Biology:Protease-activated receptor 2

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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,[1] obesity,[2] metabolism,[3] cancers [4][5] and acts as a sensor for proteolytic enzymes generated during infection.[6] 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.[7]

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.[8]

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.[9] The newly exposed N-terminus serves as tethered activation ligand, which binds a conserved region on extracellular loop 2 (ECL2) and activates the receptor.[1] 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.[1] 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

References

  1. ↑ 1.0 1.1 1.2 "Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases". Thrombosis Journal 17 (1): 4. 2019-03-29. doi:10.1186/s12959-019-0194-8. PMID 30976204.  CC-BY icon.svg Text was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
  2. ↑ "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. doi:10.1096/fj.13-232702. PMID 23964081. 
  3. ↑ "Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation". Nature Medicine 17 (11): 1490–7. October 2011. doi:10.1038/nm.2461. PMID 22019885. 
  4. ↑ "Protease-Activated Receptors in the Intestine: Focus on Inflammation and Cancer" (in en). Frontiers in Endocrinology 10: 717. 2019. doi:10.3389/fendo.2019.00717. PMID 31708870. 
  5. ↑ "PAR2 induces ovarian cancer cell motility by merging three signalling pathways to transactivate EGFR". British Journal of Pharmacology 178 (4): 913–932. November 2020. doi:10.1111/bph.15332. PMID 33226635. 
  6. ↑ "Protease and protease-activated receptor-2 signaling in the pathogenesis of atopic dermatitis". Yonsei Medical Journal 51 (6): 808–22. November 2010. doi:10.3349/ymj.2010.51.6.808. PMID 20879045. 
  7. ↑ "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. doi:10.1358/dnp.2008.21.7.1255294. PMID 19259550. 
  8. ↑ "Entrez Gene: F2RL1 coagulation factor II (thrombin) receptor-like 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2150. 
  9. ↑ "Protease-activated receptors and their biological role - focused on skin inflammation". The Journal of Pharmacy and Pharmacology 67 (12): 1623–33. December 2015. doi:10.1111/jphp.12447. PMID 26709036. 
  10. ↑ "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. doi:10.1124/jpet.103.061010. PMID 14976227. 
  11. ↑ "Thrombin-Mediated Direct Activation of Proteinase-Activated Receptor-2: Another Target for Thrombin Signaling". Molecular Pharmacology 89 (5): 606–14. May 2016. doi:10.1124/mol.115.102723. PMID 26957205. 
  12. ↑ "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. doi:10.1152/ajplung.2000.278.1.l193. PMID 10645907. 
  13. ↑ "Kallikrein protease activated receptor (PAR) axis: an attractive target for drug development". Journal of Medicinal Chemistry 55 (15): 6669–86. August 2012. doi:10.1021/jm300407t. PMID 22607152. 
  14. ↑ "Macrophage TLR4 and PAR2 Signaling: Role in Regulating Vascular Inflammatory Injury and Repair" (in en). Frontiers in Immunology 11: 2091. 2020. doi:10.3389/fimmu.2020.02091. PMID 33072072. 
  15. ↑ "PAR2 induces ovarian cancer cell motility by merging three signalling pathways to transactivate EGFR". British Journal of Pharmacology 178 (4): 913–932. November 2020. doi:10.1111/bph.15332. PMID 33226635. 
  16. ↑ "Protease-activated receptors and their biological role - focused on skin inflammation". The Journal of Pharmacy and Pharmacology 67 (12): 1623–33. December 2015. doi:10.1111/jphp.12447. PMID 26709036. 
  17. ↑ "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. doi:10.1152/ajplung.2000.278.1.l193. PMID 10645907. 
  18. ↑ "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. doi:10.4049/jimmunol.168.7.3577. PMID 11907122. 
  19. ↑ "Attenuated vasodilator effectiveness of protease-activated receptor 2 agonist in heterozygous par2 knockout mice". PLOS ONE 8 (2): e55965. 2013-02-07. doi:10.1371/journal.pone.0055965. PMID 23409098. Bibcode: 2013PLoSO...855965H. 
  20. ↑ "Protease-activated receptors (PARs) in cancer". G Protein-Coupled Receptors - Signaling, Trafficking and Regulation. Methods in Cell Biology. 132. 2016. pp. 341–58. doi:10.1016/bs.mcb.2015.11.006. ISBN 9780128035955. 
  21. ↑ "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. doi:10.1124/jpet.108.142570. PMID 18768780. 
  22. ↑ "Novel agonists and antagonists for human protease activated receptor 2". Journal of Medicinal Chemistry 53 (20): 7428–40. October 2010. doi:10.1021/jm100984y. PMID 20873792. 
  23. ↑ "PAR2 Modulators Derived from GB88". ACS Medicinal Chemistry Letters 7 (12): 1179–1184. December 2016. doi:10.1021/acsmedchemlett.6b00306. PMID 27994760. 
  24. ↑ "Biased signaling of protease-activated receptors". Frontiers in Endocrinology 5: 67. 2014. doi:10.3389/fendo.2014.00067. PMID 24860547. 
  25. ↑ "Biased Signaling by Agonists of Protease Activated Receptor 2". ACS Chemical Biology 12 (5): 1217–1226. May 2017. doi:10.1021/acschembio.6b01088. PMID 28169521. https://espace.library.uq.edu.au/view/UQ:635773/acschembio2017.pdf. 
  26. ↑ "Structural insight into allosteric modulation of protease-activated receptor 2". Nature 545 (7652): 112–115. May 2017. doi:10.1038/nature22309. PMID 28445455. Bibcode: 2017Natur.545..112C. 
  27. ↑ "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. doi:10.1021/acsptsci.8b00019. PMID 32219208. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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