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词条 EMR2
释义

  1. Ligand

  2. Signaling

  3. Function

  4. Clinical significance

  5. See also

  6. References

  7. External links

{{Infobox_gene}}EGF-like module-containing mucin-like hormone receptor-like 2 also known as CD312 (cluster of differentiation 312) is a protein encoded by the ADGRE2 gene.[1] EMR2 is a member of the adhesion GPCR family.[2][3]

Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.[4]

EMR2 is expressed by monocytes/macrophages, dendritic cells and all types of granulocytes.[5] In the case of EMR2 the N-terminal domains consist of alternatively spliced epidermal growth factor-like (EGF-like) domains. EMR2 is closely related to CD97 with 97% amino-acid identity in the EGF-like domains. The N-terminal fragment (NTF) of EMR2 presents 2-5 EGF-like domains in human.[6] Mice lack the Emr2 gene.[7] This gene is closely linked to the gene encoding EGF-like molecule containing mucin-like hormone receptor 3 EMR3 on chromosome 19.

Ligand

Like the related CD97 protein, the fourth EGF-like domain of EMR2 binds chondroitin sulfate B to mediate cell attachment.[8] However, unlike CD97 EMR2 does not interact with the complement regulatory protein, decay accelerating factor CD55, and indicating that these very closely related proteins likely have nonredundant functions.[9]

Signaling

Inositol phosphate (IP3) accumulation assays in overexpressing HEK293 cells have demonstrated coupling of EMR2 to Gα15.[10] EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2) is an adhesion GPCR that undergoes GPS autoproteolysis before being trafficked to the plasma membrane.[11] Further, distribution, translocation, co-localization of the N-terminal fragment (NTF) and N-terminal fragment (CTF) of EMR2 within lipid rafts may affect cell signaling.[12] Mutations in the GPS have shown that EMR2 does not need to undergo autoproteolysis to be trafficked, but loses function. EMR2 has been shown to be necessary for in vitro cell migration. Upon cleavage the N-terminus has been shown to associate with the 7TM, but to also dissociate, giving two possible functions. When the N-terminus dissociates it can be found in lipid rafts. Additionally, the cleaved EMR2 protein 7TM has been found to associate with EMR4 N-terminus.

Function

The expression of EMR2 and CD97 on activated lymphocytes and myeloid cells promotes binding with their ligand chondroitin sulfate B on peripheral B cells, indicating a role in leukocyte interaction.[13] The interaction between EMR2 and chondroitin sulfate B in inflamed rheumatoid synovial tissue suggests a role of the receptors in the recruitment and retention of leukocytes in synovium of arthritis patients.[14] Upon neutrophil activation, EMR2 rapidly moves to membrane ruffles and the leading edge of the cell. Additionally, ligation of EMR2 by antibody promotes neutrophil and macrophage effector functions suggesting a role in potentiating inflammatory responses.[12][15]

Clinical significance

EMR2 is rarely expressed by tumor cell lines and tumors, but has been found on breast and colorectal adenocarcinoma.[16][17] In breast cancer, robust expression and different distribution of EMR2 is inversely correlated with survival.[18]

Gain of function mutations within the GAIN domain of EMR2 of certain patient cohorts were shown to result in excessive degranulation by mast cells resulting in vibratory urticaria[19]

