NCOA4

Summary

NCOA4 (nuclear receptor coactivator 4, HGNC:7671) is a protein-coding gene on chromosome 10q11.22, encoding Nuclear receptor coactivator 4 (Q13772). Cargo receptor for the autophagic turnover of the iron-binding ferritin complex, playing a central role in iron homeostasis. It is a selective cancer dependency (DepMap: 32.5% of cell lines).

This gene encodes an androgen receptor coactivator. The encoded protein interacts with the androgen receptor in a ligand-dependent manner to enhance its transcriptional activity. Chromosomal translocations between this gene and the ret tyrosine kinase gene, also located on chromosome 10, have been associated with papillary thyroid carcinoma. Alternatively spliced transcript variants have been described. Pseudogenes are present on chromosomes 4, 5, 10, and 14.

Source: NCBI Gene 8031 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 100 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 32.5% of screened cell lines
• MANE Select transcript: NM_001145263

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7671
Approved symbol	NCOA4
Name	nuclear receptor coactivator 4
Location	10q11.22
Locus type	gene with protein product
Status	Approved
Aliases	ARA70, RFG, ELE1, PTC3, DKFZp762E1112
Ensembl gene	ENSG00000266412
Ensembl biotype	protein_coding
OMIM	601984
Entrez	8031

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 38 protein_coding

ENST00000578454, ENST00000579039, ENST00000580070, ENST00000581486, ENST00000583565, ENST00000585056, ENST00000585132, ENST00000863402, ENST00000863403, ENST00000863404, ENST00000863405, ENST00000863406, ENST00000863407, ENST00000863408, ENST00000863409, ENST00000863410, ENST00000863411, ENST00000863412, ENST00000863413, ENST00000863414, ENST00000863415, ENST00000863416, ENST00000863417, ENST00000863418, ENST00000863419, ENST00000863420, ENST00000863421, ENST00000863422, ENST00000863423, ENST00000863424, ENST00000915122, ENST00000915123, ENST00000915124, ENST00000915125, ENST00000962476, ENST00000962477, ENST00000962478, ENST00000962479

RefSeq mRNA: 5 — MANE Select: NM_001145263 NM_001145260, NM_001145261, NM_001145262, NM_001145263, NM_005437

CCDS: CCDS73092, CCDS73093, CCDS73094

Canonical transcript exons

ENST00000581486 — 10 exons

Exon	Start	End
ENSE00002684537	46005088	46006597
ENSE00002725494	46030526	46030623
ENSE00002730115	46010223	46011206
ENSE00003465758	46009411	46009551
ENSE00003488392	46014444	46014552
ENSE00003516530	46014854	46014942
ENSE00003523231	46013550	46013639
ENSE00003540768	46015126	46015266
ENSE00003670291	46012883	46013026
ENSE00003689360	46016540	46016694

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 127.1975 / max 3574.0280, expressed in 1827 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
109264	65.4126	1824
109261	26.5675	1501
109263	25.6295	1809
109262	6.2881	966
109265	2.1486	1158
109260	0.6858	225
109258	0.1314	49
109257	0.1300	70
109259	0.1077	41
109256	0.0849	51

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.84	gold quality
trabecular bone tissue	UBERON:0002483	99.83	gold quality
visceral pleura	UBERON:0002401	99.78	gold quality
parietal pleura	UBERON:0002400	99.73	gold quality
pleura	UBERON:0000977	99.70	gold quality
esophagus squamous epithelium	UBERON:0006920	99.69	gold quality
epithelium of nasopharynx	UBERON:0001951	99.67	gold quality
palpebral conjunctiva	UBERON:0001812	99.60	gold quality
squamous epithelium	UBERON:0006914	99.60	gold quality
gingival epithelium	UBERON:0001949	99.58	gold quality
tibia	UBERON:0000979	99.56	gold quality
nephron tubule	UBERON:0001231	99.55	gold quality
choroid plexus epithelium	UBERON:0003911	99.52	gold quality
gingiva	UBERON:0001828	99.51	gold quality
pancreatic ductal cell	CL:0002079	99.49	gold quality
parotid gland	UBERON:0001831	99.48	gold quality
germinal epithelium of ovary	UBERON:0001304	99.43	gold quality
jejunum	UBERON:0002115	99.43	gold quality
tongue squamous epithelium	UBERON:0006919	99.43	gold quality
monocyte	CL:0000576	99.41	gold quality
mononuclear cell	CL:0000842	99.41	gold quality
epithelium of esophagus	UBERON:0001976	99.38	gold quality
duodenum	UBERON:0002114	99.38	gold quality
oral cavity	UBERON:0000167	99.36	gold quality
leukocyte	CL:0000738	99.35	gold quality
upper leg skin	UBERON:0004262	99.33	gold quality
cervix squamous epithelium	UBERON:0006922	99.30	gold quality
ileal mucosa	UBERON:0000331	99.29	gold quality
kidney epithelium	UBERON:0004819	99.25	gold quality
endothelial cell	CL:0000115	99.16	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	48.23
E-CURD-112	yes	43.21
E-MTAB-9221	yes	23.75
E-CURD-122	yes	21.36
E-HCAD-10	yes	16.76
E-MTAB-9388	yes	8.42
E-HCAD-1	yes	7.94
E-HCAD-9	yes	6.28
E-MTAB-6379	no	1187.07
E-GEOD-36552	no	959.83
E-MTAB-9467	no	2.36
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
AR	Activation
KLK3	Activation
TFF1	Unknown

