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ADGRE2

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 183

Nomenclature: ADGRE2

Family: Adhesion Class GPCRs

Contents:

Gene and Protein Information Click here for help
Adhesion G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 823 19p13.12 ADGRE2 adhesion G protein-coupled receptor E2 15,17,20
Previous and Unofficial Names Click here for help
EMR2 (EGF-like module-containing, mucin-like, hormone receptor-like 2) | CD312 (cluster of differentiation 312)
Database Links Click here for help
Specialist databases
GPCRdb agre2_human (Hs)
Other databases
Alphafold Q9UHX3 (Hs)
Ensembl Gene ENSG00000127507 (Hs)
Entrez Gene 30817 (Hs)
Human Protein Atlas ENSG00000127507 (Hs)
KEGG Gene hsa:30817 (Hs)
OMIM 606100 (Hs)
Pharos Q9UHX3 (Hs)
RefSeq Nucleotide NM_013447 (Hs)
RefSeq Protein NP_038475 (Hs)
UniProtKB Q9UHX3 (Hs)
Wikipedia ADGRE2 (Hs)
Associated Protein Comments
Extracellular interactors: FHR1 (CFHR1; Q03591) [13].
Agonist Comments
No ligands identified: orphan receptor. No data found to show chondroitin sulfate B can act as an agonist at this receptor when tested by [18,22].
Immunopharmacology Comments
ADGRE2 is included in GtoImmuPdb because its tissue expression profile and its ability to activate secretion of inflammatory cytokines (IL-8, TNF) by monocytes and macrophages [12] suggest an involvement in inflammation.
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gq/G11 family
Comments:  Induces inositiol phosphate accumulation when co-transfected with Gα15. Yeast-based assay data showed broad G protein-coupling [3].
References:  11
Tissue Distribution Click here for help
Spleen, lymph node, peripheral blood leukocyte, lung, bone marrow, fetal liver
Species:  Human
Technique:  Northern blot
References:  20
All types of myeloid cells including monocytes, monocyte-derived macrophages, myeloid dendritic cells and neutrophilic, basophilic and eosinophilic granulocytes, upregulated during differentiation and maturation of macrophages and in neutrophils in patients with systemic inflammation, expressed by hematopoietic stem and progenitor cells
Species:  Human
Technique:  Flow cytometry
References:  6,9-10,15,24
Tissue macrophages in skin, spleen (red-pulp macrophages), tonsil, lung and placenta (interstitial macrophages)
Species:  Human
Technique:  Immunohistochemistry
References:  15
Subsets of infiltrating macrophages, dendritic cells and neutrophilic granulocytes in rheumatoid arthritis, in liver and lung abscesses, in severe acute suppurative appendicitis and in atherosclerosis
Species:  Human
Technique:  Immunohistochemistry
References:  6,14,23
Expression in breast carcinomas, weak expression in colorectal adenocarcinomas, not expressed in esophageal, gastric and pancreatic carcinomas
Species:  Human
Technique:  Immunocytochemistry
References:  1-2,8
Functional Assays Click here for help
Elevated neutrophil migration, and augmented superoxide production/proteolytic enzyme degranulation
Species:  Human
Tissue:  Neutrophils
Response measured:  Elevated in-vitro migration/superoxide production
References:  7,24
Activates monocytes and macrophages to secrete inflammatory cytokines (IL-8, TNF)
Species:  Human
Tissue:  Monocytes, macrophages
Response measured:  Elevated cytokine secretion
References:  12
Physiological Functions Click here for help
Increases neutrophil adhesion and migration, and augments superoxide production and proteolytic enzyme degranulation by potentiating the effects of proinflammatory mediators
Species:  Human
Tissue:  Neutrophilic granulocytes
References:  7,24
FHR1 triggers the phospholipase C-pathway via ADGRE2 independent of complement.
Species:  Human
Tissue:  Peripheral blood monocytes
References:  13
Gene Expression and Pathophysiology Comments
Vibratory urticaria is associated with a missense variant in ADGRE2 [5].
Biologically Significant Variants Click here for help
Type:  Splice variant
Species:  Human
Description:  Full-length isoform with 5 EGF-like domains (EGF1-5), binds chondroitin sulfate B
Amino acids:  823
Nucleotide accession:  NM_013447
Protein accession:  NP_038475
References:  1,20-22
Type:  Splice variant
Species:  Human
Description:  Isoform with 4 EGF-like domains (EGF1,2,3,5), does not bind chondroitin sulfate B
Amino acids:  774
References:  1,20-22
Type:  Splice variant
Species:  Human
Description:  Isoform with 3 EGF-like domains (EGF1,2,5), does not bind chondroitin sulfate B
Amino acids:  730
References:  1,20-22
Type:  Splice variant
Species:  Human
Description:  Isoform with 2 EGF-like domains (EGF1,2), does not bind chondroitin sulfate B
Amino acids:  681
References:  1,20-22
Biologically Significant Variant Comments
The interaction with chondroitin sulfate B is mediated by the 4th EGF-like domain [1].
General Comments
ADGRE2 (adhesion G protein-coupled receptor E2, formerly known as EMR2: EGF-like module containing, mucin-like, hormone receptor-like 2) is a receptor that belongs to Family II Adhesion-GPCRs together with CD97 and ADGRE1, ADGRE3 and ADGRE4 [4,16]. The genes of Family II Adhesion-GPCRs are syntenically clustered on human chromosome 19 suggesting the evolution from an ancestral gene through gene duplication and exon shuffling [17]. No mouse or rat ADGRE2 orthologues exist. ADGRE2 possesses a chimeric structure with a seven-span transmembrane region most related to ADGRE3 and an EGF-like domain region nearly identical to ADGRE5 [20]. This structure has evolved by gene conversion between the ADGRE2 gene and the oppositely orientated and physically adjacent genes ADGRE5 and ADGRE3 [17]. Most highly conserved between ADGRE2 and ADGRE5 is the 4th EGF-like domain, which mediates binding to chondroitin sulfate, a ligand shared by both receptors [22].

