NR4A3

Summary

NR4A3 (nuclear receptor subfamily 4 group A member 3, HGNC:7982) is a protein-coding gene on chromosome 9q31.1, encoding Nuclear receptor subfamily 4 group A member 3 (Q92570). Transcriptional activator that binds to regulatory elements in promoter regions in a cell- and response element (target)-specific manner.

This gene encodes a member of the steroid-thyroid hormone-retinoid receptor superfamily. The encoded protein may act as a transcriptional activator. The protein can efficiently bind the NGFI-B Response Element (NBRE). Three different versions of extraskeletal myxoid chondrosarcomas (EMCs) are the result of reciprocal translocations between this gene and other genes. The translocation breakpoints are associated with Nuclear Receptor Subfamily 4, Group A, Member 3 (on chromosome 9) and either Ewing Sarcome Breakpoint Region 1 (on chromosome 22), RNA Polymerase II, TATA Box-Binding Protein-Associated Factor, 68-KD (on chromosome 17), or Transcription factor 12 (on chromosome 15). Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8013 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 48 total
• Phenotypes (HPO): 2
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• Transcription factor: yes — 43 downstream targets (CollecTRI)
• MANE Select transcript: NM_006981

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7982
Approved symbol	NR4A3
Name	nuclear receptor subfamily 4 group A member 3
Location	9q31.1
Locus type	gene with protein product
Status	Approved
Aliases	CSMF, CHN, NOR1, MINOR
Ensembl gene	ENSG00000119508
Ensembl biotype	protein_coding
OMIM	600542
Entrez	8013

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000330847, ENST00000338488, ENST00000395097, ENST00000618101

RefSeq mRNA: 3 — MANE Select: NM_006981 NM_006981, NM_173199, NM_173200

CCDS: CCDS6742, CCDS6743, CCDS6744

Canonical transcript exons

ENST00000395097 — 8 exons

Exon	Start	End
ENSE00000805727	99832689	99832818
ENSE00000805731	99844649	99844848
ENSE00000805733	99847437	99847615
ENSE00001384030	99833282	99833454
ENSE00001389327	99863620	99866891
ENSE00001409394	99825659	99825832
ENSE00003527866	99828041	99828993
ENSE00003850329	99821885	99822407

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 95.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.3104 / max 4981.4765, expressed in 1289 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
97683	10.4825	934
97680	8.4007	755
97679	4.5868	764
97682	3.1562	629
97684	1.1888	356
97681	0.5708	226
97691	0.4984	205
97685	0.3684	87
97693	0.2448	114
97692	0.2119	70

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of paranasal sinus	UBERON:0005030	95.89	gold quality
mucosa of urinary bladder	UBERON:0001259	94.77	gold quality
cauda epididymis	UBERON:0004360	94.64	gold quality
mucosa of stomach	UBERON:0001199	90.98	gold quality
adrenal tissue	UBERON:0018303	90.65	gold quality
vena cava	UBERON:0004087	90.23	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.03	gold quality
gall bladder	UBERON:0002110	89.27	gold quality
cortical plate	UBERON:0005343	89.10	gold quality
heart right ventricle	UBERON:0002080	88.68	gold quality
popliteal artery	UBERON:0002250	88.62	gold quality
tibial artery	UBERON:0007610	88.62	gold quality
left uterine tube	UBERON:0001303	88.06	gold quality
parietal pleura	UBERON:0002400	87.45	gold quality
nephron tubule	UBERON:0001231	86.74	gold quality
right atrium auricular region	UBERON:0006631	86.46	gold quality
gastrocnemius	UBERON:0001388	86.36	gold quality
omental fat pad	UBERON:0010414	86.28	gold quality
peritoneum	UBERON:0002358	86.22	gold quality
buccal mucosa cell	CL:0002336	86.05	silver quality
endothelial cell	CL:0000115	85.95	gold quality
cardiac atrium	UBERON:0002081	85.95	gold quality
pleura	UBERON:0000977	85.89	gold quality
cranial nerve II	UBERON:0000941	85.29	gold quality
metanephric glomerulus	UBERON:0004736	85.02	gold quality
lower lobe of lung	UBERON:0008949	84.96	silver quality
superficial temporal artery	UBERON:0001614	84.55	gold quality
renal glomerulus	UBERON:0000074	84.48	gold quality
left ventricle myocardium	UBERON:0006566	84.47	gold quality
left ovary	UBERON:0002119	84.14	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	13.01
E-CURD-46	yes	8.80
E-MTAB-8498	yes	8.67
E-MTAB-6678	yes	5.35
E-HCAD-29	no	3028.00
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

43 targets.

