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Target not currently curated in GtoImmuPdb
Target id: 614
Nomenclature: Testicular receptor 4
Systematic Nomenclature: NR2C2
Family: 2C. Testicular receptors
Gene and Protein Information | |||||
Species | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | 596 | 3p25.1 | NR2C2 | nuclear receptor subfamily 2 group C member 2 | 1,4 |
Mouse | 596 | 6 D1 | Nr2c2 | nuclear receptor subfamily 2, group C, member 2 | 15 |
Rat | 596 | 4q34 | Nr2c2 | nuclear receptor subfamily 2, group C, member 2 | 1 |
Previous and Unofficial Names |
TAK1 | orphan nuclear receptor TR4 | TR4 orphan receptor | TR4-NS orphan receptor | nuclear receptor subfamily 2 |
Database Links | |
Alphafold | P49116 (Hs), P49117 (Mm), P55094 (Rn) |
CATH/Gene3D | 3.30.50.10 |
ChEMBL Target | CHEMBL5716 (Hs), CHEMBL4295769 (Mm) |
Ensembl Gene | ENSG00000177463 (Hs), ENSMUSG00000005893 (Mm), ENSRNOG00000010536 (Rn) |
Entrez Gene | 7182 (Hs), 22026 (Mm), 50659 (Rn) |
Human Protein Atlas | ENSG00000177463 (Hs) |
KEGG Gene | hsa:7182 (Hs), mmu:22026 (Mm), rno:50659 (Rn) |
OMIM | 601426 (Hs) |
Pharos | P49116 (Hs) |
RefSeq Nucleotide | NM_003298 (Hs), NM_011630 (Mm), NM_017323 (Rn) |
RefSeq Protein | NP_003289 (Hs), NP_035760 (Mm), NP_059019 (Rn) |
UniProtKB | P49116 (Hs), P49117 (Mm), P55094 (Rn) |
Wikipedia | NR2C2 (Hs) |
Natural/Endogenous Ligands |
retinol |
tretinoin |
Comments: Orphan |
Download all structure-activity data for this target as a CSV file
Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Co-binding Partners | |||
Name | Interaction | Effect | Reference |
Testicular receptor 2 | Physical, Functional | DNA binding : TR2 and TR4 form heterodimers. The dimerization interface is localized in the ligand-binding domains, and three leucine residues in helix H10 are critical for this interaction. Coexpression of TR2 and TR4 exerts a stronger repressive activity than expressing either receptor alone in a reporter gene assay. | 14 |
Estrogen receptor-α | Physical, Functional | DNA binding | 12 |
Androgen receptor | Physical, Functional | DNA binding, AR heterodimerize with TR4, and function as a repressor to down-regulate TR4 target genes by preventing the binding of TR4 to the promoter region of those genes. Reciprocally, TR4 can repress AR target gene expression. | 9 |
Main Co-regulators | ||||||
Name | Activity | Specific | Ligand dependent | AF-2 dependent | Comments | References |
JAZF1 | Co-repressor | No | No | Yes | 11 | |
NR2C2AP | Co-repressor | Yes | No | Yes | 13 |
Main Target Genes | |||||
Name | Species | Effect | Technique | Comments | References |
LHCGR | Human | Activated | Transient transfection,EMSA ,Other | LHR: TR4 binds to an imperfect DR element in the promoter of the human luteinizing hormone receptor (LHR) gene and activate LRH promoter activity in transient transfections assays in CV1 cells. Findings suggest that TR4 is able to contribute to the differential expression of the LHR gene in gonadal and non-gonadal tissues. | 16 |
CYP21A2 | Human | Activated | Transient transfection,EMSA ,Other | Steroid 21-hydroxylase (CYP21A2): the expression of the human steroid 21-hydroxylase (21-OHase) gene is repressed by TR4 via the monomeric AGGTCA motif (−228TR4RE) in its 5 flanking region. | 8 |
CNTFR | Human | Activated | Transient transfection,EMSA | CNTFRa: A CNTFR-DR1 was identified in the fifth intron of the alpha component of the human CNTFRα gene. Reporter gene assay demonstrated that the fifth intronof the CNTFRα gene has enhancer activity, which could be induced by TR4 in a dose-dependent manner | 14 |
Apoplipoprotein E | Human | Activated | Induction of apoplipoprotein E expression by TR4 orphan receptor via 5’ proximal region | 7 | |
Main Target Genes Comments | |||||
HIV1-LTR: TR4 showed high affinity to a palindromic (symmetric) element (PR9) at the 5'-end of the HIV-LTR but is not able to regulate transcription activity of the LTR on its own in transient reporter assays. TR4 may nevertheless associate with other NRs in the regulation of HIV replication [6]. |
Tissue Distribution | ||||||||
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Tissue Distribution Comments | ||||||||
The mouse TR4 is expressed as two mRNAs of 8 kb and 3.5 kb. The 8 kb form appears ubiquitously expressed whereas the 3.5 kb is restricted to some tissues such as brain or at much lower levels in lungs. A small 2.8 kb TR4 transcript was also observed in testis, mainly in spermatocytes and a specific 4.5 kb transcript was detected in rat spleen. The relationship between these various small transcripts (4.5, 3.5 and 2.8 kb) are still unclear. The large transcript exhibits a predominant expression in rat central nervous system, with a prominent expression in hippocampus, cerebellum and hypothalamic area as well as in adrenal gland, spleen, testis and prostate. The expression of TR4 in adult brain as well as in neuronal precursors during embryogenesis has been confirmed by in situ hybridization. It has been suggested that TR4 expression in brain is located in areas known to be involved in stress response and that TR4 expression is up-regulated by NMDA. |