Upstream regulators (CollecTRI, top): AR, TP53, TP73

miRNA regulators (miRDB)

111 targeting NCOA4, 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-1277-5P	100.00	73.95	5056
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 32.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma. (PMID:11786418)
• Domain interactions between coregulator ARA(70) and the androgen receptor (AR); structure activity relationship (PMID:11818501)
• ARA70 has a role in enhancing the androgen receptor during testicular development (PMID:12068007)
• role in reducing agonist activity of antiandrogens (PMID:12649293)
• causes increases in nuclear NF-kappaB activity and secretion of MCP-1 and GM-CSF; studies implicate oncogene-induced cytokine-signaling pathways in a new mechanism linking inflammation with cancer (PMID:12881713)
• ARA70 was identifed as a coactivator of PPARalpha in the prostate cancer cell line DU145. In the adrenal cell line Y1, ARA70 behaved as a repressor of PPARalpha while still able to coactivate PPARgamma. (PMID:12897377)
• The refolding and one-step purification of ARA70 from inclusion bodies over-expressed in Escherichia coli is reported. (PMID:15642480)
• ARA70 is a coactivator for estrogen receptor alpha (ERalpha) and may represent a functional link between ERalpha/androgen receptor (AR) modulating their cross-talk in models of estrogen signaling in MCF-7 and HeLa cells (PMID:15772083)
• Together, ARA54 and ARA70 modulate vitamin D receptor transactivation, and the competition for ARA70 mediates the suppressive affect of androgen-androgen receptor on vitamin D receptor transactivation. (PMID:15805579)
• a functional interaction between NcoA4 and AhR that may alter AhR activity to affect disease development and progression is demonstrated (PMID:16762319)
• Expression of androgen receptor co-regulators in the testes of men with azoospermia. (PMID:17919607)
• in prostate cancer cell lines, ARA70beta localized to the cytosol, whereas ARA70alpha was found in the nucleus, supporting the notion of their dissimilar functions (PMID:18091327)
• ARA70 beta is a regulator of tumor cell growth and metastasis by affecting gene expression (PMID:18156210)
• PTC1 and PTC3 are highly oncogenic proteins when overexpressed, but result in indolent disease compared with RET-related MTCs due to their relatively low expression from the NCOA4 and CCDC6 promoters in vivo. (PMID:19487296)
• Screening for BRAF, RET, KRAS, NRAS, and HRAS mutations, as well as RET-PTC1 and RET-PTC3 rearrangements, was performed on cases of Hashimoto thyroiditis with a dominant nodule (PMID:20012784)
• ARA70alpha functions as a tumor suppressor gene (PMID:20167864)
• Suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells. (PMID:21085629)
• Studies indicate nuclear receptor coactivator 4 (NcoA4) as a coactivator for a variety of nuclear receptors. (PMID:22562579)
• Computational network analysis reveals that the MSMB gene is functionally connected to NCOA4 and the androgen receptor signaling pathway. The data provide an example of how GWAS-associated variants may have multiple genetic and epigenetic effects (PMID:22661295)
• Data indicate that the increase in prostate cancer (PC) risk associated with rs10993994:C>T is likely mediated by the variant’s effect of MSMB-encoded protein PSP94 expression; however, this effect does not extend to NCOA4 in the data. (PMID:22887727)
• mechanism dissection shows that KLK2 may cooperate with the AR coregulator, ARA70, to enhance AR transactivation that may result in alteration of prostate cancer formation (PMID:24122203)
• identification of NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy), which is critical for iron homeostasis, and provides a resource for further dissection of autophagosomal cargo-receptor connectivity (PMID:24695223)
• NCOA4 acts as a regulator of DNA replication origins that helps prevent inappropriate DNA synthesis and replication stress. (PMID:24910095)
• RET/PTC3 gene rearrangements are the most prevalent form of rearrangements in papillary thyroid carcinomas of Chennai population. (PMID:24957039)
