IREB2

Summary

IREB2 (iron responsive element binding protein 2, HGNC:6115) is a protein-coding gene on chromosome 15q25.1, encoding Iron-responsive element-binding protein 2 (P48200). RNA-binding protein that binds to iron-responsive elements (IRES), which are stem-loop structures found in the 5’-UTR of ferritin, and delta aminolevulinic acid synthase mRNAs, and in the 3’-UTR of transferrin receptor mRNA. It is a selective cancer dependency (DepMap: 14.3% of cell lines).

The protein encoded by this gene is an RNA-binding protein that acts to regulate iron levels in the cells by regulating the translation and stability of mRNAs that affect iron homeostasis under conditions when iron is depleted. When iron levels are low, this protein binds to iron-responsive elements (IRES), stem-loop structures located either in the 5’ or 3’ UTRs. Binding to the 5’ UTR represses translation, while binding to the 3’ UTR inhibits mRNA degradation. When iron is found in the cell, this protein is degraded in a F-box and leucine rich repeat protein 5-dependent manner. Variants in this gene have been associated with lung cancer and chronic obstructive pulmonary disease (COPD). Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 3658 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia (Strong, GenCC)
• GWAS associations: 174
• Clinical variants (ClinVar): 300 total — 2 likely-pathogenic
• Phenotypes (HPO): 32
• Cancer dependency (DepMap): dependent in 14.3% of screened cell lines
• MANE Select transcript: NM_004136

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6115
Approved symbol	IREB2
Name	iron responsive element binding protein 2
Location	15q25.1
Locus type	gene with protein product
Status	Approved
Aliases	IRP2
Ensembl gene	ENSG00000136381
Ensembl biotype	protein_coding
OMIM	147582
Entrez	3658

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 9 protein_coding, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000258886, ENST00000558525, ENST00000558570, ENST00000559091, ENST00000559215, ENST00000559427, ENST00000559676, ENST00000560440, ENST00000560454, ENST00000560840, ENST00000925635, ENST00000925636, ENST00000925637, ENST00000925638, ENST00000953046

RefSeq mRNA: 5 — MANE Select: NM_004136 NM_001320941, NM_001320942, NM_001320943, NM_001354994, NM_004136

CCDS: CCDS10302, CCDS81912

Canonical transcript exons

ENST00000258886 — 22 exons

Exon	Start	End
ENSE00001218361	78498033	78501453
ENSE00001366257	78438216	78438356
ENSE00003491126	78490619	78490761
ENSE00003500075	78462922	78463087
ENSE00003518092	78488647	78488771
ENSE00003543977	78485705	78485840
ENSE00003548044	78484761	78484920
ENSE00003552011	78476188	78476359
ENSE00003554040	78483318	78483434
ENSE00003596075	78466271	78466489
ENSE00003598671	78465251	78465388
ENSE00003604900	78490422	78490526
ENSE00003605363	78488180	78488336
ENSE00003614611	78473242	78473381
ENSE00003649899	78470532	78470601
ENSE00003651606	78497126	78497311
ENSE00003652918	78439795	78439881
ENSE00003658813	78487733	78487817
ENSE00003677990	78478297	78478397
ENSE00003690837	78494142	78494264
ENSE00003692272	78493909	78494056
ENSE00003692794	78471741	78471924