Target	Regulation
ADAM2
ADCYAP1
AK5
ALS3
BAX	Activation
BBC3	Activation
BIRC3
BTK
CCL2	Repression
CCL3	Repression
CCND1	Activation
CD28
CRH
CSF2
CYBB
CYP19A1
EHD1
EMD
F2
GUSB
HGF
HLA-G
ICAM1	Activation
IL1B	Repression
IL2
IL4
IL6	Repression
INS
ITK
KRT5

Upstream regulators (CollecTRI, top): CREB1, HIF1A, HSF1, NR3C1, NR4A1, NR4A3, NRF1, PDGFB, RELA, TLX1, TP53

miRNA regulators (miRDB)

271 targeting NR4A3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3120-5P	100.00	65.56	965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964

Literature-anchored findings (GeneRIF, showing 40)

• The homeotic protein Six3 is a coactivator of the nuclear receptor NOR-1 and a corepressor of the fusion protein EWS/NOR-1 in human extraskeletal myxoid chondrosarcomas. (PMID:12543801)
• The genes identified here are novel candidates as key early mediators of VEGF-induced endothelial functions. (PMID:14525795)
• In vascular smooth muscle cells, LDL-induced mitogenesis involves NOR-1 upregulation through a CREB-dependent mechanism. Mutation of specific CRE sites in the NOR-1 promoter abolishes LDL-induced NOR-1 promoter activity. (PMID:14962944)
• Aberrant coexpression of NOR1 and SIX3 is a potential alternative mechanism underlying the development of extraskeletal myxoid chondrosarcomas (PMID:15262426)
• different SIX3 mutations in HPE2 may affect different signaling pathways, and that one of these pathways may involve the nuclear receptor NOR1 (PMID:15523651)
• Neuron-derived orphan receptor-1 (NOR-1) is a transcription factor over-expressed in human atherosclerotic plaques that is involved in vascular smooth muscle cell proliferation. (PMID:15949808)
• NR4A nuclear receptors NR4A1, NR4A2, NR4A3 are potential transcriptional mediators of inflammatory signals in activated macrophages (PMID:15964844)
• Nur77, Nurr1, and NOR-1 are expressed in human atherosclerotic lesion macrophages and reduce human macrophage lipid loading and inflammatory responses, providing further evidence for a protective role of these factors in atherogenesis. (PMID:16873729)
• platelet-derived growth factor-induced NOR1 transcription in smooth muscle cell is mediated through cAMP-response element-binding protein-dependent transactivation of the NOR1 promoter (PMID:16945922)
• NOR-1 is a critical tumor suppressor of myeloid leukemogenesis that is downregulated in leukemic blasts from acute myeloid leukemia patients. (PMID:17515897)
• NOR-1 up-regulation plays a key role in thrombin-induced endothelial cell growth (PMID:17596136)
• NOR-1 is over-expressed in human atherosclerotic plaques and in porcine arteries subjected to angioplasty, is induced by growth factors in vascular cells and it has been involved in cell migration and proliferation (PMID:17981763)
• NOR-1 is necessary for oxidative metabolism in skeletal muscle. (PMID:18325999)
• common genetic variation within the NR4A3 locus determines insulin secretion (PMID:19682370)
• NOR-1 is a downstream effector of HIF-1 signaling involved in the survival response of endothelial cells to hypoxia. (PMID:19720740)
• NOR1 protein is frequently down-expressed in Nasopharyngeal carcinoma. (PMID:19727524)
• These results suggest that FISH analysis of formalin-fixed, paraffin-embedded specimens using EWSR1 and NR4A3 probes is useful and convenient and may provide an ancillary method for the diagnosis of extraskeletal myxoid chondrosarcomas. (PMID:19775727)
• Protein kinase C-regulated role in TCR-induced thymocyte apoptosis (PMID:20411565)
• A novel pathway is identified that establishes NOR1 orphan nuclear receptor in an atherogenic role by positively regulating monocyte recruitment to the vascular wall. (PMID:20558821)
• Results identified the NR4A3 gene is associated with the quantity of tobacco smoked in subjects with schizophrenia; this association was replicated in a population of individuals with bipolar disorder. (PMID:20659174)
• Loss of NR4A3 is associated with thyroid follicular neoplasia. (PMID:20668010)
• stimulation of peripheral blood mast cells caused a robust upregulation of NR4A2 and, in particular, NR4A3, while NR4A1 expression was only moderately affected (PMID:21621845)
• Data from patients with familial platelet disorder/acute myelogenous leukemia indicate a correlation between increased clonogenic potential of patient hematopoietic progenitor cells and NR4A3 expression. Data indicate NR4A3 is direct target of RUNX1. (PMID:21725049)
• Low expression of NR4A gene family members (NR4A1, NR4A3) and 1-alpha25-dihydroxyvitamin D3 receptor (VDR) genes is demonstrated in peripheral blood mononuclear cells of multiple sclerosis patients. (PMID:21752397)
• NOR1 isoform 1 and isoform 2 are both detected in fetal brain. NOR1 isoform 2 lacking exon 2 is the sole isoform in multiple tissues except for brain. (PMID:21873782)
• Data show altered adipose tissue expression of the NOR1 stress-responsive nuclear receptor in obesity, suggesting it may modulate pathogenic potential in humans. (PMID:22143616)
• The pathognomic rearrangement of NR4A3 is a useful diagnostic feature in identifying cellular extraskeletal myxoid chondrosarcomas. (PMID:22569967)
• Pin1 enhances the transcriptional activity of all three NR4A nuclear receptors and increases protein stability of Nur77 through inhibition of its ubiquitination. (PMID:22789442)
• present work is the first report of a novel mechanism of HDAC inhibitor-induced apoptosis in AML that involves restoration of the silenced nuclear receptors Nur77 and Nor1 (PMID:23247046)
• Over-expression of neuron-derived orphan receptor-1 (NOR-1) exacerbates neointimal hyperplasia after vascular injury (PMID:23390133)
• Nor-1 and its gene targets are also up-regulated in human HCC samples. (PMID:23462179)
• Results indicate that miR-638 is a key molecule in regulating vascular smooth muscle cell proliferation and migration by targeting the NOR1/cyclin D pathway. (PMID:23554459)
• We molecularly confirmed NR4A3/EWSR1 rearrangements as myxochondroid sarcoma, either osseous or extraskeletal variants. (PMID:23588370)
• NR4A nuclear receptors are involved in negative selection of thymocytes, Treg differentiation and the development of Ly6C monocytes. Nur77 and Nurr1 attenuate atherosclerosis in mice whereas NOR-1 aggravates vascular lesion formation. (PMID:24005216)
• Results indicate that DNA hypomethylation of the CpG island at Nr4a3 exon 3 is associated with low Nr4a3 expression, and correlates with poor prognosis of neuroblastoma. (PMID:24626568)
• These results reinforce the role of NOR-1 in vascular smooth muscle cells proliferation and in vascular remodelling (PMID:24630523)
• NOR1 suppresses slug/vimentin expression to inhibit epithelial-mesenchymal transformation in nasopharyngeal carcinoma. (PMID:24657653)
• NOR1 expression causes apoptosis of tumor cells in hypoxia by altering the expression of PDK1 expression and mitochondrial Bax-Bcl2 balance thus suppress tumor cell adaptation to hypoxia (PMID:24788728)
• Studies demonstrate that NOR1 deletion in hematopoietic stem cells accelerates atherosclerosis formation by promoting myelopoiesis in the stem cell compartment and by inducing local proatherogenic activities in the macrophage. (PMID:24806827)
• In this review, a concise overview of the current understanding of the important metabolic roles governed by NR4A members NR4A1, NR4A2 and NR4A3 including their participation in a number of diseases shall be provided (PMID:25089663)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nr4a3	ENSDARG00000055854
mus_musculus	Nr4a3	ENSMUSG00000028341
rattus_norvegicus	Nr4a3	ENSRNOG00000005964
drosophila_melanogaster	Hr38	FBGN0014859
caenorhabditis_elegans		WBGENE00003605