See also

  • EGF module-containing mucin-like hormone receptor

References

1. ^{{cite journal | vauthors = Hamann J, Aust G, Araç D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin HH, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T, Schiöth HB | display-authors = 6 | title = International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors | journal = Pharmacological Reviews | volume = 67 | issue = 2 | pages = 338–67 | date = April 2015 | pmid = 25713288 | doi = 10.1124/pr.114.009647 | pmc=4394687}}
2. ^{{cite book | author = Stacey M, Yona S | title = Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology) | publisher = Springer | location = Berlin | year = 2011 | pages = | isbn = 978-1-4419-7912-4 }}
3. ^{{cite journal | vauthors = Langenhan T, Aust G, Hamann J | title = Sticky signaling--adhesion class G protein-coupled receptors take the stage | journal = Science Signaling | volume = 6 | issue = 276 | pages = re3 | date = May 2013 | pmid = 23695165 | doi = 10.1126/scisignal.2003825 }}
4. ^{{cite journal | vauthors = Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, Brunger AT | title = A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis | journal = The EMBO Journal | volume = 31 | issue = 6 | pages = 1364–78 | date = March 2012 | pmid = 22333914 | pmc = 3321182 | doi = 10.1038/emboj.2012.26 }}
5. ^{{cite journal | vauthors = Lin HH, Stacey M, Hamann J, Gordon S, McKnight AJ | title = Human EMR2, a novel EGF-TM7 molecule on chromosome 19p13.1, is closely related to CD97 | journal = Genomics | volume = 67 | issue = 2 | pages = 188–200 | date = July 2000 | pmid = 10903844 | doi = 10.1006/geno.2000.6238 }}
6. ^{{cite journal | vauthors = Gordon S, Hamann J, Lin HH, Stacey M | title = F4/80 and the related adhesion-GPCRs | journal = European Journal of Immunology | volume = 41 | issue = 9 | pages = 2472–6 | date = September 2011 | pmid = 21952799 | doi = 10.1002/eji.201141715 }}
7. ^{{cite journal | vauthors = Kwakkenbos MJ, Matmati M, Madsen O, Pouwels W, Wang Y, Bontrop RE, Heidt PJ, Hoek RM, Hamann J | title = An unusual mode of concerted evolution of the EGF-TM7 receptor chimera EMR2 | journal = FASEB Journal | volume = 20 | issue = 14 | pages = 2582–4 | date = December 2006 | pmid = 17068111 | doi = 10.1096/fj.06-6500fje }}
8. ^{{cite journal | vauthors = Stacey M, Chang GW, Davies JQ, Kwakkenbos MJ, Sanderson RD, Hamann J, Gordon S, Lin HH | title = The epidermal growth factor-like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans | journal = Blood | volume = 102 | issue = 8 | pages = 2916–24 | date = October 2003 | pmid = 12829604 | doi = 10.1182/blood-2002-11-3540 }}
9. ^{{cite journal | vauthors = Kwakkenbos MJ, Chang GW, Lin HH, Pouwels W, de Jong EC, van Lier RA, Gordon S, Hamann J | title = The human EGF-TM7 family member EMR2 is a heterodimeric receptor expressed on myeloid cells | journal = Journal of Leukocyte Biology | volume = 71 | issue = 5 | pages = 854–62 | date = May 2002 | pmid = 11994511 }}
10. ^{{cite journal | vauthors = Gupte J, Swaminath G, Danao J, Tian H, Li Y, Wu X | title = Signaling property study of adhesion G-protein-coupled receptors | journal = FEBS Letters | volume = 586 | issue = 8 | pages = 1214–9 | date = April 2012 | pmid = 22575658 | doi = 10.1016/j.febslet.2012.03.014 }}
11. ^{{cite journal | vauthors = Lin HH, Chang GW, Davies JQ, Stacey M, Harris J, Gordon S | title = Autocatalytic cleavage of the EMR2 receptor occurs at a conserved G protein-coupled receptor proteolytic site motif | journal = The Journal of Biological Chemistry | volume = 279 | issue = 30 | pages = 31823–32 | date = July 2004 | pmid = 15150276 | doi = 10.1074/jbc.M402974200 }}