• provide a new mechanism for selective autophagy of ferritin and reveal a previously unappreciated role for autophagy and NCOA4 in the control of iron homeostasis in vivo (PMID:25327288)
• Ubiquitin-dependent NCOA4 turnover is promoted by excess iron and involves an iron-dependent interaction between NCOA4 and the HERC2 ubiquitin ligase. (PMID:26436293)
• the ATG5-ATG7-NCOA4 autophagic pathway has a role in ferroptosis (PMID:27245739)
• The H-ferritin could bind up to 24 NCOA4(383-522) fragments forming highly stable and insoluble complexes. The binding was partially inhibited only by Fe(II) among the various divalent metal ions analyzed. The iron-dependent, highly-specific formation of the remarkably stable H-ferritin-NCOA4 complex shown in this work may be important for the characterization of the mechanism of ferritinophagy. (PMID:28754384)
• Thyroid hormone receptor beta and NCOA4 regulate terminal erythrocyte differentiation. (PMID:28864529)
• the actions of PCBP1 and NCOA4 on ferritin allow erythroid cells to rapidly respond to changes in cellular iron availability, which could provide a strategy to maintain cellular iron storage and utilization at a constant rate despite fluctuation in the total cellular iron supply. (PMID:29032941)
• NCOA4-RET as the dominant fusion in intercalated duct type salivary gland intraductal carcinoma. (PMID:30045065)
• Study showed that NCOA4-mediated ferritin complex degradation supplies iron to mitochondria. (PMID:31061094)
• Tumor-type-specific NCOA4-RET or TRIM27-RET translocations are found in a subset of widely invasive salivary carcinomas with intercalated duct-like immunoprofiles. (PMID:31162284)
• Thermodynamic and Kinetic Studies of the Interaction of Nuclear Receptor Coactivator-4 (NCOA4) with Human Ferritin. (PMID:32608971)
• Ferritinophagy is not required for colon cancer cell growth. (PMID:32767706)
• Low expression of ferritinophagy-related NCOA4 gene in relation to unfavorable outcome and defective immune cells infiltration in clear cell renal carcinoma. (PMID:33402128)
• Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines. (PMID:33420375)
• NCOA4-mediated ferritinophagy promoted inflammatory responses in periodontitis. (PMID:33533512)
• Nuclear receptor coactivator 4-mediated ferritinophagy drives proliferation of dental pulp stem cells in hypoxia. (PMID:33784507)
• Intraductal carcinoma of the salivary gland with NCOA4-RET: expanding the morphologic spectrum and an algorithmic diagnostic approach. (PMID:33991527)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ncoa4	ENSDARG00000021439
mus_musculus	Ncoa4	ENSMUSG00000056234
rattus_norvegicus	Ncoa4	ENSRNOG00000019768

Protein

Protein identifiers

Nuclear receptor coactivator 4 — Q13772 (reviewed: Q13772)

Alternative names: Androgen receptor coactivator 70 kDa protein, Androgen receptor-associated protein of 70 kDa, Ferritin cargo receptor NCOA4, Ret-activating protein ELE1

All UniProt accessions (3): B4DF87, B4DZ85, Q13772

UniProt curated annotations — full annotation on UniProt →

Function. Cargo receptor for the autophagic turnover of the iron-binding ferritin complex, playing a central role in iron homeostasis. Acts as an adapter for delivery of ferritin to lysosomes and autophagic degradation of ferritin, a process named ferritinophagy. Targets the iron-binding ferritin complex to autolysosomes following starvation or iron depletion. Ensures efficient erythropoiesis, possibly by regulating hemin-induced erythroid differentiation. In some studies, has been shown to enhance the androgen receptor AR transcriptional activity as well as acting as ligand-independent coactivator of the peroxisome proliferator-activated receptor (PPAR) gamma. Another study shows only weak behavior as a coactivator for the androgen receptor and no alteration of the ligand responsiveness of the AR. Binds to DNA replication origins, binding is not restricted to sites of active transcription and may likely be independent from the nuclear receptor transcriptional coactivator function. May inhibit activation of DNA replication origins, possibly by obstructing DNA unwinding via interaction with the MCM2-7 complex.