There are three well characterized amino acid-changing SNPs.

Full coding sequence human cDNA is publicly available, IMAGE:8317326 [19] in mammalian expression vector pCDNA3.1. This clone differs from the RefSeq and human reference genomic sequence at a know SNP. It has the less common Phe614 allele.

References

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1. Aust G, Hamann J, Schilling N, Wobus M. (2003) Detection of alternatively spliced EMR2 mRNAs in colorectal tumor cell lines but rare expression of the molecule in colorectal adenocarcinomas. Virchows Arch, 443 (1): 32-7. [PMID:12761622]

2. Aust G, Steinert M, Schütz A, Boltze C, Wahlbuhl M, Hamann J, Wobus M. (2002) CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on gastric, pancreatic, and esophageal carcinomas. Am J Clin Pathol, 118 (5): 699-707. [PMID:12428789]

3. Bhudia N, Desai S, King N, Ancellin N, Grillot D, Barnes AA, Dowell SJ. (2020) Author Correction: G Protein-Coupling of Adhesion GPCRs ADGRE2/EMR2 and ADGRE5/CD97, and Activation of G Protein Signalling by an Anti-EMR2 Antibody. Sci Rep, 10 (1): 5097. [PMID:32184438]

4. Bjarnadóttir TK, Fredriksson R, Höglund PJ, Gloriam DE, Lagerström MC, Schiöth HB. (2004) The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. Genomics, 84 (1): 23-33. [PMID:15203201]

5. Boyden SE, Desai A, Cruse G, Young ML, Bolan HC, Scott LM, Eisch AR, Long RD, Lee CC, Satorius CL et al.. (2016) Vibratory Urticaria Associated with a Missense Variant in ADGRE2. N Engl J Med, 374 (7): 656-63. [PMID:26841242]

6. Chang GW, Davies JQ, Stacey M, Yona S, Bowdish DM, Hamann J, Chen TC, Lin CY, Gordon S, Lin HH. (2007) CD312, the human adhesion-GPCR EMR2, is differentially expressed during differentiation, maturation, and activation of myeloid cells. Biochem Biophys Res Commun, 353 (1): 133-8. [PMID:17174274]

7. Chen TY, Hwang TL, Lin CY, Lin TN, Lai HY, Tsai WP, Lin HH. (2011) EMR2 receptor ligation modulates cytokine secretion profiles and cell survival of lipopolysaccharide-treated neutrophils. Chang Gung Med J, 34 (5): 468-77. [PMID:22035891]

8. Davies JQ, Lin HH, Stacey M, Yona S, Chang GW, Gordon S, Hamann J, Campo L, Han C, Chan P et al.. (2011) Leukocyte adhesion-GPCR EMR2 is aberrantly expressed in human breast carcinomas and is associated with patient survival. Oncol Rep, 25 (3): 619-27. [PMID:21174063]

9. Florian S, Sonneck K, Czerny M, Hennersdorf F, Hauswirth AW, Bühring HJ, Valent P. (2006) Detection of novel leukocyte differentiation antigens on basophils and mast cells by HLDA8 antibodies. Allergy, 61 (9): 1054-62. [PMID:16918507]

10. Glaeser RM, Zilker A, Radermacher M, Gaub HE, Hartmann T, Baumeister W. (1991) Interfacial energies and surface-tension forces involved in the preparation of thin, flat crystals of biological macromolecules for high-resolution electron microscopy. J Microsc, 161 (Pt 1): 21-45. [PMID:2016735]