Paralogs (2): NR4A1 (ENSG00000123358), NR4A2 (ENSG00000153234)

Protein

Protein identifiers

Nuclear receptor subfamily 4 group A member 3 — Q92570 (reviewed: Q92570)

Alternative names: Mitogen-induced nuclear orphan receptor, Neuron-derived orphan receptor 1, Nuclear hormone receptor NOR-1, Translocated in extraskeletal chondrosarcoma

All UniProt accessions (1): Q92570

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator that binds to regulatory elements in promoter regions in a cell- and response element (target)-specific manner. Induces gene expression by binding as monomers to the NR4A1 response element (NBRE) 5’-AAAAGGTCA-3’ site and as homodimers to the Nur response element (NurRE) site in the promoter of their regulated target genes. Plays a role in the regulation of proliferation, survival and differentiation of many different cell types and also in metabolism and inflammation. Mediates proliferation of vascular smooth muscle, myeloid progenitor cell and type B pancreatic cells; promotes mitogen-induced vascular smooth muscle cell proliferation through transactivation of SKP2 promoter by binding a NBRE site. Upon PDGF stimulation, stimulates vascular smooth muscle cell proliferation by regulating CCND1 and CCND2 expression. In islets, induces type B pancreatic cell proliferation through up-regulation of genes that activate cell cycle, as well as genes that cause degradation of the CDKN1A. Negatively regulates myeloid progenitor cell proliferation by repressing RUNX1 in a NBRE site-independent manner. During inner ear, plays a role as a key mediator of the proliferative growth phase of semicircular canal development. Also mediates survival of neuron and smooth muscle cells; mediates CREB-induced neuronal survival, and during hippocampus development, plays a critical role in pyramidal cell survival and axonal guidance. Is required for S phase entry of the cell cycle and survival of smooth muscle cells by inducing CCND1, resulting in RB1 phosphorylation. Binds to NBRE motif in CCND1 promoter, resulting in the activation of the promoter and CCND1 transcription. Also plays a role in inflammation; upon TNF stimulation, mediates monocyte adhesion by inducing the expression of VCAM1 and ICAM1 by binding to the NBRE consensus site. In mast cells activated by Fc-epsilon receptor cross-linking, promotes the synthesis and release of cytokines but impairs events leading to degranulation. Also plays a role in metabolism; by modulating feeding behavior; and by playing a role in energy balance by inhibiting the glucocorticoid-induced orexigenic neuropeptides AGRP expression, at least in part by forming a complex with activated NR3C1 on the AGRP- glucocorticoid response element (GRE), and thus weakening the DNA binding activity of NR3C1. Upon catecholamines stimulation, regulates gene expression that controls oxidative metabolism in skeletal muscle. Plays a role in glucose transport by regulating translocation of the SLC2A4 glucose transporter to the cell surface. Finally, during gastrulation plays a crucial role in the formation of anterior mesoderm by controlling cell migration. Inhibits adipogenesis. Also participates in cardiac hypertrophy by activating PARP1.