Subunit / interactions. Interacts with the ferritin complex, an oligomeric structure composed of varying combinations of ferritin heavy chains and ferritin light chains. Interacts (via C-terminus) with ferritin heavy chain FTH1 (via ‘Arg-23’); thereby targeting the iron-binding ferritin complex to autolysosomes following starvation or iron depletion. Interacts with ferritin light chain FTL. Interacts (via C-terminus) with ATG8-like proteins GABARAP and GABARAPL1; thereby mediating localization to autophagosomes and ferritinophagy. Interacts with MAP1LC3C/LC3C and GABARAPL2. Interacts with the androgen receptor AR (via NR DNA binding domain and NR LBD) in a ligand-dependent manner. Interacts with the retinoid acid receptor RXR-gamma (RXRG) in a ligand-dependent manner. Interacts (via N-terminus) with MCM7. Interacts with MCM3. Interacts with CDC45. Interacts (via C-terminus) with ferritin heavy chain FTH1. Does not interact with ferritin heavy chain FTH1.

Subcellular location. Cytoplasmic vesicle. Autophagosome. Autolysosome. Nucleus. Chromosome.

Tissue specificity. Widely expressed. Also detected in adipose tissues and in different cell lines. Isoform Beta is only expressed in testis.

Post-translational modifications. NCOA4 levels may be regulated via HERC2-mediated ubiquitination leading to proteosomal degradation; HERC2 association is dependent on NCOA4 iron occupancy.

Disease relevance. A chromosomal aberration involving NCOA4 is found in papillary thyroid carcinomas (PTCs). Inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene.

Induction. Down-regulated by nutrient deprivation (at protein level).

Isoforms (4)

UniProt ID	Names	Canonical?
Q13772-1	Alpha	yes
Q13772-2	Beta
Q13772-3	3
Q13772-4	4

RefSeq proteins (5): NP_001138732, NP_001138733, NP_001138734, NP_001138735, NP_005428 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR022174	NCOA4_N	Domain
IPR039947	NCoA-4	Family

Pfam: PF12489

UniProt features (24 total): sequence conflict 6, sequence variant 5, helix 3, splice variant 3, region of interest 2, mutagenesis site 2, chain 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9L93	X-RAY DIFFRACTION	1.73
1T5Z	X-RAY DIFFRACTION	2.3
8QU9	ELECTRON MICROSCOPY	2.88

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13772-F1	56.41	0.19

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 238–239 (breakpoint for rearrangement to form ret/ptc3 oncogene)

Mutagenesis-validated functional residues (2):

Position	Phenotype
95–96	decreased interaction with ppar and rxr. no impact on interaction with mcm7. no impact on binding to dna replication ori
489–497	abrogates interaction with ferritin heavy chain fth1. attenuates fth1 localization to lysosomes following iron chelation

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-74160	Gene expression (Transcription)
R-HSA-9818564	Epigenetic regulation of gene expression by MLL3 and MLL4 complexes
R-HSA-9851695	Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes
R-HSA-9917777	Epigenetic regulation by WDR5-containing histone modifying complexes

MSigDB gene sets: 261 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_LYSOSOMAL_TRANSPORT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_LIPID, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, GOBP_PROTEIN_TARGETING, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_VACUOLAR_TRANSPORT, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_PROTEIN_LOCALIZATION_TO_LYSOSOME, GTGCCTT_MIR506