12. ^1 {{cite journal | vauthors = Huang YS, Chiang NY, Hu CH, Hsiao CC, Cheng KF, Tsai WP, Yona S, Stacey M, Gordon S, Chang GW, Lin HH | title = 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 | journal = Molecular and Cellular Biology | volume = 32 | issue = 8 | pages = 1408–20 | date = April 2012 | pmid = 22310662 | doi = 10.1128/MCB.06557-11 | pmc=3318590}}
13. ^{{cite journal | vauthors = Kwakkenbos MJ, Pouwels W, Matmati M, Stacey M, Lin HH, Gordon S, van Lier RA, Hamann J | title = Expression of the largest CD97 and EMR2 isoforms on leukocytes facilitates a specific interaction with chondroitin sulfate on B cells | journal = Journal of Leukocyte Biology | volume = 77 | issue = 1 | pages = 112–9 | date = January 2005 | pmid = 15498814 | doi = 10.1189/jlb.0704402 }}
14. ^{{cite journal | vauthors = Kop EN, Kwakkenbos MJ, Teske GJ, Kraan MC, Smeets TJ, Stacey M, Lin HH, Tak PP, Hamann J | title = Identification of the epidermal growth factor-TM7 receptor EMR2 and its ligand dermatan sulfate in rheumatoid synovial tissue | journal = Arthritis and Rheumatism | volume = 52 | issue = 2 | pages = 442–50 | date = February 2005 | pmid = 15693006 | doi = 10.1002/art.20788 }}
15. ^{{cite journal | vauthors = Yona S, Lin HH, Dri P, Davies JQ, Hayhoe RP, Lewis SM, Heinsbroek SE, Brown KA, Perretti M, Hamann J, Treacher DF, Gordon S, Stacey M | title = Ligation of the adhesion-GPCR EMR2 regulates human neutrophil function | journal = FASEB Journal | volume = 22 | issue = 3 | pages = 741–51 | date = March 2008 | pmid = 17928360 | doi = 10.1096/fj.07-9435com }}
16. ^{{cite journal | vauthors = Aust G, Hamann J, Schilling N, Wobus M | title = Detection of alternatively spliced EMR2 mRNAs in colorectal tumor cell lines but rare expression of the molecule in colorectal adenocarcinomas | journal = Virchows Archiv | volume = 443 | issue = 1 | pages = 32–7 | date = July 2003 | pmid = 12761622 | doi = 10.1007/s00428-003-0812-4 }}
17. ^{{cite journal | vauthors = Aust G, Steinert M, Schütz A, Boltze C, Wahlbuhl M, Hamann J, Wobus M | title = CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on gastric, pancreatic, and esophageal carcinomas | journal = American Journal of Clinical Pathology | volume = 118 | issue = 5 | pages = 699–707 | date = November 2002 | pmid = 12428789 | doi = 10.1309/A6AB-VF3F-7M88-C0EJ }}
18. ^{{cite journal | vauthors = Davies JQ, Lin HH, Stacey M, Yona S, Chang GW, Gordon S, Hamann J, Campo L, Han C, Chan P, Fox SB | title = Leukocyte adhesion-GPCR EMR2 is aberrantly expressed in human breast carcinomas and is associated with patient survival | journal = Oncology Reports | volume = 25 | issue = 3 | pages = 619–27 | date = March 2011 | pmid = 21174063 | doi = 10.3892/or.2010.1117 }}
19. ^{{cite journal | vauthors = Boyden SE, Desai A, Cruse G, Young ML, Bolan HC, Scott LM, Eisch AR, Long RD, Lee CC, Satorius CL, Pakstis AJ, Olivera A, Mullikin JC, Chouery E, Mégarbané A, Medlej-Hashim M, Kidd KK, Kastner DL, Metcalfe DD, Komarow HD | title = Vibratory Urticaria Associated with a Missense Variant in ADGRE2 | journal = The New England Journal of Medicine | volume = 374 | issue = 7 | pages = 656–63 | date = February 2016 | pmid = 26841242 | doi = 10.1056/NEJMoa1500611 | pmc=4782791}}

External links

  • GPCR consortium
{{PDB Gallery|geneid=30817}}{{Clusters of differentiation}}{{G protein-coupled receptors}}

3 : Clusters of differentiation|G protein-coupled receptors|Adhesion GPCRs
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