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Target not currently curated in GtoImmuPdb
Target id: 629
Nomenclature: Nerve Growth factor IB
Systematic Nomenclature: NR4A1
Gene and Protein Information  |
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| Species | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 598 | 12q13.13 | NR4A1 | nuclear receptor subfamily 4 group A member 1 | 4-5,18 |
| Mouse | 601 | 15 F1 | Nr4a1 | nuclear receptor subfamily 4, group A, member 1 | 9,23 |
| Rat | 597 | 7q36 | Nr4a1 | nuclear receptor subfamily 4, group A, member 1 | 1,16 |
| Previous and Unofficial Names |
| Gfrp | GFRP1 | Hbr1 | immediate early gene transcription factor NGFI-B | NAK1 | nerve growth factor-induced protein I-B | NGFIB | nuclear receptor subfamily 4 | NUR77 | Orphan nuclear receptor HMR | ST59 | TIS1 | TR3 |
| Database Links |
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| Alphafold | P22736 (Hs), P12813 (Mm), P22829 (Rn) |
| CATH/Gene3D | 3.30.50.10 |
| ChEMBL Target | CHEMBL1293229 (Hs), CHEMBL3308901 (Mm) |
| Ensembl Gene | ENSG00000123358 (Hs), ENSMUSG00000023034 (Mm), ENSRNOG00000007607 (Rn) |
| Entrez Gene | 3164 (Hs), 15370 (Mm), 79240 (Rn) |
| Human Protein Atlas | ENSG00000123358 (Hs) |
| KEGG Gene | hsa:3164 (Hs), mmu:15370 (Mm), rno:79240 (Rn) |
| OMIM | 139139 (Hs) |
| Pharos | P22736 (Hs) |
| RefSeq Nucleotide | NM_002135 (Hs), NM_010444 (Mm), NM_024388 (Rn) |
| RefSeq Protein | NP_002126 (Hs), NP_034574 (Mm), NP_077364 (Rn) |
| UniProtKB | P22736 (Hs), P12813 (Mm), P22829 (Rn) |
| Wikipedia | NR4A1 (Hs) |
| Selected 3D Structures |
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| Natural/Endogenous Ligands |
| Comments: Orphan |
Download all structure-activity data for this target as a CSV file 
| Agonists |
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Antagonist Comments | ||
| Based on alignment with the related NR4A subfamilly members and on 3D structure analysis of the LBD, NR4A1 as the others NR4A receptors have been shown to be unable to interact with ligands due to the lack of an identifiable ligand binding pocket (LBP) [2,8,25]. |
| DNA Binding |
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| DNA Binding Comments | |||||||
| NR4A1 is able to interact with DNA in various manner. As monomers, NR4A1 as other N4R4A subfamily members interact with the so-called NBRE sequence (AAAGGTCA). NR4A1 also interacts with DNA as an heterodimer with RXR and bind NBRE as well as DR5 response elements (AGGTCA nnnAA AGGTCA). NR4A1 is also able to homodimerize and to heterodimerize with other NR4A family members and bind the so-called NuRE sequence which has the structure of an ER10 (two AGGTCA elements as everted repeats spaced by 10 bp, the two immediate 5’ bases of each element being As). | |||||||
| Co-binding Partners |
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| Name | Interaction | Effect | Reference |
| Nuclear receptor related 1 | Physical, Functional | DNA binding | 13 |
| Neuron-derived orphan receptor 1 | Physical, Functional | DNA binding | 13 |
| Glucocorticoid receptor | Physical, Functional | DNA binding. GR antagonizes NurRE-dependent transcription induced by all members of the NR4A subfamily. These nuclear receptors can all interact directly with GR. | 14 |
| BCL2 | Physical, Functional | Cellular localization. Nur77 binding induces a Bcl-2 conformational change that exposes its BH3 domain, resulting in conversion of Bcl-2 from a protector to a killer. Non genomic effects of NR4A1 is still a controversial issue. | 12 |
| AKT1 | Physical, Functional | DNA binding:- AKT1 specifically phosphorylates Ser-350 of the Nur77 protein within its DNA-binding domain in vitro and in vivo | 15,20 |
| Notch1 | Physical, Functional | Notch-1 interacts with Nur77, the human ortholog of NGFI-B and seems to repress Nur77 dependent transcription and rescue T-cell receptor mediated apoptosis | 10 |
| Main Co-regulators |
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| Name | Activity | Specific | Ligand dependent | AF-2 dependent | Comments | References |
| EP300 | Co-activator | No | No | No | 26 | |
| KAT2B | Other | - | No | - | 26 | |
| NCOA1 | Co-activator | Yes | No | No | NR4A1 seems to interact with SRC-1 via its a/B domain. SRC-1 modulates the activity of the N-terminal AF-1 domain. | 26 |