GO Biological Process (8): protein targeting to lysosome (GO:0006622), intracellular iron ion homeostasis (GO:0006879), male gonad development (GO:0008584), response to hormone (GO:0009725), estrogen receptor signaling pathway (GO:0030520), cellular response to estrogen stimulus (GO:0071391), cellular response to testosterone stimulus (GO:0071394), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (2): transcription coactivator activity (GO:0003713), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), autophagosome (GO:0005776), cytoplasmic vesicle (GO:0031410), autolysosome (GO:0044754), lysosome (GO:0005764)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1
Gene expression (Transcription)	1
Epigenetic regulation by WDR5-containing histone modifying complexes	1
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1
Epigenetic regulation of gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein targeting to vacuole	1
lysosomal transport	1
protein localization to lysosome	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
gonad development	1
development of primary male sexual characteristics	1
response to endogenous stimulus	1
response to chemical	1
nuclear receptor-mediated steroid hormone signaling pathway	1
cellular response to hormone stimulus	1
response to estrogen	1
response to testosterone	1
cellular response to lipid	1
cellular response to ketone	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
intracellular membraneless organelle	1
vacuole	1
cytoplasm	1
intracellular vesicle	1
secondary lysosome	1
lytic vacuole	1

Protein interactions and networks

STRING

1148 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NCOA4	FTH1	P02794	989
NCOA4	AR	P10275	964
NCOA4	RET	P07949	942
NCOA4	PTCH1	Q13635	901
NCOA4	RET	P07949	897
NCOA4	PTCH2	Q9Y6C5	889
NCOA4	RNF14	Q9UBS8	860
NCOA4	GABARAPL2	P60520	831
NCOA4	F5GZY7	F5GZY7	831
NCOA4	TRIM33	Q9UPN9	758
NCOA4	FTL	P02792	755
NCOA4	GPX4	P36969	700
NCOA4	TGFB1I1	O43294	681
NCOA4	IREB2	P48200	663
NCOA4	TRIM24	O15164	658

IntAct

45 interactions, top by confidence:

A	B	Type	Score
FTH1	FTL	psi-mi:“MI:0914”(association)	0.940
HIF1AN	APBA3	psi-mi:“MI:0914”(association)	0.850
NCOA4	FTL	psi-mi:“MI:0914”(association)	0.790
NCOA4	FTL	psi-mi:“MI:0915”(physical association)	0.790
FTH1	NCOA4	psi-mi:“MI:0914”(association)	0.790
NCOA4	FTH1	psi-mi:“MI:0915”(physical association)	0.790
PSMD14	PSMD11	psi-mi:“MI:0914”(association)	0.650
FTH1	A2ML1	psi-mi:“MI:0914”(association)	0.530
NCOA4	HERC2	psi-mi:“MI:0914”(association)	0.530
P2RY10	ATM	psi-mi:“MI:0914”(association)	0.530
AR	NCOA4	psi-mi:“MI:0407”(direct interaction)	0.440
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
Psmd6	MIF4GD	psi-mi:“MI:0914”(association)	0.350
USP43	DKFZP586J0619	psi-mi:“MI:0914”(association)	0.350
PSMC1	ZNF561	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
MAPK6		psi-mi:“MI:0914”(association)	0.350
HERC2	FTL	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
PIPSL	C1orf226	psi-mi:“MI:0914”(association)	0.350
PRELID2	TP73	psi-mi:“MI:0914”(association)	0.350
FTH1	DHX16	psi-mi:“MI:0914”(association)	0.350
ASB4	AKAP10	psi-mi:“MI:0914”(association)	0.350
C6orf141	ITPRID2	psi-mi:“MI:0914”(association)	0.350
DUOXA2	CHRNB1	psi-mi:“MI:0914”(association)	0.350

BioGRID (113): NCOA4 (Protein-peptide), NCOA4 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS)

ESM2 similar proteins: A0A5K7RLP0, A6NMK8, D3ZF42, O14867, O54968, P01102, P97302, P97303, Q13772, Q1W617, Q3ULM6, Q4R7L6, Q5BLK4, Q5FWP7, Q5PQK4, Q5SXH7, Q5T0L3, Q5U4H9, Q5U5Q9, Q60795, Q66KC9, Q673G8, Q69ZK7, Q6GPJ8, Q6GQV1, Q6NRH7, Q6NZK5, Q6P1D7, Q6P1H6, Q6PJW8, Q6QZN6, Q7TP65, Q7ZUW7, Q7ZYI3, Q80XI1, Q80Y19, Q86T90, Q8BG89, Q8BLK9, Q8BP86