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 94.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.1879 / max 574.1446, expressed in 1819 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147905	32.3920	1813
147906	5.2647	1557
147907	2.3030	1019
147904	1.2116	805
147908	0.0166	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	94.94	gold quality
germinal epithelium of ovary	UBERON:0001304	94.31	gold quality
palpebral conjunctiva	UBERON:0001812	94.06	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.06	gold quality
jejunal mucosa	UBERON:0000399	93.96	gold quality
amniotic fluid	UBERON:0000173	93.74	gold quality
adrenal tissue	UBERON:0018303	93.70	gold quality
eye	UBERON:0000970	93.53	gold quality
superficial temporal artery	UBERON:0001614	93.15	gold quality
jejunum	UBERON:0002115	92.86	gold quality
epithelium of nasopharynx	UBERON:0001951	92.72	gold quality
nasopharynx	UBERON:0001728	92.70	gold quality
buccal mucosa cell	CL:0002336	92.30	gold quality
right adrenal gland cortex	UBERON:0035827	92.21	gold quality
skin of hip	UBERON:0001554	91.98	gold quality
pigmented layer of retina	UBERON:0001782	91.96	gold quality
parietal pleura	UBERON:0002400	91.93	gold quality
cortical plate	UBERON:0005343	91.88	gold quality
colonic epithelium	UBERON:0000397	91.85	gold quality
biceps brachii	UBERON:0001507	91.80	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.73	gold quality
right adrenal gland	UBERON:0001233	91.48	gold quality
adrenal cortex	UBERON:0001235	91.43	gold quality
left adrenal gland	UBERON:0001234	91.35	gold quality
trabecular bone tissue	UBERON:0002483	91.35	gold quality
adrenal gland	UBERON:0002369	91.34	gold quality
endometrium	UBERON:0001295	91.26	gold quality
lower lobe of lung	UBERON:0008949	91.21	gold quality
visceral pleura	UBERON:0002401	91.13	gold quality
left adrenal gland cortex	UBERON:0035825	91.08	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ERF, MYC, TP63

miRNA regulators (miRDB)

133 targeting IREB2, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5193	100.00	67.26	1744
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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-144-3P	99.94	73.98	2698