11. Gupte J, Swaminath G, Danao J, Tian H, Li Y, Wu X. (2012) Signaling property study of adhesion G-protein-coupled receptors. FEBS Lett, 586 (8): 1214-9. [PMID:22575658]

12. Huang YS, Chiang NY, Hu CH, Hsiao CC, Cheng KF, Tsai WP, Yona S, Stacey M, Gordon S, Chang GW et al.. (2012) Activation of myeloid cell-specific adhesion class G protein-coupled receptor EMR2 via ligation-induced translocation and interaction of receptor subunits in lipid raft microdomains. Mol Cell Biol, 32 (8): 1408-20. [PMID:22310662]

13. Irmscher S, Brix SR, Zipfel SLH, Halder LD, Mutlutürk S, Wulf S, Girdauskas E, Reichenspurner H, Stahl RAK, Jungnickel B et al.. (2019) Serum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies. Nat Commun, 10 (1): 2961. [PMID:31273197]

14. Kop EN, Kwakkenbos MJ, Teske GJ, Kraan MC, Smeets TJ, Stacey M, Lin HH, Tak PP, Hamann J. (2005) Identification of the epidermal growth factor-TM7 receptor EMR2 and its ligand dermatan sulfate in rheumatoid synovial tissue. Arthritis Rheum, 52 (2): 442-50. [PMID:15693006]

15. Kwakkenbos MJ, Chang GW, Lin HH, Pouwels W, de Jong EC, van Lier RA, Gordon S, Hamann J. (2002) The human EGF-TM7 family member EMR2 is a heterodimeric receptor expressed on myeloid cells. J Leukoc Biol, 71 (5): 854-62. [PMID:11994511]

16. Kwakkenbos MJ, Kop EN, Stacey M, Matmati M, Gordon S, Lin HH, Hamann J. (2004) The EGF-TM7 family: a postgenomic view. Immunogenetics, 55 (10): 655-66. [PMID:14647991]

17. Kwakkenbos MJ, Matmati M, Madsen O, Pouwels W, Wang Y, Bontrop RE, Heidt PJ, Hoek RM, Hamann J. (2006) An unusual mode of concerted evolution of the EGF-TM7 receptor chimera EMR2. FASEB J, 20 (14): 2582-4. [PMID:17068111]

18. Kwakkenbos MJ, Pouwels W, Matmati M, Stacey M, Lin HH, Gordon S, van Lier RA, Hamann J. (2005) Expression of the largest CD97 and EMR2 isoforms on leukocytes facilitates a specific interaction with chondroitin sulfate on B cells. J Leukoc Biol, 77 (1): 112-9. [PMID:15498814]

19. Lennon G, Auffray C, Polymeropoulos M, Soares MB. (1996) The I.M.A.G.E. Consortium: an integrated molecular analysis of genomes and their expression. Genomics, 33 (1): 151-2. [PMID:8617505]

20. Lin HH, Stacey M, Hamann J, Gordon S, McKnight AJ. (2000) Human EMR2, a novel EGF-TM7 molecule on chromosome 19p13.1, is closely related to CD97. Genomics, 67 (2): 188-200. [PMID:10903844]

21. Lin HH, Stacey M, Saxby C, Knott V, Chaudhry Y, Evans D, Gordon S, McKnight AJ, Handford P, Lea S. (2001) Molecular analysis of the epidermal growth factor-like short consensus repeat domain-mediated protein-protein interactions: dissection of the CD97-CD55 complex. J Biol Chem, 276 (26): 24160-9. [PMID:11297558]

22. Stacey M, Chang GW, Davies JQ, Kwakkenbos MJ, Sanderson RD, Hamann J, Gordon S, Lin HH. (2003) The epidermal growth factor-like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans. Blood, 102 (8): 2916-24. [PMID:12829604]

23. van Eijk M, Aust G, Brouwer MS, van Meurs M, Voerman JS, Dijke IE, Pouwels W, Sändig I, Wandel E, Aerts JM, Boot RG, Laman JD, Hamann J. (2010) Differential expression of the EGF-TM7 family members CD97 and EMR2 in lipid-laden macrophages in atherosclerosis, multiple sclerosis and Gaucher disease. Immunol Lett, 129 (2): 64-71. [PMID:20167235]

24. Yona S, Lin HH, Dri P, Davies JQ, Hayhoe RP, Lewis SM, Heinsbroek SE, Brown KA, Perretti M, Hamann J et al.. (2008) Ligation of the adhesion-GPCR EMR2 regulates human neutrophil function. FASEB J, 22 (3): 741-51. [PMID:17928360]

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