Subunit / interactions. Interacts with SIX3 (via homeobox); differentially regulates the transcriptional activities of NR4A3. Interacts with the constituents of DNA-PK heterotrimer PRKDC, XRCC6 and XRCC5; phosphorylates and prevents NR4A3 ubiquitinylation and degradation. Interacts with NCOA2; potentiates the activity of the NR4A3. Interacts with NCOA1, NCOA3, MED1 and KAT2B. Interacts with EP300 and NCOA2; mediates the recruitment of MED1 in the coactivator complex. Interacts with NR3C1 (via nuclear receptor DNA-binding domain); the interactions represses transcription activity of NR4A3 on the POMC promoter Nur response element (NurRE). Interacts with TRIM28; the interactions potentiates NR4A3 activity on NurRE promoter. Binds DNA as a monomer and homodimer. Interacts with PARP1; activates PARP1 by improving acetylation of PARP1 and suppressing the interaction between PARP1 and SIRT1.

Subcellular location. Nucleus.

Tissue specificity. Isoform alpha is highly expressed in skeletal muscle. Isoform beta is highly expressed in skeletal muscle and low expressed in fetal brain and placenta.

Post-translational modifications. Phosphorylated by PRKDC.

Disease relevance. Ewing sarcoma (ES) [MIM:612219] A highly malignant, metastatic, primitive small round cell tumor of bone and soft tissue that affects children and adolescents. It belongs to the Ewing sarcoma family of tumors, a group of morphologically heterogeneous neoplasms that share the same cytogenetic features. They are considered neural tumors derived from cells of the neural crest. Ewing sarcoma represents the less differentiated form of the tumors. The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving NR4A3 is found in patients with Erwing sarcoma. Translocation t(9;22)(q22-31;q11-12) with EWSR1. A chromosomal aberration involving NR4A3 is a cause of a form of extraskeletal myxoid chondrosarcomas (EMC). Translocation t(9;17)(q22;q11) with TAF2N.

Domain organisation. The AF-1 domain mediates transcription activation. The N-terminal region (1-292) directly interacts with the C-terminal LBD (380-627): the interaction is potentiated by AF-1-mediated recruitment of NCOA2.

Induction. Induced by inflammatory stimuli in endothelial cells through an NF-kappa-B-dependent transactivation of the NR4A3 Promoter.

Similarity. Belongs to the nuclear hormone receptor family. NR4 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q92570-1	Alpha	yes
Q92570-2	Beta
Q92570-3	3

RefSeq proteins (3): NP_008912, NP_775291, NP_775292 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001628	Znf_hrmn_rcpt	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR003070	NR4A1-3	Family
IPR003072	NR4A3	Family
IPR013088	Znf_NHR/GATA	Homologous_superfamily
IPR035500	NHR-like_dom_sf	Homologous_superfamily

Pfam: PF00104, PF00105

UniProt features (25 total): region of interest 8, compositionally biased region 5, sequence conflict 4, splice variant 3, zinc finger region 2, chain 1, domain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8XTT	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92570-F1	65.00	0.38

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8936459	RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function
R-HSA-383280	Nuclear Receptor transcription pathway

MSigDB gene sets: 755 (showing top): GOBP_PLATELET_DERIVED_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, BROWNE_HCMV_INFECTION_4HR_UP, RRAGTTGT_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_CARBOHYDRATE_TRANSPORT, WALLACE_PROSTATE_CANCER_RACE_UP, BENPORATH_ES_WITH_H3K27ME3, HNF3ALPHA_Q6, GOBP_BEHAVIOR, YAGI_AML_WITH_INV_16_TRANSLOCATION, PAX4_01, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS