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 14.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• gene coding and flanking regions were sequenced and examined for mutations that might modulate the iron burden of individuals harboring the common mutant hemochromatosis HFE genotype or cause hemochromatosis independent of mutations in the HFE gene (PMID:11783942)
• Multiple, conserved iron-responsive elements in the 3’-untranslated region of transferrin receptor mRNA enhance binding of iron regulatory protein 2 (PMID:12200453)
• data suggest that the differential regulation of IRP1 and IRP2 during hypoxia may be important for cellular adaptation to low oxygen tension. (PMID:12855587)
• 2-oxoglutarate-dependent dioxygenase activity may be involved in the oxygen and iron regulation of IRP2 protein stability (PMID:12888568)
• Mutations in the IRP2 gene are not a common cause of Parkinson Diseasse associated with SN iron accumulation. (PMID:15057521)
• IRP2 degradation involving 2-oxoglutarate-dependent oxygenase does not require the E3 ubiquitin ligase activity of pVHL (PMID:15777842)
• IRP2 exists as monomer in both the apo-IRP2 form and in the IRP2/iron regulatory element (IRE) complex. (PMID:15938636)
• IRP2 is the major regulator of intracellular iron homeostasis in humans. (PMID:16503547)
• Two mutations,rs2656070 and rs13180 showed statistically significant skewing of allelic and genotypic distributions between Alzheimer’s disease patients and controls (PMID:16914832)
• Results describe thet effect of hypoxia on the binding and subcellular distribution of iron regulatory proteins 1 and 2. (PMID:17200797)
• analysis of the iron regulatory protein system (PMID:17604281)
• Hypertransfusional (>8 transfusions/year) iron in liver biopsies correlated with increased expression (RNA) for iron regulatory proteins 1 and 2 (3-, 9- to 11-fold) and hepcidin RNA: (5- to 8-fold), while ferritin H and L RNA remained constant. (PMID:17613866)
• it is unlikely that the iron-dependent degradation of IRP2 is mediated by haem binding to the intact 73aa-Domain, since the sequence resembling an HRM in the 73aa-Domain does not provide an axial ligand of the cofactor unless this domain is cleaved (PMID:17760563)
• These data demonstrate that HOIL-1 is not required for iron-dependent degradation of IRP2 in HEK293 cells, and suggest that a HOIL-1 independent mechanism is used for IRP2 degradation in most cell types. (PMID:17822790)
• reversible phosphorylation of IRP2 during G(2)/M has a role in modulating the iron-independent expression of ferritin and other IRE-containing mRNAs during the cell cycle. (PMID:18574241)
• A role for lysosomes in the turnover of IRP2 is reported. (PMID:18582596)
• iron-independent mechanism for regulating iron homeostasis through the redox regulation of IRP2 cysteines. (PMID:19223469)
• IREB2 has a role as a COPD susceptibility gene (PMID:19800047)
• an apparent pro-oncogenic activity of IRP2 depends on its specific 73 amino acids insert, providing further evidence for a link between IRPs and cancer biology. (PMID:20405006)
• variants in the IREB2 gene were only significantly associated with FEV. (PMID:20656943)
• confirmed that the IREB2 locus is a contributor to COPD susceptibility and suggested a new pathway in COPD pathogenesis invoking iron homeostasis (PMID:21320324)
• under physiological, iron-sufficient conditions, the steady-state level of IRP2 in HEK293A cells is regulated by the nonproteasomal pathway. (PMID:21558272)
• IRP2 may affect the expressions of transferrin receptor and ferritin in lung adenocarcinoma A549 cells by changing the amount of protein and regulating the iron metabolism. (PMID:22093897)
• Ggenetic polymorphisms of the iron regulatory protein 1 and 2 genes may be associated with development of age-related macular degeneration. (PMID:22331484)
• The data showed that IREB2 and CHRNA3 are potential genetic modifiers of chronic obstructive pulmonary disease in individuals with severe alpha-1 antitrypsin deficiency and may be sex-specific in their impact. (PMID:22356581)
• A replication of association between two SNPs previously associated with COPD (CHRNA3/5 and IREB2), as well as an association with COPD of one locus initially associated with lung function (ADCY2). (PMID:22461431)
• IREB2 polymorphisms were associated with chronic obstructive pulmonary disease in non-smoking Chinese Han subjects (PMID:22914670)
• dysregulation of IRP2 is an early nodal point underlying altered iron metabolism in breast cancer and may contribute to poor outcome of some patients with breast cancer (PMID:24285726)
• Ascorbate-induced up-regulation of cellular ferroportin levels was associated with increased levels of the iron regulatory protein IRP2, and the hypoxia-inducible factor HIF2alpha. (PMID:24394537)
• Haplotypes of IREB2 carrying major alleles of rs2568494 (G), rs2656069 (A), rs10851906 (A), rs965604 (C) and minor alleles of rs1964678 (T), rs12593229 (T) showed negative correlation with lung function amongst South Indian male smokers with COPD. (PMID:24587150)
• IRE2 is located within genes previously associated with chronic obstructive pulmonary disease susceptibility. (PMID:25006744)
• Genetic variants near IREB2 and GALC likely contribute to genetic susceptibility to PAE associated with COPD. (PMID:25101718)
• IRP2 can regulate the expression of TfR and Fn by changing its own protein expression and thereby regulate iron metabolism. (PMID:25117307)
• This study confirms that the IREB2 variants contribute to an increased risk of lung cancer, whereas FAM13A predisposes to increased susceptibility to chronic obstructive pulmonary disease. (PMID:26310313)
• IREB2 - candidate gene for Chronic Obstructive Pulmonary Disease identified by Genome-wide association studies. (PMID:26527870)
• Irp2 expression is increased in airway epithelial cells exposed to cigarette smoke. (PMID:26752519)
• The current results revealed that there was significant association between IREB2 gene rs2568494 polymorphism with susceptibility to Chronic Obstructive Pulmonary Disease. (PMID:26775557)
• Five of these SNPs acted as cis-eQTLs, being associated with the transcription of IREB2 (rs2568494, rs16969968, rs11634351, rs6495309), PSMA4 (rs6495309) and ERCC1 (rs735482), out of 10,821 genes analyzed in lung. For these three genes, we obtained experimental evidence of differential allelic expression in lung tissue, pointing to the existence of in-cis genomic variants that regulate their transcription. (PMID:28181565)
• IRP2 expression was associated with mutations in BRAF. (PMID:28281325)
• Iron loading caused cell proliferation in cancer cell lines, which were less able to regulate IREB2 expression than primary bronchial epithelial cells (PBECs). Iron chelation resulted in a return of proliferation rates to baseline levels; knockdown of IREB2 had a similar effect. IRP2-positive tumours were larger and higher percentage staining related to poorer survival. (PMID:28404645)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ireb2	ENSDARG00000021466
mus_musculus	Ireb2	ENSMUSG00000032293
rattus_norvegicus	Ireb2	ENSRNOG00000013271
drosophila_melanogaster	Irp-1B	FBGN0024957
drosophila_melanogaster	Irp-1A	FBGN0024958
caenorhabditis_elegans		WBGENE00000040

Paralogs (2): ACO2 (ENSG00000100412), ACO1 (ENSG00000122729)

