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V-erbA-related gene

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Immunopharmacology Ligand 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 Click here for help
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 Click here for help
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 Click here for help
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Natural/Endogenous Ligands Click here for help
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 Click here for help
Structure:  Homodimer, Heterodimer
HRE core sequence:  AGGTCA n AGGTCA
Response element:  DR1, Other - see comments
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 Click here for help
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 Click here for help
Name Activity Specific Ligand dependent AF-2 dependent Comments References
NCOA1 Co-activator No No No 13
Main Target Genes Click here for help
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 Click here for help
Foetal liver, placenta, heart, muscle and pancreas, kidney
Species:  Human
Technique:  Northern, in situ, immunohistology, other
References:  1-2,4,7,9,13
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 Click here for help
NR2F6 as an intracellular immune checkpoint in effector T cells, and controls tumour immunity.
Species:  Mouse
References:  5
Physiological Consequences of Altering Gene Expression Click here for help
EAR2 null mice: NR2F6-null mice exhibit defects in development of the locus coeruleus (LC). Examination of the genes expressed in the LC of NR2F6-null mice suggested that NR2F6 is involved in the signaling cascade leading to LC development. More than 70% of LC neurons were absent in NR2F6-null adults. The EAR2 null mice also exhibit defects in circadian behaviors and circadian gene expression.
Species:  Human
Technique:  Gene knockout
References:  11
Nr2f6 null mice spontaneously reject implanted tumours and develop immunological memory against tumor rechallenge.
Species:  Mouse
Tissue:  Tumour xenograft
References:  5
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Nr2f6tm1Ge Nr2f6tm1Ge/Nr2f6tm1Ge
involves: 129S5/SvEvBrd * C57BL/6J
MGI:1352453  MP:0001502 abnormal circadian rhythm PMID: 15741322 
Nr2f6tm1Ge Nr2f6tm1Ge/Nr2f6tm1Ge
involves: 129S5/SvEvBrd * C57BL/6J
MGI:1352453  MP:0002736 abnormal nociception after inflammation PMID: 15741322 
Nr2f6tm1Ge Nr2f6tm1Ge/Nr2f6tm1Ge
involves: 129S5/SvEvBrd * C57BL/6J
MGI:1352453  MP:0005447 abnormal synaptic norepinephrine release PMID: 15741322 
Nr2f6tm1Ge Nr2f6tm1Ge/Nr2f6tm1Ge
involves: 129S5/SvEvBrd * C57BL/6J
MGI:1352453  MP:0002733 abnormal thermal nociception PMID: 15741322 
Nr2f6tm1Ge Nr2f6tm1Ge/Nr2f6tm1Ge
involves: 129S5/SvEvBrd * C57BL/6J
MGI:1352453  MP:0002563 shortened circadian period PMID: 15741322 


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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]


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