GO Biological Process (47): negative regulation of transcription by RNA polymerase II (GO:0000122), mesoderm formation (GO:0001707), regulation of transcription by RNA polymerase II (GO:0006357), gastrulation (GO:0007369), axon guidance (GO:0007411), positive regulation of cardiac muscle hypertrophy (GO:0010613), positive regulation of D-glucose transmembrane transport (GO:0010828), hippocampus development (GO:0021766), adult behavior (GO:0030534), positive regulation of mast cell cytokine production (GO:0032765), smooth muscle cell apoptotic process (GO:0034390), negative regulation of smooth muscle cell apoptotic process (GO:0034392), intracellular signal transduction (GO:0035556), common myeloid progenitor cell proliferation (GO:0035726), positive regulation of mast cell activation by Fc-epsilon receptor signaling pathway (GO:0038097), response to hydrogen peroxide (GO:0042542), mast cell degranulation (GO:0043303), negative regulation of neuron apoptotic process (GO:0043524), cellular response to leptin stimulus (GO:0044320), cellular respiration (GO:0045333), fat cell differentiation (GO:0045444), positive regulation of cell cycle (GO:0045787), positive regulation of transcription by RNA polymerase II (GO:0045944), platelet-derived growth factor receptor signaling pathway (GO:0048008), regulation of smooth muscle cell proliferation (GO:0048660), positive regulation of smooth muscle cell proliferation (GO:0048661), semicircular canal morphogenesis (GO:0048752), positive regulation of epithelial cell proliferation (GO:0050679), negative regulation of inflammatory response (GO:0050728), neuromuscular process controlling balance (GO:0050885), neuron apoptotic process (GO:0051402), vestibular reflex (GO:0060005), regulation of type B pancreatic cell proliferation (GO:0061469), cellular response to corticotropin-releasing hormone stimulus (GO:0071376), cellular response to catecholamine stimulus (GO:0071870), energy homeostasis (GO:0097009), dendritic cell apoptotic process (GO:0097048), positive regulation of monocyte aggregation (GO:1900625), positive regulation of vascular associated smooth muscle cell proliferation (GO:1904707), positive regulation of vascular associated smooth muscle cell migration (GO:1904754)

GO Molecular Function (18): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coactivator binding (GO:0001223), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), nuclear steroid receptor activity (GO:0003707), nuclear receptor activity (GO:0004879), zinc ion binding (GO:0008270), protein kinase binding (GO:0019901), histone acetyltransferase binding (GO:0035035), nuclear glucocorticoid receptor binding (GO:0035259), cAMP response element binding (GO:0035497), protein homodimerization activity (GO:0042803), DNA-binding transcription activator activity (GO:0001216), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Transcriptional regulation by RUNX1	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
DNA-binding transcription factor activity	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
formation of primary germ layer	1
mesoderm morphogenesis	1
ectoderm formation	1
endoderm formation	1
mesoderm formation	1
embryonic morphogenesis	1
axonogenesis	1
neuron projection guidance	1
cardiac muscle hypertrophy	1
regulation of cardiac muscle hypertrophy	1
positive regulation of muscle hypertrophy	1
regulation of D-glucose transmembrane transport	1
positive regulation of transmembrane transport	1
D-glucose transmembrane transport	1
pallium development	1
limbic system development	1
anatomical structure development	1
behavior	1
mast cell cytokine production	1
regulation of mast cell cytokine production	1
positive regulation of myeloid leukocyte cytokine production involved in immune response	1
muscle cell apoptotic process	1
negative regulation of muscle cell apoptotic process	1
smooth muscle cell apoptotic process	1
regulation of smooth muscle cell apoptotic process	1
intracellular anatomical structure	1
signal transduction	1
cell population proliferation	1
Fc receptor mediated stimulatory signaling pathway	1
positive regulation of mast cell activation	1
Fc-epsilon receptor signaling pathway	1

Protein interactions and networks

STRING

1420 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NR4A3	EWSR1	Q01844	900
NR4A3	TAF15	Q92804	866
NR4A3	TCF12	Q99081	816
NR4A3	STX17	P56962	812
NR4A3	FUS	P35637	780
NR4A3	MC1R	Q01726	588
NR4A3	JUN	P05412	582
NR4A3	NTRK1	P04629	581
NR4A3	PATZ1	Q9HBE1	567
NR4A3	TP53	P04637	559
NR4A3	NGF	P01138	550
NR4A3	SNRPC	P09234	549
NR4A3	EGR2	P11161	545
NR4A3	EGR1	P18146	526
NR4A3	FOSB	P53539	514

IntAct

121 interactions, top by confidence:

