Protease-activated receptor 2

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.

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. The newly exposed N-terminus serves as tethered activation ligand, which binds a conserved region on extracellular loop 2 (ECL2) and activates the receptor. These receptors can also be activated non-proteolytically, by exogenous peptide sequences that mimic the final amino acids of the tethered ligand, 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. Another PAR2 cleaving protease is tryptase, the main protease of mast cells, which by PAR2 proteolytic cleavage induces calcium signaling and proliferation. 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. PAR2 is known to transactivate TLR4 and epidermal growth factor receptor in diseases.

Function

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

Agonists and antagonists

Potent and selective small molecule agonists and antagonists for PAR2 have been discovered.

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

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

References

References

1. (December 2013). "Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism". FASEB Journal.
2. (October 2011). "Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation". Nature Medicine.
3. (2019). "Protease-Activated Receptors in the Intestine: Focus on Inflammation and Cancer". Frontiers in Endocrinology.
4. (November 2020). "PAR2 induces ovarian cancer cell motility by merging three signalling pathways to transactivate EGFR". British Journal of Pharmacology.
5. (November 2010). "Protease and protease-activated receptor-2 signaling in the pathogenesis of atopic dermatitis". Yonsei Medical Journal.
6. (September 2008). "Proteinase-activated receptor-2 in the skin: receptor expression, activation and function during health and disease". Drug News & Perspectives.
7. "Entrez Gene: F2RL1 coagulation factor II (thrombin) receptor-like 1".
8. (December 2015). "Protease-activated receptors and their biological role - focused on skin inflammation". The Journal of Pharmacy and Pharmacology.
9. (2019-03-29). "Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases". Thrombosis Journal.
10. (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.
11. (May 2016). "Thrombin-Mediated Direct Activation of Proteinase-Activated Receptor-2: Another Target for Thrombin Signaling". Molecular Pharmacology.
12. (January 2000). "Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2". American Journal of Physiology. Lung Cellular and Molecular Physiology.
13. (August 2012). "Kallikrein protease activated receptor (PAR) axis: an attractive target for drug development". Journal of Medicinal Chemistry.
14. (2020). "Macrophage TLR4 and PAR2 Signaling: Role in Regulating Vascular Inflammatory Injury and Repair". Frontiers in Immunology.
15. (November 2020). "PAR2 induces ovarian cancer cell motility by merging three signalling pathways to transactivate EGFR". British Journal of Pharmacology.
16. (December 2015). "Protease-activated receptors and their biological role - focused on skin inflammation". The Journal of Pharmacy and Pharmacology.
17. (January 2000). "Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2". American Journal of Physiology. Lung Cellular and Molecular Physiology.
18. (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.
19. (2013-02-07). "Attenuated vasodilator effectiveness of protease-activated receptor 2 agonist in heterozygous par2 knockout mice". PLOS ONE.
20. (2016). "G Protein-Coupled Receptors - Signaling, Trafficking and Regulation".
21. (December 2008). "Identification and characterization of novel small-molecule protease-activated receptor 2 agonists". The Journal of Pharmacology and Experimental Therapeutics.
22. (October 2010). "Novel agonists and antagonists for human protease activated receptor 2". Journal of Medicinal Chemistry.
23. (December 2016). "PAR2 Modulators Derived from GB88". ACS Medicinal Chemistry Letters.
24. (2014). "Biased signaling of protease-activated receptors". Frontiers in Endocrinology.
25. (May 2017). "Biased Signaling by Agonists of Protease Activated Receptor 2". ACS Chemical Biology.
26. (May 2017). "Structural insight into allosteric modulation of protease-activated receptor 2". Nature.
27. (November 2018). "Structural Characterization of Agonist Binding to Protease-Activated Receptor 2 through Mutagenesis and Computational Modeling". ACS Pharmacology & Translational Science.