EMR2

Last updated
ADGRE2
Protein EMR2 PDB 2bo2.png
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases ADGRE2 , CD312, VBU, EMR2, adhesion G protein-coupled receptor E2, CD97
External IDs OMIM: 606100 HomoloGene: 113735 GeneCards: ADGRE2
Orthologs
SpeciesHumanMouse
Entrez

30817

n/a

Ensembl

ENSG00000127507

n/a

UniProt

Q9UHX3

n/a

RefSeq (mRNA)

n/a

RefSeq (protein)

NP_001257981
NP_038475

n/a

Location (UCSC) Chr 19: 14.73 – 14.78 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

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. [3] EMR2 is a member of the adhesion GPCR family. [4] [5] 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. [6]

Contents

EMR2 is expressed by monocytes/macrophages, dendritic cells and all types of granulocytes. [7] 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. [8] Mice lack the Emr2 gene. [9] 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. [10] 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. [11]

Signaling

Inositol phosphate (IP3) accumulation assays in overexpressing HEK293 cells have demonstrated coupling of EMR2 to Gα15. [12] 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. [13] 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. [14] 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. [15] 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. [16] 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. [14] [17]

Clinical significance

EMR2 is rarely expressed by tumor cell lines and tumors, but has been found on breast and colorectal adenocarcinoma. [18] [19] In breast cancer, robust expression and different distribution of EMR2 is inversely correlated with survival. [20] 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 [21]

See also

Related Research Articles

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Versican is a large extracellular matrix proteoglycan that is present in a variety of human tissues. It is encoded by the VCAN gene.

The EGF module-containing Mucin-like hormone Receptors (EMRs) are closely related subgroup of G protein-coupled receptors (GPCRs). These receptors have a unique hybrid structure in which an extracellular epidermal growth factor (EGF)-like domain is fused to a GPCR domain through a mucin-like stalk. There are four variants of EMR labeled 1–4, each encoded by a separate gene. These receptors are predominantly expressed in cells of the immune system and bind ligands such as CD55.

<span class="mw-page-title-main">EMR1</span> Protein-coding gene in the species Homo sapiens

EGF-like module-containing mucin-like hormone receptor-like 1 also known as F4/80 is a protein encoded by the ADGRE1 gene. EMR1 is a member of the adhesion GPCR family. 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.

<span class="mw-page-title-main">EMR3</span> Protein-coding gene in the species Homo sapiens

EGF-like module-containing mucin-like hormone receptor-like 3 is a protein encoded by the ADGRE3 gene. EMR3 is a member of the adhesion GPCR family. 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.

<span class="mw-page-title-main">CD97</span> Mammalian protein found in Homo sapiens

Cluster of differentiation 97 is a protein also known as BL-Ac[F2] encoded by the ADGRE5 gene. CD97 is a member of the adhesion G protein-coupled receptor (GPCR) family. 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.

<span class="mw-page-title-main">GPR64</span> Protein-coding gene in humans

G protein-coupled receptor 64 also known as HE6 is a protein encoded by the ADGRG2 gene. GPR64 is a member of the adhesion GPCR family. 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.

<span class="mw-page-title-main">Latrophilin 1</span> Protein-coding gene in the species Homo sapiens

Latrophilin 1 is a protein that in humans is encoded by the ADGRL1 gene. It is a member of the adhesion-GPCR family of receptors. Family members are characterized by an extended extracellular region with a variable number of protein domains coupled to a TM7 domain via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR124</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 124 is a protein that in humans is encoded by the GPR124 gene. It is a member of the adhesion-GPCR family of receptors. Family members are characterized by an extended extracellular region with a variable number of protein domains coupled to a TM7 domain via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR126</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 126 also known as VIGR and DREG is a protein encoded by the ADGRG6 gene. GPR126 is a member of the adhesion GPCR family. 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.

<span class="mw-page-title-main">GPR123</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 123 is a protein that in humans is encoded by the GPR123 gene. It is a member of the adhesion-GPCR family of receptors. Family members are normally characterized by an extended extracellular region with a variable number of protein domains coupled to a TM7 domain via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR128</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 128 is a protein encoded by the ADGRG7 gene. GPR128 is a member of the adhesion GPCR family. 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.

<span class="mw-page-title-main">GPR112</span> Protein-coding gene in humans

G protein-coupled receptor 112 is a protein encoded by the ADGRG4 gene. GPR112 is a member of the adhesion GPCR family. 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.

<span class="mw-page-title-main">GPR114</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 114 is a protein encoded by the ADGRG5 gene. GPR114 is a member of the adhesion GPCR family. 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.