Diamond homologs: Q13772, Q5FWP7, Q5U4H9, Q802X2

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
KLK2	up-regulates	NCOA4
NCOA4	“up-regulates quantity by expression”	KLK3	“transcriptional regulation”
NCOA4	up-regulates	AR	binding
NCOA4	up-regulates	PPARG	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 55 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
KEAP1-NFE2L2 pathway	5	16.2×	2e-03
Neutrophil degranulation	7	4.4×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	66
Likely benign	7
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1510 predictions. Top by Δscore:

Variant	Effect	Δscore
10:46006974:C:G	donor_gain	1.0000
10:46009407:T:A	donor_loss	1.0000
10:46009410:AGG:A	donor_loss	1.0000
10:46009411:CAGGT:C	donor_loss	1.0000
10:46009550:G:GG	acceptor_gain	1.0000
10:46009550:GG:G	acceptor_gain	1.0000
10:46009550:GGA:G	acceptor_gain	1.0000
10:46009550:GGAA:G	acceptor_gain	1.0000
10:46009551:A:AG	acceptor_gain	1.0000
10:46009551:A:T	acceptor_loss	1.0000
10:46009551:AG:A	acceptor_gain	1.0000
10:46009553:GCAG:G	acceptor_loss	1.0000
10:46009554:TGCA:T	acceptor_loss	1.0000
10:46010220:G:T	donor_loss	1.0000
10:46010222:AGGTG:A	donor_loss	1.0000
10:46010223:CAG:C	donor_loss	1.0000
10:46013025:G:GG	acceptor_gain	1.0000
10:46013025:GA:G	acceptor_gain	1.0000
10:46013025:GAA:G	acceptor_gain	1.0000
10:46013026:A:AG	acceptor_gain	1.0000
10:46013547:GTA:G	donor_loss	1.0000
10:46013550:CAG:C	donor_loss	1.0000
10:46013551:GCAG:G	donor_gain	1.0000
10:46013638:G:GT	acceptor_gain	1.0000
10:46013638:GC:G	acceptor_gain	1.0000
10:46013638:GCA:G	acceptor_gain	1.0000
10:46013638:GCAA:G	acceptor_gain	1.0000
10:46013638:GCAAA:G	acceptor_gain	1.0000
10:46013639:A:AC	acceptor_loss	1.0000
10:46013639:A:AG	acceptor_gain	1.0000

AlphaMissense

4093 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:46015237:G:C	S57R	0.994
10:46015237:G:T	S57R	0.994
10:46015239:T:G	S57R	0.994
10:46010675:A:G	C416R	0.991
10:46010693:A:G	C410R	0.991
10:46010711:A:G	C404R	0.991
10:46015211:C:G	R66P	0.991
10:46015220:A:G	L63P	0.991
10:46014462:A:C	F154L	0.988
10:46014462:A:T	F154L	0.988
10:46014464:A:G	F154L	0.988
10:46015213:G:C	S65R	0.988
10:46015213:G:T	S65R	0.988
10:46015215:T:G	S65R	0.988
10:46015229:A:G	L60P	0.988
10:46010691:G:C	C410W	0.986
10:46010710:C:G	C404S	0.986
10:46010711:A:T	C404S	0.986
10:46015235:C:G	R58P	0.986
10:46010709:G:C	C404W	0.985
10:46010674:C:G	C416S	0.984
10:46010675:A:T	C416S	0.984
10:46015199:A:G	L70P	0.984
10:46014472:A:T	I151N	0.983
10:46009434:A:G	W606R	0.982
10:46009434:A:T	W606R	0.982
10:46010692:C:T	C410Y	0.981
10:46015216:T:A	R64S	0.981
10:46015216:T:G	R64S	0.981
10:46010710:C:T	C404Y	0.980

dbSNP variants (sampled 300 via entrez): RS1000106704 (10:46020806 A>C), RS1000138055 (10:46021123 T>C), RS1000340146 (10:46027162 T>C), RS1000920605 (10:46013158 C>A,T), RS1001394426 (10:46013405 C>T), RS1001851782 (10:46023998 G>C), RS1001919755 (10:46025621 A>G), RS1002121163 (10:46017313 A>C,G), RS1002152227 (10:46017560 G>A,C,T), RS1002292057 (10:46031282 A>C,T), RS1002635706 (10:46029937 C>T), RS1002666661 (10:46030311 A>T), RS1003408093 (10:46004849 A>G), RS1003553935 (10:46022953 A>G), RS1003756562 (10:46015429 A>T)