| NCOA2 | Co-activator | No | No | No | NR4A1 seems to interact with SRC-2 via its a/B domain. SRC-2 modulates the activity of the N-terminal AF-1 domain. | 26 |
| NCOA3 | Co-activator | No | No | No | NR4A1 seems to interact with SRC-3 via its a/B domain. SRC-3 modulates the activity of the N-terminal AF-1 domain. | 26 |
| MED1 | Co-activator | No | No | No | TRAP220 interacts with the NR4A1-3 subgroup in an AF-1-dependent manner depending of the cellular context. | 26 |
| Main Target Genes |
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| Name | Species | Effect | Technique | Comments | References |
| POMC | Human | Activated | ChIP, Transient transfection, EMSA | 21 | |
| CYP21A2 | Human | Activated | Transient transfection, EMSA, Footprint | NR4A1 activates transcription of the steroid 21-hydroxylase gene in adrenal, this is seen in rodents as well | 29 |
| CYP17A1 | Human | Activated | Transient transfection, EMSA | NR4A1 can not activate CYP17A1 (steroid 17-hydroxylase) alone but synergize with other transcription factors in adrenal.(NB this interaction is also seen in rodents) | 31 |
| INSL3 | Human | Activated | ChIP, Transient transfection, EMSA | 22 | |
| E2F1 | Human | Activated | Transient transfection, EMSA | 17,19 | |
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| NR4A1 is expressed as a 2.5 kb mRNA which is inducible by growth factors and serum. The three NR4A subfamily members are expressed in a complex pattern in the nervous system where they are induced as part of the immediate early response to stimuli such as growth factors, membrane depolarisation and seizure. Their expression pattern outside the nervous system is quite large. Major sites of expression of NR4A1 outside brain involve pituitary, adrenal, thyroid as well as liver, testis, ovary, thymus, muscle, lung and prostate. The regulation of NR4A1 expression by growth factors has been studied in details by the cloning and characterisation of its promoter. Several elements able to respond to serum have been located in the NR4A1 promoter and its response to members of the AP-1 complex such as c-fos or junD has been studied. NB: similar express patterns are seen in all mammals including the rat and mouse. | ||||||||
| 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. Altin JG, Kujubu DA, Raffioni S, Eveleth DD, Herschman HR, Bradshaw RA. (1991) Differential induction of primary-response (TIS) genes in PC12 pheochromocytoma cells and the unresponsive variant PC12nnr5. J Biol Chem, 266 (9): 5401-6. [PMID:2005087]
2. Baker KD, Shewchuk LM, Kozlova T, Makishima M, Hassell A, Wisely B, Caravella JA, Lambert MH, Reinking JL, Krause H, Thummel CS, Willson TM, Mangelsdorf DJ. (2003) The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway. Cell, 113 (6): 731-42. [PMID:12809604]
3. Bandoh S, Tsukada T, Maruyama K, Ohkura N, Yamaguchi K. (1997) Differential expression of NGFI-B and RNR-1 genes in various tissues and developing brain of the rat: comparative study by quantitative reverse transcription-polymerase chain reaction. J Neuroendocrinol, 9 (1): 3-8. [PMID:9023733]
4. Bondy GP. (1991) Phorbol ester, forskolin, and serum induction of a human colon nuclear hormone receptor gene related to the NUR 77/NGFI-B genes. Cell Growth Differ, 2 (4): 203-8. [PMID:1651101]
5. Chandy KG, Williams CB, Spencer RH, Aguilar BA, Ghanshani S, Tempel BL, Gutman GA. (1990) A family of three mouse potassium channel genes with intronless coding regions. Science, 247 (4945): 973-5. [PMID:2305265]
6. Chen Z, Zhang D, Yan S, Hu C, Huang Z, Li Z, Peng S, Li X, Zhu Y, Yu H et al.. (2019) SAR study of celastrol analogs targeting Nur77-mediated inflammatory pathway. Eur J Med Chem, 177: 171-187. [PMID:31132532]
7. Ethier I, Beaudry G, St-Hilaire M, Milbrandt J, Rouillard C, Lévesque D. (2004) The transcription factor NGFI-B (Nur77) and retinoids play a critical role in acute neuroleptic-induced extrapyramidal effect and striatal neuropeptide gene expression. Neuropsychopharmacology, 29 (2): 335-46. [PMID:14603264]
8. Flaig R, Greschik H, Peluso-Iltis C, Moras D. (2005) Structural basis for the cell-specific activities of the NGFI-B and the Nurr1 ligand-binding domain. J Biol Chem, 280 (19): 19250-8. [PMID:15716272]
9. Hazel TG, Nathans D, Lau LF. (1988) A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc Natl Acad Sci USA, 85 (22): 8444-8. [PMID:3186734]