Protein

Protein identifiers

Iron-responsive element-binding protein 2 — P48200 (reviewed: P48200)

Alternative names: Iron regulatory protein 2

All UniProt accessions (6): P48200, H0YL48, H0YLE0, H0YMA8, H0YN46, H0YNL8

UniProt curated annotations — full annotation on UniProt →

Function. RNA-binding protein that binds to iron-responsive elements (IRES), which are stem-loop structures found in the 5’-UTR of ferritin, and delta aminolevulinic acid synthase mRNAs, and in the 3’-UTR of transferrin receptor mRNA. Binding to the IRE element in ferritin results in the repression of its mRNA translation. Binding of the protein to the transferrin receptor mRNA inhibits the degradation of this otherwise rapidly degraded mRNA.

Subunit / interactions. Interacts with RBCK1 isoform 1 and isoform 2 only in iron-rich conditions. Interacts (when associated with the 4Fe-4S) with FBXL5. Interacts with CIAO1 and CIAO2A.

Subcellular location. Cytoplasm.

Post-translational modifications. Ubiquitinated and degraded by the proteasome in presence of high level of iron and oxygen. Ubiquitinated by a SCF complex containing FBXL5. Upon iron and oxygen depletion FBXL5 is degraded, preventing ubiquitination and allowing its RNA-binding activity.

Disease relevance. Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia (NDCAMA) [MIM:618451] An autosomal recessive disorder characterized by severe neurological and extra-neurological manifestations. Clinical features include early-onset global developmental delay, absent speech, dystonia, spasticity, choreoathetoid movement disorder, seizures, and microcytic hypochromic anaemia unresponsive to iron supplementation. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 [4Fe-4S] cluster per subunit. [4Fe-4S]-binding affects RNA-binding activity, thereby inhibiting activity of the protein.

Similarity. Belongs to the aconitase/IPM isomerase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P48200-1	1	yes
P48200-2	2

RefSeq proteins (5): NP_001307870, NP_001307871, NP_001307872, NP_001341923, NP_004127* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000573	AconitaseA/IPMdHydase_ssu_swvl	Domain
IPR001030	Acoase/IPM_deHydtase_lsu_aba	Domain
IPR006249	Aconitase/IRP2	Family
IPR015928	Aconitase/3IPM_dehydase_swvl	Homologous_superfamily
IPR015931	Acnase/IPM_dHydase_lsu_aba_1/3	Homologous_superfamily
IPR018136	Aconitase_4Fe-4S_BS	Binding_site
IPR036008	Aconitase_4Fe-4S_dom	Homologous_superfamily
IPR044137	AcnA_IRP_Swivel	Domain

Pfam: PF00330, PF00694

UniProt features (79 total): strand 30, helix 27, turn 9, sequence conflict 4, binding site 3, sequence variant 3, splice variant 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6VCD	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48200-F1	87.11	0.66

Functional residue map

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

Ligand- & substrate-binding residues (3): 512; 578; 581

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-917937	Iron uptake and transport
R-HSA-382551	Transport of small molecules

MSigDB gene sets: 292 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_DIGESTION, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_ERYTHROCYTE_HOMEOSTASIS, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, BROWNE_HCMV_INFECTION_16HR_UP, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, GOBP_TETRAPYRROLE_BIOSYNTHETIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, GOBP_PORPHYRIN_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION

GO Biological Process (11): obsolete protoporphyrinogen IX biosynthetic process (GO:0006782), intracellular iron ion homeostasis (GO:0006879), post-embryonic development (GO:0009791), osteoclast differentiation (GO:0030316), erythrocyte homeostasis (GO:0034101), mRNA stabilization (GO:0048255), intestinal absorption (GO:0050892), multicellular organismal-level iron ion homeostasis (GO:0060586), regulation of translation (GO:0006417), regulation of gene expression (GO:0010468), negative regulation of translation (GO:0017148)