Physiological Consequences of Altering Gene Expression | ||||||||||
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Phenotypes, Alleles and Disease Models | Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||
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General Comments |
There are still questions as to why in certain cases TR4 is a transcriptional repressor but behaves as an activator in others. Target promoter analysis seems to exclude that response element sequence is the determinant of this differential activity. |
1. Chang C, Da Silva SL, Ideta R, Lee Y, Yeh S, Burbach JP. (1994) Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily. Proc Natl Acad Sci USA, 91 (13): 6040-4. [PMID:8016112]
2. Chen YT, Collins LL, Uno H, Chang C. (2005) Deficits in motor coordination with aberrant cerebellar development in mice lacking testicular orphan nuclear receptor 4. Mol Cell Biol, 25 (7): 2722-32. [PMID:15767677]
3. Collins LL, Lee YF, Heinlein CA, Liu NC, Chen YT, Shyr CR, Meshul CK, Uno H, Platt KA, Chang C. (2004) Growth retardation and abnormal maternal behavior in mice lacking testicular orphan nuclear receptor 4. Proc Natl Acad Sci USA, 101 (42): 15058-63. [PMID:15477591]
4. Hirose T, Fujimoto W, Tamaai T, Kim KH, Matsuura H, Jetten AM. (1994) TAK1: molecular cloning and characterization of a new member of the nuclear receptor superfamily. Mol Endocrinol, 8 (12): 1667-80. [PMID:7708055]
5. Hirose T, O'Brien DA, Jetten AM. (1995) Cloning of the gene encoding the murine orphan receptor TAK1 and cell-type-specific expression in testis. Gene, 163 (2): 239-42. [PMID:7590273]
6. Hwang SB, Burbach JP, Chang C. (1998) TR4 orphan receptor crosstalks to chicken ovalbumin upstream protein-transcription factor and thyroid hormone receptor to induce the transcriptional activity of the human immunodeficiency virus type 1 long-terminal repeat. Endocrine, 8 (2): 169-75. [PMID:9704574]
7. Kim E, Yang Z, Liu NC, Chang C. (2005) Induction of apolipoprotein E expression by TR4 orphan nuclear receptor via 5' proximal promoter region. Biochem Biophys Res Commun, 328 (1): 85-90. [PMID:15670754]
8. Lee HJ, Lee YF, Chang C. (2001) TR4 orphan receptor represses the human steroid 21-hydroxylase gene expression through the monomeric AGGTCA motif. Biochem Biophys Res Commun, 285 (5): 1361-8. [PMID:11478808]
9. Lee YF, Shyr CR, Thin TH, Lin WJ, Chang C. (1999) Convergence of two repressors through heterodimer formation of androgen receptor and testicular orphan receptor-4: a unique signaling pathway in the steroid receptor superfamily. Proc Natl Acad Sci USA, 96 (26): 14724-9. [PMID:10611280]
10. Mu X, Lee YF, Liu NC, Chen YT, Kim E, Shyr CR, Chang C. (2004) Targeted inactivation of testicular nuclear orphan receptor 4 delays and disrupts late meiotic prophase and subsequent meiotic divisions of spermatogenesis. Mol Cell Biol, 24 (13): 5887-99. [PMID:15199144]
11. Nakajima T, Fujino S, Nakanishi G, Kim YS, Jetten AM. (2004) TIP27: a novel repressor of the nuclear orphan receptor TAK1/TR4. Nucleic Acids Res, 32 (14): 4194-204. [PMID:15302918]
12. Shyr CR, Hu YC, Kim E, Chang C. (2002) Modulation of estrogen receptor-mediated transactivation by orphan receptor TR4 in MCF-7 cells. J Biol Chem, 277 (17): 14622-8. [PMID:11844790]
13. Yang Y, Wang X, Dong T, Kim E, Lin WJ, Chang C. (2003) Identification of a novel testicular orphan receptor-4 (TR4)-associated protein as repressor for the selective suppression of TR4-mediated transactivation. J Biol Chem, 278 (9): 7709-17. [PMID:12486131]
14. Young WJ, Lee YF, Smith SM, Chang C. (1998) A bidirectional regulation between the TR2/TR4 orphan receptors (TR2/TR4) and the ciliary neurotrophic factor (CNTF) signaling pathway. J Biol Chem, 273 (33): 20877-85. [PMID:9694834]
15. Young WJ, Smith SM, Chang C. (1997) Induction of the intronic enhancer of the human ciliary neurotrophic factor receptor (CNTFRalpha) gene by the TR4 orphan receptor. A member of steroid receptor superfamily. J Biol Chem, 272 (5): 3109-16. [PMID:9006963]
16. Zhang Y, Dufau ML. (2000) Nuclear orphan receptors regulate transcription of the gene for the human luteinizing hormone receptor. J Biol Chem, 275 (4): 2763-70. [PMID:10644740]
17. Zhou XE, Suino-Powell KM, Xu Y, Chan CW, Tanabe O, Kruse SW, Reynolds R, Engel JD, Xu HE. (2011) The orphan nuclear receptor TR4 is a vitamin A-activated nuclear receptor. J Biol Chem, 286 (4): 2877-85. [PMID:21068381]
2C. Testicular receptors: Testicular receptor 4. Last modified on 07/09/2015. Accessed on 08/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=614.