10. Jehn BM, Bielke W, Pear WS, Osborne BA. (1999) Cutting edge: protective effects of notch-1 on TCR-induced apoptosis. J Immunol, 162 (2): 635-8. [PMID:9916679]
11. Lee SL, Wesselschmidt RL, Linette GP, Kanagawa O, Russell JH, Milbrandt J. (1995) Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science, 269 (5223): 532-5. [PMID:7624775]
12. Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK. (2004) Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell, 116 (4): 527-40. [PMID:14980220]
13. Maira M, Martens C, Philips A, Drouin J. (1999) Heterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activation. Mol Cell Biol, 19 (11): 7549-57. [PMID:10523643]
14. Martens C, Bilodeau S, Maira M, Gauthier Y, Drouin J. (2005) Protein-protein interactions and transcriptional antagonism between the subfamily of NGFI-B/Nur77 orphan nuclear receptors and glucocorticoid receptor. Mol Endocrinol, 19 (4): 885-97. [PMID:15591535]
15. Masuyama N, Oishi K, Mori Y, Ueno T, Takahama Y, Gotoh Y. (2001) Akt inhibits the orphan nuclear receptor Nur77 and T-cell apoptosis. J Biol Chem, 276 (35): 32799-805. [PMID:11438550]
16. Milbrandt J. (1988) Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron, 1 (3): 183-8. [PMID:3272167]
17. Mu X, Chang C. (2003) TR3 orphan nuclear receptor mediates apoptosis through up-regulating E2F1 in human prostate cancer LNCaP cells. J Biol Chem, 278 (44): 42840-5. [PMID:12947120]
18. Nakai A, Kartha S, Sakurai A, Toback FG, DeGroot LJ. (1990) A human early response gene homologous to murine nur77 and rat NGFI-B, and related to the nuclear receptor superfamily. Mol Endocrinol, 4 (10): 1438-43. [PMID:2283997]
19. Park KC, Song KH, Chung HK, Kim H, Kim DW, Song JH, Hwang ES, Jung HS, Park SH, Bae I, Lee IK, Choi HS, Shong M. (2005) CR6-interacting factor 1 interacts with orphan nuclear receptor Nur77 and inhibits its transactivation. Mol Endocrinol, 19 (1): 12-24. [PMID:15459248]
20. Pekarsky Y, Hallas C, Palamarchuk A, Koval A, Bullrich F, Hirata Y, Bichi R, Letofsky J, Croce CM. (2001) Akt phosphorylates and regulates the orphan nuclear receptor Nur77. Proc Natl Acad Sci USA, 98 (7): 3690-4. [PMID:11274386]
21. Philips A, Lesage S, Gingras R, Maira MH, Gauthier Y, Hugo P, Drouin J. (1997) Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol, 17 (10): 5946-51. [PMID:9315652]
22. Robert NM, Martin LJ, Tremblay JJ. (2006) The orphan nuclear receptor NR4A1 regulates insulin-like 3 gene transcription in Leydig cells. Biol Reprod, 74 (2): 322-30. [PMID:16237153]
23. Ryseck RP, Macdonald-Bravo H, Mattéi MG, Ruppert S, Bravo R. (1989) Structure, mapping and expression of a growth factor inducible gene encoding a putative nuclear hormonal binding receptor. EMBO J, 8 (11): 3327-35. [PMID:2555161]
24. Stiller T, Merk D. (2023) Exploring Fatty Acid Mimetics as NR4A Ligands. J Med Chem, 66 (22): 15362-15369. [PMID:37918435]
25. Wang Z, Benoit G, Liu J, Prasad S, Aarnisalo P, Liu X, Xu H, Walker NP, Perlmann T. (2003) Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature, 423 (6939): 555-60. [PMID:12774125]
26. Wansa KD, Harris JM, Muscat GE. (2002) The activation function-1 domain of Nur77/NR4A1 mediates trans-activation, cell specificity, and coactivator recruitment. J Biol Chem, 277 (36): 33001-11. [PMID:12082103]
27. Watson MA, Milbrandt J. (1990) Expression of the nerve growth factor-regulated NGFI-A and NGFI-B genes in the developing rat. Development, 110 (1): 173-83. [PMID:2081458]
28. Williams GT, Lau LF. (1993) Activation of the inducible orphan receptor gene nur77 by serum growth factors: dissociation of immediate-early and delayed-early responses. Mol Cell Biol, 13 (10): 6124-36. [PMID:8413214]
29. Wilson TE, Mouw AR, Weaver CA, Milbrandt J, Parker KL. (1993) The orphan nuclear receptor NGFI-B regulates expression of the gene encoding steroid 21-hydroxylase. Mol Cell Biol, 13 (2): 861-8. [PMID:8380897]
30. Zetterström RH, Williams R, Perlmann T, Olson L. (1996) Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system. Brain Res Mol Brain Res, 41 (1-2): 111-20. [PMID:8883941]
31. Zhang P, Mellon SH. (1997) Multiple orphan nuclear receptors converge to regulate rat P450c17 gene transcription: novel mechanisms for orphan nuclear receptor action. Mol Endocrinol, 11 (7): 891-904. [PMID:9178749]
4A. Nerve growth factor IB-like receptors: Nerve Growth factor IB. Last modified on 11/09/2024. Accessed on 14/01/2025. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=629.
