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target has curated data in GtoImmuPdb
Target id: 619
Nomenclature: V-erbA-related gene
Systematic Nomenclature: NR2F6
Family: 2F. COUP-TF-like receptors
Gene and Protein Information  |
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| Species | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 404 | 19p13.11 | NR2F6 | nuclear receptor subfamily 2 group F member 6 | 9 |
| Mouse | 390 | 8 34.43 cM | Nr2f6 | nuclear receptor subfamily 2, group F, member 6 | 7 |
| Rat | 390 | 16p14 | Nr2f6 | nuclear receptor subfamily 2, group F, member 6 | |
| Previous and Unofficial Names |
| EAR2 | ERBAL2 | COUPg | orphan nuclear receptor EAR-2 | ovalbumin upstream promoter gamma nuclear receptor rCOUPg | V-erbA-related protein 2 | V-erbA-related protein EAR-2 | COUP-TF3 | nuclear receptor subfamily 2 |
| Database Links |
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| Alphafold | P10588 (Hs), Q922G8 (Mm), O09017 (Rn) |
| CATH/Gene3D | 3.30.50.10 |
| ChEMBL Target | CHEMBL1961791 (Hs) |
| Ensembl Gene | ENSG00000160113 (Hs), ENSMUSG00000002393 (Mm), ENSRNOG00000016892 (Rn) |
| Entrez Gene | 2063 (Hs), 13864 (Mm), 245980 (Rn) |
| Human Protein Atlas | ENSG00000160113 (Hs) |
| KEGG Gene | hsa:2063 (Hs), mmu:13864 (Mm), rno:245980 (Rn) |
| OMIM | 132880 (Hs) |
| Pharos | P10588 (Hs) |
| RefSeq Nucleotide | NM_005234 (Hs), NM_010150 (Mm), NM_139113 (Rn) |
| RefSeq Protein | NP_005225 (Hs), NP_034280 (Mm), NP_620813 (Rn) |
| UniProtKB | P10588 (Hs), Q922G8 (Mm), O09017 (Rn) |
| Wikipedia | NR2F6 (Hs) |
| Natural/Endogenous Ligands |
| Comments: Orphan |
| Immunopharmacology Comments |
| NR2F6 as an intracellular immune checkpoint in effector T cells, and controls tumour immunity (at least in mice) [5]. In mouse tumour models genetic ablation of Nr2f6 enhances production of IL-2, IFNγ, and tumor necrosis factor-α. In conjunction with increased effector CD4+ and CD8+ T cell infiltration in the tumour, loss of this gene allows establishment of an anti-tumour micro-environment [5]. |
| DNA Binding |
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| DNA Binding Comments | |||||||
| EAR2 seems to be much more specific for DR1 element than other members of the COUP-TF group since it does not interact with other direct repeats. | |||||||
| Co-binding Partners |
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| Name | Interaction | Effect | Reference |
| Thyroid hormone receptor-β | Physical, Functional | Heterodimerization with TRbeta 1 (NR1A2) inhibit TRbeta1 binding to its response element. | 13 |
| COUP-TF2 | Physical, Functional | DNA binding | 2 |
| CBFA2 | Physical, Functional | EAR2 interaction with CBFA2 inhibit activity of CBFA2. | 1 |
| Estrogen receptor-α | Physical | 13 | |
| Glucocorticoid receptor | Physical | 13 | |
| ZFPM2 | Physical, Functional | The carboxyl terminus of the COUP-TF proteins interacts with multiple ZFPM2 zinc finger. | 6 |
| BCL11A | Physical, Functional | NR2F6 interacts with BCL11A to repress its endogenous target. | 3 |
| Rasd1 | Physical, Functional | Rasd1 interacts with Nr2f6 ligand binding domain to regulate renin transcription. | 10 |
| Main Co-regulators |
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| Name | Activity | Specific | Ligand dependent | AF-2 dependent | Comments | References |
| NCOA1 | Co-activator | No | No | No | 13 | |
| Main Target Genes |
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| Name | Species | Effect | Technique | Comments | References |
| renin | Mouse | Repressed | Transient transfection ,EMSA | Ear2 potently decreases both baseline and retinoid-induced mouse renin promoter activity in a dose-dependent, enhancer-dependent, and sequence-specific manner. | 8 |
| LH | Human | Repressed | Transient transfection, EMSA | EAR2 and COUP-TFI contributes to gonadotropin-induced derepression of LHR promoter activity in granulosa cells. (seen in all species) | 12 |
| GRIK5 | Human | Repressed | Transient transfection, EMSA | The GRIK5 gene, which encodes the kainate-preferring glutamate receptor subunit KA2, is regulated by several orphan nuclear receptors, including EAR2 and COUP-TFs. (this is observed in all species) | 11 |
