Protease-activated receptor 2

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
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q13.3 Start 76,818,933 bp[1] End 76,835,315 bp[1]
Gene location (Mouse) Chr. Chromosome 13 (mouse)[2] Band 13 D1|13 49.53 cM Start 95,648,240 bp[2] End 95,661,735 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in jejunal mucosa duodenum kidney tubule rectum islet of Langerhans nipple caput epididymis seminal vesicula human penis vulva Top expressed in epithelium of stomach left colon pineal gland ileum corneal stroma mucous cell of stomach pyloric antrum jejunum lip duodenum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled receptor activity signal transducer activity thrombin-activated receptor activity G-protein beta-subunit binding protein binding G-protein alpha-subunit binding signaling receptor binding signaling receptor activity Cellular component integral component of membrane Golgi apparatus pseudopodium membrane plasma membrane integral component of plasma membrane early endosome Biological process positive regulation of Rho protein signal transduction establishment of endothelial barrier thrombin-activated receptor signaling pathway neutrophil activation positive regulation of phagocytosis, engulfment positive regulation of toll-like receptor 3 signaling pathway positive regulation of eosinophil degranulation positive regulation of neutrophil mediated killing of gram-negative bacterium negative regulation of tumor necrosis factor-mediated signaling pathway immune system process positive regulation of cell migration positive regulation of cytosolic calcium ion concentration blood coagulation positive regulation of JNK cascade positive regulation of leukocyte chemotaxis negative regulation of JNK cascade leukocyte proliferation regulation of JNK cascade positive regulation of pseudopodium assembly positive regulation of renin secretion into blood stream defense response to virus positive regulation of chemotaxis positive regulation of ERK1 and ERK2 cascade positive regulation of toll-like receptor 4 signaling pathway positive regulation of I-kappaB kinase/NF-kappaB signaling positive regulation of toll-like receptor 2 signaling pathway positive regulation of phosphatidylinositol 3-kinase signaling positive regulation of superoxide anion generation positive regulation of glomerular filtration regulation of blood coagulation inflammatory response innate immune response mature conventional dendritic cell differentiation negative regulation of toll-like receptor 3 signaling pathway positive regulation of actin filament depolymerization leukocyte migration regulation of I-kappaB kinase/NF-kappaB signaling positive regulation of transcription by RNA polymerase II positive regulation of positive chemotaxis signal transduction T cell activation involved in immune response positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway G protein-coupled receptor signaling pathway positive regulation of GTPase activity cell-cell junction maintenance Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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]
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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]

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

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

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

References

Further reading

External links

• "Protease-Activated Receptors: PAR2". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2008-12-09.

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