Disease associations

OMIM: gene MIM:601984 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000585_12	Mean corpuscular volume	7.000000e-09
GCST000587_13	Mean corpuscular hemoglobin	6.000000e-10
GCST005993_47	Mean corpuscular hemoglobin	7.000000e-36
GCST005996_32	Red blood cell count	2.000000e-10
GCST006011_79	Mean corpuscular volume	2.000000e-42
GCST007830_2	Anti-thyroid peroxidase (TPOAb) levels in Hashimoto’s thyroiditis	1.000000e-06
GCST007851_9	Anti-thyroid peroxidase (TPOAb) and anti-thyroglobulin (TgAb) levels in Hashimoto’s thyroiditis	7.000000e-06
GCST010241_302	Apolipoprotein A1 levels	1.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0004305	erythrocyte count
EFO:0004614	apolipoprotein A 1 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3430877 (CHIMERIC PROTEIN), CHEMBL6066137 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 9,920 (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
CHEMBL1289601	LENVATINIB	4	8,784
CHEMBL2029988	CEP-32496	2	1,136

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.39	IC50	0.41	nM	CEP-32496
8.00	IC50	10	nM	LENVATINIB

PubChem BioAssay actives

2 with measured affinity, of 23 total; 2 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
1-[3-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-3-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]urea	1895751: Inhibition of NCOA4-RET (unknown origin)	ic50	0.0004	uM
Lenvatinib	1204920: Inhibition of NcoA4/RET (unknown origin) autophoshorylation	ic50	0.0100	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases reaction, affects expression, affects binding, affects folding, affects reaction (+2 more)	5
Chloroquine	affects expression, affects reaction, affects response to substance, decreases expression, decreases reaction (+1 more)	4
Deferoxamine	decreases reaction, increases expression, increases reaction	4
sodium arsenite	increases expression	2
3-methyladenine	decreases reaction, increases expression, increases abundance	2
bisphenol S	affects binding, affects folding, affects reaction, increases methylation	2
Dihydrotestosterone	increases activity, increases reaction	2
Tamoxifen	affects expression, affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	decreases expression, increases activity, increases reaction	2
Raloxifene Hydrochloride	decreases expression, affects expression, affects cotreatment	2
Particulate Matter	decreases reaction, increases expression, decreases expression, increases abundance	2
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	decreases expression	1
glycidyl methacrylate	increases expression	1
25-hydroxycholesterol	increases expression	1
trichostatin A	affects expression, decreases reaction	1
ferric ammonium citrate	decreases reaction, increases expression	1
beta-lapachone	increases expression, affects expression	1
arsenite	affects binding, decreases reaction	1
beryllium sulfate	affects reaction, decreases expression, increases abundance, increases expression, decreases reaction	1
zinc chromate	increases abundance, increases expression	1
ochratoxin A	increases expression, increases reaction, decreases reaction	1
nickel sulfate	decreases expression	1
sodium sulfide	decreases reaction, increases abundance, increases expression	1
toosendanin	affects expression, increases expression	1
bafilomycin A1	affects expression, affects reaction, affects response to substance	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	increases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3428925	Binding	Inhibition of NcoA4/RET (unknown origin) autophoshorylation	Progress in Discovery of KIF5B-RET Kinase Inhibitors for the Treatment of Non-Small-Cell Lung Cancer. — J Med Chem

Cellosaurus cell lines

9 cell lines: 6 cancer cell line, 2 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8EK	Ubigene BEAS-2B NCOA4 KO	Transformed cell line	Male
CVCL_F2A2	mCherry-NCOA4 WT RAW 264.7	Cancer cell line	Male
CVCL_F2A3	mCherry-NCOA4 LRRK2 G2019S RAW 264.7	Cancer cell line	Male
CVCL_KX93	PathHunter CHO-K1 LXRbeta Protein Interaction	Spontaneously immortalized cell line	Female
CVCL_KZ08	PathHunter CHO-K1 RXRgamma Protein Interaction	Spontaneously immortalized cell line	Female
CVCL_LB12	PathHunter U2OS PRalpha Protein Interaction	Cancer cell line	Female
CVCL_LB13	PathHunter U2OS PRbeta Protein Interaction	Cancer cell line	Female
CVCL_TA10	HAP1 NCOA4 (-) 2	Cancer cell line	Male
CVCL_TA11	HAP1 NCOA4 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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