A	B	Type	Score
KRTAP6-3	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-6	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
NR4A3	PCSK5	psi-mi:“MI:0915”(physical association)	0.560
KPRP	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
CYP21A2	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
LCE2B	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
NR4A3	KRTAP9-2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-5	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
UBE3A	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
LCE2D	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
CDKN2D	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
NR4A3	SMOC1	psi-mi:“MI:0915”(physical association)	0.560
NR4A3	NECTIN2	psi-mi:“MI:0915”(physical association)	0.560
RECK	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
TSPAN4	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
KRTAP12-4	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
PIN1	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
NR4A3	CHRD	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-9	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
NR4A3	KRTAP9-8	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-11	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
NR4A3	ZNF330	psi-mi:“MI:0915”(physical association)	0.560
VWC2L	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
NR4A3	HSD3B7	psi-mi:“MI:0915”(physical association)	0.560
	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
KRTAP12-3	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
ADAMTSL4	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
NR4A3	KRTAP4-2	psi-mi:“MI:0915”(physical association)	0.560
EFEMP1	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-3	NR4A3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (51): SIX3 (Reconstituted Complex), SIX3 (Two-hybrid), NR4A3 (Affinity Capture-MS), NR4A3 (Affinity Capture-RNA), NR4A3 (Two-hybrid), NR4A3 (Two-hybrid), NR4A3 (Two-hybrid), NR4A3 (Two-hybrid), NR4A3 (Two-hybrid), NR4A3 (Two-hybrid), RECK (Two-hybrid), PIN1 (Two-hybrid), CDKN2D (Two-hybrid), PVRL2 (Two-hybrid), ADAMTSL4 (Two-hybrid)

ESM2 similar proteins: A4IIG7, B3SV56, O13012, O42132, P03372, P06211, P06212, P16058, P16375, P19785, P20393, P35398, P43354, P49883, P49884, P50240, P50241, P50242, P51128, P51129, P51179, P51448, P57717, P57781, P57783, P81559, Q04913, Q06219, Q07917, Q08E02, Q08E53, Q14995, Q29040, Q3UV55, Q53AD2, Q5R5Y4, Q60674, Q63503, Q63504, Q64249

Diamond homologs: A0JNE3, A2T928, A4IIG7, G5ECR9, G5EDJ0, O02151, O45666, O76202, O97716, P10276, P10588, P10826, P10827, P10828, P11416, P12813, P13056, P13631, P16376, P18117, P18514, P18515, P18516, P18911, P20153, P22448, P22449, P22605, P22736, P22829, P28699, P31396, P33242, P33244, P41828, P41830, P43354, P45447, P49116, P49117

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
NR3C1	“down-regulates quantity by repression”	NR4A3	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	NR4A3	“transcriptional regulation”
RPS6KA1	unknown	NR4A3	phosphorylation
RPS6K	“down-regulates activity”	NR4A3	phosphorylation
TP53	“up-regulates quantity by expression”	NR4A3	“transcriptional regulation”
NR4A3	down-regulates	Proliferation
NR4A3	“up-regulates quantity by expression”	BBC3	“transcriptional regulation”
NR4A3	“up-regulates quantity by expression”	BAX	“transcriptional regulation”
NR4A3	up-regulates	Apoptosis
NR4A3	“down-regulates activity”	BCL2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 39 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Keratinization	17	30.6×	2e-20

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

48 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1730 predictions. Top by Δscore:

Variant	Effect	Δscore
9:99822408:G:GG	donor_gain	1.0000
9:99825646:A:AG	acceptor_gain	1.0000
9:99825657:A:AG	acceptor_gain	1.0000
9:99825658:G:GG	acceptor_gain	1.0000
9:99825658:GA:G	acceptor_gain	1.0000
9:99825829:CCAG:C	donor_loss	1.0000
9:99825833:G:GG	donor_gain	1.0000
9:99825833:G:T	donor_loss	1.0000
9:99825834:T:A	donor_loss	1.0000
9:99828989:TCAAG:T	donor_loss	1.0000
9:99828990:CAAG:C	donor_loss	1.0000
9:99828992:AGGT:A	donor_loss	1.0000
9:99828994:GT:G	donor_loss	1.0000
9:99828995:T:G	donor_loss	1.0000
9:99832687:A:AG	acceptor_gain	1.0000
9:99832688:G:GG	acceptor_gain	1.0000
9:99832688:GA:G	acceptor_gain	1.0000
9:99833273:T:A	acceptor_gain	1.0000
9:99833453:GA:G	donor_gain	1.0000
9:99833455:G:GG	donor_gain	1.0000
9:99844644:TCTA:T	acceptor_loss	1.0000
9:99844646:TAGT:T	acceptor_loss	1.0000
9:99844647:A:AG	acceptor_gain	1.0000
9:99844647:AGTA:A	acceptor_loss	1.0000
9:99844648:G:GC	acceptor_gain	1.0000
9:99844648:GT:G	acceptor_gain	1.0000
9:99844648:GTA:G	acceptor_gain	1.0000
9:99844648:GTAC:G	acceptor_gain	1.0000
9:99844648:GTACT:G	acceptor_gain	1.0000
9:99847428:A:AG	acceptor_gain	1.0000