<span class="mw-page-title-main">GPR97</span> Protein-coding gene in the species Homo sapiens

G-protein coupled receptor 97 also known as adhesion G protein-coupled receptor G3 (ADGRG3) is a protein that in humans is encoded by the ADGRG3 gene. GPR97 is a member of the adhesion GPCR family. 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.

<span class="mw-page-title-main">GPR110</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 110 is a protein that in humans is encoded by the GPR110 gene. This gene encodes a member of the adhesion-GPCR receptor family. Family members are characterized by an extended extracellular region with a variable number of N-terminal protein modules coupled to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR133</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 133 is a protein that in humans is encoded by the GPR133 gene.

<span class="mw-page-title-main">GPR144</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 144 is a protein that in humans is encoded by the GPR144 gene. This gene encodes a member of the adhesion-GPCR family of receptors. Family members are characterised by an extended extracellular region with a variable number of protein domains coupled to a TM7 domain via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR56</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ADGRG1 gene. GPR56 is a member of the adhesion GPCR family. 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.

<span class="mw-page-title-main">Adhesion G protein-coupled receptor</span> Class of 33 human protein receptors

Adhesion G protein-coupled receptors are a class of 33 human protein receptors with a broad distribution in embryonic and larval cells, cells of the reproductive tract, neurons, leukocytes, and a variety of tumours. Adhesion GPCRs are found throughout metazoans and are also found in single-celled colony forming choanoflagellates such as Monosiga brevicollis and unicellular organisms such as Filasterea. The defining feature of adhesion GPCRs that distinguishes them from other GPCRs is their hybrid molecular structure. The extracellular region of adhesion GPCRs can be exceptionally long and contain a variety of structural domains that are known for the ability to facilitate cell and matrix interactions. Their extracellular region contains the membrane proximal GAIN domain. Crystallographic and experimental data has shown this structurally conserved domain to mediate autocatalytic processing at a GPCR-proteolytic site (GPS) proximal to the first transmembrane helix. Autocatalytic processing gives rise to an extracellular (α) and a membrane-spanning (β) subunit, which are associated non-covalently, resulting in expression of a heterodimeric receptor at the cell surface. Ligand profiles and in vitro studies have indicated a role for adhesion GPCRs in cell adhesion and migration. Work utilizing genetic models confined this concept by demonstrating that the primary function of adhesion GPCRs may relate to the proper positioning of cells in a variety of organ systems. Moreover, growing evidence implies a role of adhesion GPCRs in tumour cell metastasis. Formal G protein-coupled signalling has been demonstrated for a number for adhesion GPCRs, however, the orphan receptor status of many of the receptors still hampers full characterisation of potential signal transduction pathways. In 2011, the adhesion GPCR consortium was established to facilitate research of the physiological and pathological functions of adhesion GPCRs.

