microscopic pinholes in these foreign objects, causing loss of water and sometimes death. C5a, the other cleavage product of C5, acts as a highly inflammatory peptide, encouraging complement activation, formation of the MAC, attraction of innate immune cells, and histamine release involved in allergic responses. The origin of C5 is in the hepatocyte, but its synthesis can also be found in macrophages, where it may cause local increase of C5a. C5a is a chemotactic agent and an anaphylatoxin; it is essential in the innate immunity but it is also linked with the adaptive immunity. The increased production of C5a is connected with a number of inflammatory diseases.

5-HT<sub>2A</sub> receptor Subtype of serotonin receptor

The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations.

<span class="mw-page-title-main">Cathepsin S</span> Protein-coding gene in the species Homo sapiens

Cathepsin S is a protein that in humans is encoded by the CTSS gene. Transcript variants utilizing alternative polyadenylation signals exist for this gene.

Kininogens are precursor proteins for kinins, biologically active polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, inflammatory regulation, and the regulation of the cardiovascular and renal systems.

<span class="mw-page-title-main">Thrombin receptor</span>

There are three known thrombin receptors (ThrR), termed PAR1, PAR3 and PAR4.

<span class="mw-page-title-main">Thromboxane receptor</span> Mammalian protein found in Homo sapiens

The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.

<span class="mw-page-title-main">C5a receptor</span> Mammalian protein found in Homo sapiens

The C5a receptor also known as complement component 5a receptor 1 (C5AR1) or CD88 is a G protein-coupled receptor for C5a. It functions as a complement receptor. C5a receptor 1 modulates inflammatory responses, obesity, development and cancers. From a signaling transduction perspective, C5a receptor 1 activation is implicated in β-arrestin2 recruitment via Rab5a, coupling of Gαi proteins, ERK1/2 phosphorylation, calcium mobilization and Rho activation leading to downstream functions, such as secretion of cytokines, chemotaxis, and phagocytosis.

<span class="mw-page-title-main">Toll-like receptor 4</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 4 (TLR4), also designated as CD284, is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approximately 95 kDa that is encoded by the TLR4 gene.

<span class="mw-page-title-main">TRPA1</span> Protein and coding gene in humans

Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1, TRPA1, or The Wasabi Receptor, is a protein that in humans is encoded by the TRPA1 gene.

Prostaglandin EP<sub>4</sub> receptor Protein-coding gene in the species Homo sapiens

Prostaglandin E2 receptor 4 (EP4) is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the PTGER4 gene in humans; it is one of four identified EP receptors, the others being EP1, EP2, and EP3, all of which bind with and mediate cellular responses to PGE2 and also, but generally with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP4 has been implicated in various physiological and pathological responses in animal models and humans.

<span class="mw-page-title-main">F2RL2</span> Protein-coding gene in the species Homo sapiens

Protease activated receptor 3 (PAR-3) also known as coagulation factor II receptor-like 2 (F2RL2) and thrombin receptor-like 2, is a protein that in humans is encoded by the F2RL2 gene.

<span class="mw-page-title-main">Coagulation factor II receptor</span> Mammalian protein found in humans

Proteinase-activated receptor 1 (PAR1) also known as protease-activated receptor 1 or coagulation factor II (thrombin) receptor is a protein that in humans is encoded by the F2R gene. PAR1 is a G protein-coupled receptor and one of four protease-activated receptors involved in the regulation of thrombotic response. Highly expressed in platelets and endothelial cells, PAR1 plays a key role in mediating the interplay between coagulation and inflammation, which is important in the pathogenesis of inflammatory and fibrotic lung diseases. It is also involved both in disruption and maintenance of endothelial barrier integrity, through interaction with either thrombin or activated protein C, respectively.

<span class="mw-page-title-main">F2RL3</span> Protein-coding gene in the species Homo sapiens

Protease-activated receptor 4 (PAR-4), also known as coagulation factor II (thrombin) receptor-like 3, is a protein that in humans is encoded by the F2RL3 gene.

<span class="mw-page-title-main">Endothelial protein C receptor</span> Protein-coding gene in the species Homo sapiens

Endothelial protein C receptor (EPCR) also known as activated protein C receptor is a protein that in humans is encoded by the PROCR gene. PROCR has also recently been designated CD201.

<span class="mw-page-title-main">Thymic stromal lymphopoietin</span> Cytokine, alarmin, and growth factor.

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-2-like cytokine, alarmin, and growth factor involved in numerous physiological and pathological processes, primarily those of the immune system. It shares a common ancestor with IL-7.

<span class="mw-page-title-main">PAR1 (gene)</span>

Prader-Willi/Angelman region-1, also known as PWAR1, is an exon of the lncRNA Small nucleolar RNA host gene 14 (SNHG14).

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

<span class="mw-page-title-main">SCH-79797</span> Chemical compound

SCH-79797 is a drug which acts as a potent and selective antagonist of the thrombin receptor proteinase activated receptor 1 (PAR1). It has anticoagulant, anticonvulsant and antiinflammatory effects and has been researched as a treatment for heart attack and stroke, though never developed for medical use. It also shows antibiotic actions which are not shared with other PAR1 antagonists such as vorapaxar, so may be mediated through a different target than PAR1.

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. CC-BY icon.svg 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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