AlphaMissense

4066 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:99828916:T:A	C292S	1.000
9:99828916:T:C	C292R	1.000
9:99828916:T:G	C292G	1.000
9:99828917:G:A	C292Y	1.000
9:99828917:G:C	C292S	1.000
9:99828917:G:T	C292F	1.000
9:99828918:T:G	C292W	1.000
9:99828922:G:A	V294M	1.000
9:99828922:G:C	V294L	1.000
9:99828922:G:T	V294L	1.000
9:99828923:T:A	V294E	1.000
9:99828923:T:C	V294A	1.000
9:99828925:T:A	C295S	1.000
9:99828925:T:C	C295R	1.000
9:99828925:T:G	C295G	1.000
9:99828926:G:A	C295Y	1.000
9:99828926:G:C	C295S	1.000
9:99828926:G:T	C295F	1.000
9:99828927:C:G	C295W	1.000
9:99828931:G:C	D297H	1.000
9:99828931:G:T	D297Y	1.000
9:99828932:A:C	D297A	1.000
9:99828932:A:G	D297G	1.000
9:99828932:A:T	D297V	1.000
9:99828933:C:A	D297E	1.000
9:99828933:C:G	D297E	1.000
9:99828938:C:A	A299D	1.000
9:99828941:C:A	A300D	1.000
9:99828943:T:A	C301S	1.000
9:99828943:T:C	C301R	1.000

dbSNP variants (sampled 300 via entrez): RS1000009968 (9:99850661 T>C), RS1000123128 (9:99821161 A>C,G), RS1000165899 (9:99843242 C>T), RS1000313591 (9:99863295 C>T), RS1000332340 (9:99828921 C>A,G,T), RS1000344779 (9:99850412 G>A,T), RS1000361767 (9:99829209 G>A), RS1000520283 (9:99822100 G>A,C), RS1000544952 (9:99857630 C>G,T), RS1000685656 (9:99864795 C>A), RS1000718399 (9:99849310 A>C,G), RS1000899393 (9:99857586 A>G), RS1000922255 (9:99834933 C>T), RS1000947705 (9:99849015 T>A,C), RS1000948495 (9:99848723 T>C)

Disease associations

OMIM: gene MIM:600542 | disease phenotypes: MIM:612237

GenCC curated gene-disease

Mondo (1): extraskeletal myxoid chondrosarcoma (MONDO:0012825)

Orphanet (1): Extraskeletal myxoid chondrosarcoma (Orphanet:209916)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0001442	Typified by somatic mosaicism
HP:0006765	Chondrosarcoma

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001713_32	Dental caries	5.000000e-06
GCST004748_135	Lung cancer	1.000000e-07
GCST006427_53	Depression in smokers	5.000000e-06
GCST011096_9	Systemic lupus erythematosus	2.000000e-08
GCST90002382_296	Eosinophil percentage of white cells	2.000000e-10
GCST90013445_48	Type 1 diabetes	3.000000e-08
GCST90013445_58	Type 1 diabetes	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563195	Chondrosarcoma, Extraskeletal Myxoid (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1961792 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 59,846 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1071	OXAPROZIN	4	51,044
CHEMBL1873475	IBRUTINIB	4	7,994
CHEMBL197194	VIDOFLUDIMUS	3	808

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: nhr — 4A. Nerve growth factor IB-like receptors

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 111 [PMID: 37918435]	Agonist	6.82	pEC50

ChEMBL bioactivities

11 potent at pChembl≥5 of 18 total, top 11 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.92	IC50	1.2	nM	CHEMBL4560385
8.24	IC50	5.7	nM	IBRUTINIB
7.75	IC50	18	nM	CHEMBL5404368
7.16	EC50	70	nM	CHEMBL5405485
7.11	IC50	78	nM	IBRUTINIB
6.82	EC50	150	nM	CHEMBL5427562
6.68	IC50	210.6	nM	CHEMBL4755698
5.54	EC50	2900	nM	VIDOFLUDIMUS
5.42	IC50	3800	nM	CHEMBL5417665
5.22	EC50	6000	nM	CHEMBL5397121
5.00	IC50	1e+04	nM	CHEMBL4851009

