Nerve Growth factor IB

Nomenclature: Nerve Growth factor IB

Systematic Nomenclature: NR4A1

Family: 4A. Nerve growth factor IB-like receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 598 12q13 NR4A1 nuclear receptor subfamily 4, group A, member 1 4-5,17
Mouse 601 15F3 Nr4a1 nuclear receptor subfamily 4, group A, member 1 8,22
Rat 563 7q36 Nr4a1 nuclear receptor subfamily 4, group A, member 1 1,15
Previous and Unofficial Names
NGFIB
GFRP1
MGC9485
N10
NAK-1
NP10
NUR77
NGFI-B
NAK1
ST59
nur77
TR3
HMR
Orphan nuclear receptor HMR
immediate early gene transcription factor NGFI-B
nerve growth factor induced protein I-B
nerve growth factor-induced protein I-B
nuclear receptor subfamily 4 group A member 1
nuclear receptor subfamily 4, group A, member 1
TIS1
Hbr-1
Gfrp
Hbr1
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
NURSA Receptor
OMIM
PharmGKB Gene
PhosphoSitePlus
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Nr4A1 Ligand-Binding Domain
PDB Id:  2QW4
Resolution:  2.8Å
Species:  Human
References: 
Natural/Endogenous Ligands
Comments: Orphan
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) [2,7,23].
DNA Binding
Structure:  Monomer, Homodimer, Heterodimer, RXR partner
HRE core sequence:  AAAGGTCA
Response element:  Other - see comments
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
Name Interaction Effect Reference
Nuclear receptor related 1 Physical, Functional DNA binding 12
Neuron-derived orphan receptor 1 Physical, Functional DNA binding 12
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. 13
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. 11
AKT1 Physical, Functional DNA binding:- AKT1 specifically phosphorylates Ser-350 of the Nur77 protein within its DNA-binding domain in vitro and in vivo 14,19
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 9
Main Co-regulators
Name Activity Specific Ligand dependent AF-2 dependent Comments References
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. 24
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. 24
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. 24
EP300 Co-activator No No No 24
MED1 Co-activator No No No TRAP220 interacts with the NR4A1-3 subgroup in an AF-1-dependent manner depending of the cellular context. 24
KAT2B Other - No - 24
Main Target Genes
Name Species Effect Technique Comments References
POMC Human Activated ChIP, Transient transfection, EMSA 20
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 27
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) 29
INSL3 Human Activated ChIP, Transient transfection, EMSA 21
E2F1 Human Activated Transient transfection, EMSA 16,18
Tissue Distribution
Nervous system, pituitary, adrenal, thyroid, liver, testis, ovary, thymus, muscle, lung, prostate
Species:  Human
Technique:  Northern, in situ, Western, immunohistology, other
References:  3,8,15,22,25-26,28
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
NR4A1 knockout mice exhibit no clear phenotype suggesting functional redundancy between NR4A subfamilly members in vivo. However, an altered neuropeptide expression pattern is observed in NGFI-B knock-out mice
Species:  Mouse
Tissue: 
Technique:  Knockout
References:  6,10
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0000172 abnormal bone marrow cell number PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0006410 abnormal common myeloid progenitor cell morphology PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0005460 abnormal leukopoiesis PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0001601 abnormal myelopoiesis PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0000689 abnormal spleen morphology PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0000703 abnormal thymus morphology PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0001577 anemia PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0001265 decreased body size PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0005016 decreased lymphocyte cell number PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0000599 enlarged liver PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0000702 enlarged lymph nodes PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0000691 enlarged spleen PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0001505 hunched posture PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0005011 increased eosinophil cell number PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0000322 increased granulocyte number PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0004809 increased hematopoietic stem cell number PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0000218 increased leukocyte cell number PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0000219 increased neutrophil cell number PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0002026 leukemia PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0002082 postnatal lethality PMID: 17515897 
Nr4a1tm1Jmi|Nr4a3tm1Omc Nr4a1tm1Jmi/Nr4a1tm1Jmi,Nr4a3tm1Omc/Nr4a3tm1Omc
involves: 129S/SvEv * 129S2/SvPas * C57BL/6
MGI:1352454  MGI:1352457  MP:0000420 ruffled hair PMID: 17515897 

References

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How to cite this page

4A. Nerve growth factor IB-like receptors: Nerve Growth factor IB. Last modified on 13/12/2013. Accessed on 17/09/2014. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=629.