| oxytocin receptor | Human | Repressed | Transient transfection, EMSA, Other | 4 | |
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| Few data are available on the expression pattern of EAR2. A 2.5 kb transcript was found in human foetal liver as well as in placenta, heart, muscle and pancreas, weak expression was noticed in kidney and no expression was detected in lung and brain or kidney. Other studies in mouse, including in situ hybridisation, also found a broad expression pattern of EAR2. Consistent with its interaction with the CBFA2 transcription factor which play an important role in granulocytic differentiation, EAR2 was found expressed in myeloid progenitor cells and down-regulated during differentiation induced by G-CSF. An expression of EAR2 in uterine epithelial cells was also described. | ||||||||
| Physiological Functions
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| Physiological Consequences of Altering Gene Expression
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||
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1. Ahn MJ, Nason-Burchenal K, Moasser MM, Dmitrovsky E. (1995) Growth suppression of acute promyelocytic leukemia cells having increased expression of the non-rearranged alleles: RAR alpha or PML. Oncogene, 10 (12): 2307-14. [PMID:7784078]
2. Avram D, Ishmael JE, Nevrivy DJ, Peterson VJ, Lee SH, Dowell P, Leid M. (1999) Heterodimeric interactions between chicken ovalbumin upstream promoter-transcription factor family members ARP1 and ear2. J Biol Chem, 274 (20): 14331-6. [PMID:10318855]
3. Chan CM, Fulton J, Montiel-Duarte C, Collins HM, Bharti N, Wadelin FR, Moran PM, Mongan NP, Heery DM. (2013) A signature motif mediating selective interactions of BCL11A with the NR2E/F subfamily of orphan nuclear receptors. Nucleic Acids Res, 41 (21): 9663-79. [PMID:23975195]
4. Chu K, Boutin JM, Breton C, Zingg HH. (1998) Nuclear orphan receptors COUP-TFII and Ear-2: presence in oxytocin-producing uterine cells and functional interaction with the oxytocin gene promoter. Mol Cell Endocrinol, 137 (2): 145-54. [PMID:9605516]
5. Hermann-Kleiter N, Klepsch V, Wallner S, Siegmund K, Klepsch S, Tuzlak S, Villunger A, Kaminski S, Pfeifhofer-Obermair C, Gruber T et al.. (2015) The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance. Cell Rep, 12 (12): 2072-85. [PMID:26387951]
6. Huggins GS, Bacani CJ, Boltax J, Aikawa R, Leiden JM. (2001) Friend of GATA 2 physically interacts with chicken ovalbumin upstream promoter-TF2 (COUP-TF2) and COUP-TF3 and represses COUP-TF2-dependent activation of the atrial natriuretic factor promoter. J Biol Chem, 276 (30): 28029-36. [PMID:11382775]
7. Jonk LJ, de Jonge ME, Pals CE, Wissink S, Vervaart JM, Schoorlemmer J, Kruijer W. (1994) Cloning and expression during development of three murine members of the COUP family of nuclear orphan receptors. Mech Dev, 47 (1): 81-97. [PMID:7947324]
8. Liu X, Huang X, Sigmund CD. (2003) Identification of a nuclear orphan receptor (Ear2) as a negative regulator of renin gene transcription. Circ Res, 92 (9): 1033-40. [PMID:12690040]
9. Miyajima N, Kadowaki Y, Fukushige S, Shimizu S, Semba K, Yamanashi Y, Matsubara K, Toyoshima K, Yamamoto T. (1988) Identification of two novel members of erbA superfamily by molecular cloning: the gene products of the two are highly related to each other. Nucleic Acids Res, 16 (23): 11057-74. [PMID:2905047]
10. Tan JJ, Ong SA, Chen KS. (2011) Rasd1 interacts with Ear2 (Nr2f6) to regulate renin transcription. BMC Mol Biol, 12: 4. [PMID:21247419]
11. Warnecke M, Oster H, Revelli JP, Alvarez-Bolado G, Eichele G. (2005) Abnormal development of the locus coeruleus in Ear2(Nr2f6)-deficient mice impairs the functionality of the forebrain clock and affects nociception. Genes Dev, 19 (5): 614-25. [PMID:15741322]
12. Zhang Y, Dufau ML. (2001) EAR2 and EAR3/COUP-TFI regulate transcription of the rat LH receptor. Mol Endocrinol, 15 (11): 1891-905. [PMID:11682620]
13. Zhu XG, Park KS, Kaneshige M, Bhat MK, Zhu Q, Mariash CN, McPhie P, Cheng SY. (2000) The orphan nuclear receptor Ear-2 is a negative coregulator for thyroid hormone nuclear receptor function. Mol Cell Biol, 20 (7): 2604-18. [PMID:10713182]