PubChem BioAssay actives

11 with measured affinity, of 127 total; 10 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5-amino-1-[(3R)-1-cyanopiperidin-3-yl]-3-[4-(2,4-difluorophenoxy)phenyl]pyrazole-4-carboxamide	1940003: Inhibition of TEC (unknown origin)	ic50	0.0012	uM
Ibrutinib	2001967: Inhibition of TEC (unknown origin) by filter binding method	ic50	0.0057	uM
1-[(3R)-3-[5-(4-phenoxyanilino)-2,6,7,9,11-pentazatricyclo[6.3.1.04,12]dodeca-1,3,5,8(12),9-pentaen-7-yl]pyrrolidin-1-yl]prop-2-en-1-one	2001967: Inhibition of TEC (unknown origin) by filter binding method	ic50	0.0180	uM
3-[(4-tert-butylphenyl)methoxy]benzoic acid	2037852: Agonist activity at human NOR-1 LBD transiently transfected in HEK293T cells incubated for 16 hrs by Gal4-hybrid reporter gene based Dual-glo luciferase assay	ec50	0.0700	uM
3-[(2,4-dichlorophenyl)methoxy]benzoic acid	2037852: Agonist activity at human NOR-1 LBD transiently transfected in HEK293T cells incubated for 16 hrs by Gal4-hybrid reporter gene based Dual-glo luciferase assay	ec50	0.1500	uM
1-[4-[[4-amino-5-(1,3-benzodioxol-5-yl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]piperidin-1-yl]prop-2-en-1-one	1714834: Inhibition of Tec (unknown origin)	ic50	0.2106	uM
2-[[2-fluoro-4-(3-methoxyphenyl)phenyl]carbamoyl]cyclopentene-1-carboxylic acid	2031372: Agonist activity at NOR1 (unknown origin) by Gal4 hybrid reporter gene assay	ec50	2.9000	uM
(E)-3-(4,5-diphenyl-1,3-oxazol-2-yl)prop-2-enoic acid	2087299: Inverse agonist activity at human NOR-1 (393 to 626 residues) transfected in HEK293T cells incubated for 16 hrs by firefly/renilla based Dual-Glo luciferase assay	ic50	3.8000	uM
5-(3-fluorophenyl)furan-2-carboxylic acid	2037852: Agonist activity at human NOR-1 LBD transiently transfected in HEK293T cells incubated for 16 hrs by Gal4-hybrid reporter gene based Dual-glo luciferase assay	ec50	6.0000	uM
2-(4,5-diphenyl-1,3-oxazol-2-yl)acetic acid	2087299: Inverse agonist activity at human NOR-1 (393 to 626 residues) transfected in HEK293T cells incubated for 16 hrs by firefly/renilla based Dual-Glo luciferase assay	ic50	10.0000	uM

CTD chemical–gene interactions

91 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, affects cotreatment, increases expression	6
Silicon Dioxide	decreases expression, increases expression	4
sodium arsenite	decreases expression, increases expression	3
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression	3
Tretinoin	affects cotreatment, increases expression	3
arsenite	affects expression, increases methylation	2
cadmium acetate	increases expression	2
torcetrapib	increases expression	2
Nickel	increases expression	2
Tetradecanoylphorbol Acetate	affects cotreatment, decreases reaction, increases expression, affects expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Zinc	affects cotreatment, increases expression, affects expression	2
Asbestos, Crocidolite	affects expression, increases expression	2
Particulate Matter	increases abundance, increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
geranylgeranyl pyrophosphate	decreases expression, decreases reaction	1
bisphenol A	decreases expression	1
deoxynivalenol	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
hydroxyhydroquinone	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sulforaphane	decreases expression	1
butyraldehyde	increases expression	1
pyrrolidine dithiocarbamic acid	affects cotreatment, decreases reaction, increases expression	1
didecyldimethylammonium	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
bathocuproine sulfonate	increases expression, affects cotreatment, decreases reaction	1

ChEMBL screening assays

64 unique, capped per target: 63 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1227068	Functional	Agonist activity at nuclear orphan receptor NOR1 expressed in human BGC823 cells co-transfected with fused GAL4-NOR1(LBD) assessed as transactivation after 12 hrs by transactivation assay	Cytosporone B is an agonist for nuclear orphan receptor Nur77. — Nat Chem Biol
CHEMBL1961866	Binding	Effect on NOR1(NR4A3) dependent reporter activity in HEK293 cells at 20 uM	Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. — Nature

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 2 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4X2	SEES3-1V human NR4A3, clone2	Embryonic stem cell	Male
CVCL_A4X3	SEES3-1V human NR4A3, clone3	Embryonic stem cell	Male
CVCL_B8LN	Abcam HCT 116 NR4A3 KO	Cancer cell line	Male
CVCL_B8ZM	Abcam MCF-7 NR4A3 KO	Cancer cell line	Female
CVCL_B9NT	Abcam A-549 NR4A3 KO	Cancer cell line	Male
CVCL_C6MX	USZ20-EMC1	Cancer cell line	Female
CVCL_C6MY	USZ22-EMC2	Cancer cell line	Male

Clinical trials (associated diseases)

6 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02066285	PHASE2	COMPLETED	Trial of Pazopanib in Patients With Solitary Fibrous Tumor and Extraskeletal Myxoid Chondrosarcoma
NCT05836571	PHASE2	ACTIVE_NOT_RECRUITING	Testing Ipilimumab and Nivolumab Combination With or Without Cabozantinib in People >= 18 Years Old With Advanced Soft Tissue Sarcoma
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT02180867	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Before Surgery in Treating Patients With Newly Diagnosed Non-rhabdomyosarcoma Soft Tissue Sarcomas That Can Be Removed by Surgery
NCT05266196	PHASE1/PHASE2	UNKNOWN	A Rollover Protocol to Allow for Continued Access to the LSD1 Inhibitor Seclidemstat (SP-2577)
NCT06526897	Not specified	NOT_YET_RECRUITING	Evaluation of Chest CT Versus Chest X-Ray for Lung Surveillance After Curative-Intent Resection of High-Risk Truncal-Extremity Soft Tissue Sarcoma