<span class="mw-page-title-main">GAIN domain</span> Protein domain

The GAIN domain is a protein domain found in a number of cell surface receptors, including adhesion-GPCRs and polycystic kidney disease proteins PKD1 and PKD2. The domain is involved in the self-cleavage of these transmembrane receptors, and has been shown to be crucial for their function. Point mutations within the GAIN domain of PKD1 and GPR56 are known to cause polycystic kidney disease and polymicrogyria, respectively.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000127507 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ↑ Hamann J, Aust G, Araç D, Engel FB, Formstone C, Fredriksson R, et al. (April 2015). "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors". Pharmacological Reviews. 67 (2): 338–67. doi:10.1124/pr.114.009647. PMC   4394687 . PMID   25713288.
  4. ↑ Stacey M, Yona S (2011). Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology). Berlin: Springer. ISBN   978-1-4419-7912-4.
  5. ↑ Langenhan T, Aust G, Hamann J (May 2013). "Sticky signaling--adhesion class G protein-coupled receptors take the stage". Science Signaling. 6 (276): re3. doi:10.1126/scisignal.2003825. PMID   23695165. S2CID   6958640.
  6. ↑ Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, Brunger AT (March 2012). "A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis". The EMBO Journal. 31 (6): 1364–78. doi:10.1038/emboj.2012.26. PMC   3321182 . PMID   22333914.
  7. ↑ Lin HH, Stacey M, Hamann J, Gordon S, McKnight AJ (July 2000). "Human EMR2, a novel EGF-TM7 molecule on chromosome 19p13.1, is closely related to CD97". Genomics. 67 (2): 188–200. doi:10.1006/geno.2000.6238. PMID   10903844.
  8. ↑ Gordon S, Hamann J, Lin HH, Stacey M (September 2011). "F4/80 and the related adhesion-GPCRs". European Journal of Immunology. 41 (9): 2472–6. doi: 10.1002/eji.201141715 . PMID   21952799. S2CID   29257475.
  9. ↑ Kwakkenbos MJ, Matmati M, Madsen O, Pouwels W, Wang Y, Bontrop RE, Heidt PJ, Hoek RM, Hamann J (December 2006). "An unusual mode of concerted evolution of the EGF-TM7 receptor chimera EMR2". FASEB Journal. 20 (14): 2582–4. doi: 10.1096/fj.06-6500fje . PMID   17068111. S2CID   16254868.
  10. ↑ Stacey M, Chang GW, Davies JQ, Kwakkenbos MJ, Sanderson RD, Hamann J, Gordon S, Lin HH (October 2003). "The epidermal growth factor-like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans". Blood. 102 (8): 2916–24. doi: 10.1182/blood-2002-11-3540 . PMID   12829604.
  11. ↑ Kwakkenbos MJ, Chang GW, Lin HH, Pouwels W, de Jong EC, van Lier RA, Gordon S, Hamann J (May 2002). "The human EGF-TM7 family member EMR2 is a heterodimeric receptor expressed on myeloid cells". Journal of Leukocyte Biology. 71 (5): 854–62. doi:10.1189/jlb.71.5.854. PMID   11994511. S2CID   16582952.
  12. ↑ Gupte J, Swaminath G, Danao J, Tian H, Li Y, Wu X (April 2012). "Signaling property study of adhesion G-protein-coupled receptors". FEBS Letters. 586 (8): 1214–9. doi: 10.1016/j.febslet.2012.03.014 . PMID   22575658. S2CID   3020230.
  13. ↑ Lin HH, Chang GW, Davies JQ, Stacey M, Harris J, Gordon S (July 2004). "Autocatalytic cleavage of the EMR2 receptor occurs at a conserved G protein-coupled receptor proteolytic site motif". The Journal of Biological Chemistry. 279 (30): 31823–32. doi: 10.1074/jbc.M402974200 . PMID   15150276.
  14. 1 2 Huang YS, Chiang NY, Hu CH, Hsiao CC, Cheng KF, Tsai WP, Yona S, Stacey M, Gordon S, Chang GW, Lin HH (April 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". Molecular and Cellular Biology. 32 (8): 1408–20. doi:10.1128/MCB.06557-11. PMC   3318590 . PMID   22310662.
  15. ↑ Kwakkenbos MJ, Pouwels W, Matmati M, Stacey M, Lin HH, Gordon S, van Lier RA, Hamann J (January 2005). "Expression of the largest CD97 and EMR2 isoforms on leukocytes facilitates a specific interaction with chondroitin sulfate on B cells". Journal of Leukocyte Biology. 77 (1): 112–9. doi: 10.1189/jlb.0704402 . PMID   15498814. S2CID   15589445.
  16. ↑ Kop EN, Kwakkenbos MJ, Teske GJ, Kraan MC, Smeets TJ, Stacey M, Lin HH, Tak PP, Hamann J (February 2005). "Identification of the epidermal growth factor-TM7 receptor EMR2 and its ligand dermatan sulfate in rheumatoid synovial tissue". Arthritis and Rheumatism. 52 (2): 442–50. doi: 10.1002/art.20788 . PMID   15693006.
  17. ↑ 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 (March 2008). "Ligation of the adhesion-GPCR EMR2 regulates human neutrophil function". FASEB Journal. 22 (3): 741–51. doi: 10.1096/fj.07-9435com . PMID   17928360. S2CID   16235723.
  18. ↑ Aust G, Hamann J, Schilling N, Wobus M (July 2003). "Detection of alternatively spliced EMR2 mRNAs in colorectal tumor cell lines but rare expression of the molecule in colorectal adenocarcinomas". Virchows Archiv. 443 (1): 32–7. doi:10.1007/s00428-003-0812-4. PMID   12761622. S2CID   31812716.
  19. ↑ Aust G, Steinert M, Schütz A, Boltze C, Wahlbuhl M, Hamann J, Wobus M (November 2002). "CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on gastric, pancreatic, and esophageal carcinomas". American Journal of Clinical Pathology. 118 (5): 699–707. doi: 10.1309/A6AB-VF3F-7M88-C0EJ . PMID   12428789.
  20. ↑ Davies JQ, Lin HH, Stacey M, Yona S, Chang GW, Gordon S, Hamann J, Campo L, Han C, Chan P, Fox SB (March 2011). "Leukocyte adhesion-GPCR EMR2 is aberrantly expressed in human breast carcinomas and is associated with patient survival". Oncology Reports. 25 (3): 619–27. doi: 10.3892/or.2010.1117 . PMID   21174063.
  21. ↑ 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 (February 2016). "Vibratory Urticaria Associated with a Missense Variant in ADGRE2". The New England Journal of Medicine. 374 (7): 656–63. doi:10.1056/NEJMoa1500611. PMC   4782791 . PMID   26841242.
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