GO Molecular Function (8): mRNA regulatory element binding translation repressor activity (GO:0000900), RNA binding (GO:0003723), aconitate hydratase activity (GO:0003994), iron-responsive element binding (GO:0030350), metal ion binding (GO:0046872), 4 iron, 4 sulfur cluster binding (GO:0051539), protein binding (GO:0005515), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
inorganic ion homeostasis	2
translation	2
mRNA binding	2
cellular anatomical structure	2
intracellular monoatomic cation homeostasis	1
multicellular organism development	1
multicellular organismal process	1
myeloid leukocyte differentiation	1
myeloid cell homeostasis	1
regulation of mRNA stability	1
RNA stabilization	1
negative regulation of mRNA catabolic process	1
digestive system process	1
monoatomic cation homeostasis	1
multicellular organismal-level chemical homeostasis	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
translation repressor activity	1
nucleic acid binding	1
hydro-lyase activity	1
cation binding	1
iron-sulfur cluster binding	1
binding	1
metal cluster binding	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

3798 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IREB2	FBXL5	Q9UKA1	966
IREB2	SLC11A2	P49281	921
IREB2	TFRC	P02786	913
IREB2	RBCK1	Q9BYM8	901
IREB2	NFS1	Q9Y697	892
IREB2	RNF31	Q96EP0	885
IREB2	FAM13A	O94988	869
IREB2	FTL	P02792	853
IREB2	SLC40A1	Q9NP59	830
IREB2	FXN	Q16595	813
IREB2	ISCU	Q9H1K1	800
IREB2	TFR2	Q9UP52	780
IREB2	ALAS2	P22557	775
IREB2	SHARPIN	Q9H0F6	763
IREB2	FTH1	P02794	755

IntAct

42 interactions, top by confidence:

A	B	Type	Score
CIAO2A	CIAO1	psi-mi:“MI:0914”(association)	0.950
RGS20	GLRX3	psi-mi:“MI:0914”(association)	0.810
CAMKK2	OBSL1	psi-mi:“MI:0914”(association)	0.640
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
Cdc20	BUB1	psi-mi:“MI:0914”(association)	0.560
ALDH3B1	UBA6	psi-mi:“MI:0914”(association)	0.530
INSL3	GAPDHS	psi-mi:“MI:0914”(association)	0.530
CCNL2	ZBTB43	psi-mi:“MI:0914”(association)	0.530
ARL15	SLC25A20	psi-mi:“MI:0914”(association)	0.530
ELAVL2	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
CAMKMT	COL1A1	psi-mi:“MI:0914”(association)	0.530
GSPT2	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
IREB2	NDUFA9	psi-mi:“MI:0915”(physical association)	0.400
IREB2	MCCC1	psi-mi:“MI:0915”(physical association)	0.400
IREB2	H1-5	psi-mi:“MI:0915”(physical association)	0.400
FBXL5	IREB2	psi-mi:“MI:0915”(physical association)	0.400
IREB2	TFRC	psi-mi:“MI:0915”(physical association)	0.400
IREB2	USP53	psi-mi:“MI:0915”(physical association)	0.370
Hdac6	TDG	psi-mi:“MI:0914”(association)	0.350
ENSA	QSOX1	psi-mi:“MI:0914”(association)	0.350
ELAVL2	IGF2BP3	psi-mi:“MI:0914”(association)	0.350
ZNF174	FAM171A2	psi-mi:“MI:0914”(association)	0.350
RGS20	KIF3B	psi-mi:“MI:0914”(association)	0.350
BORCS8	TP73	psi-mi:“MI:0914”(association)	0.350
HS1BP3	TAF5L	psi-mi:“MI:0914”(association)	0.350

BioGRID (104): RBCK1 (Two-hybrid), IREB2 (Affinity Capture-MS), IREB2 (Affinity Capture-MS), IREB2 (Affinity Capture-MS), IREB2 (Co-fractionation), SF1 (Co-fractionation), IREB2 (Synthetic Lethality), IREB2 (Affinity Capture-MS), IREB2 (Affinity Capture-MS), IREB2 (Affinity Capture-MS), IREB2 (Affinity Capture-MS), IREB2 (Affinity Capture-MS), IREB2 (Affinity Capture-MS), IREB2 (Affinity Capture-MS), IREB2 (Affinity Capture-MS)

ESM2 similar proteins: A0JMA0, B0B7M4, B0BBT9, B3VKQ2, C4K3J5, O04916, O08451, O19906, O84310, P05990, P07264, P09339, P21399, P25516, P28271, P37032, P43847, P48200, P49601, P49608, P51375, P70920, Q00464, Q01059, Q0I5H4, Q0VCU1, Q1XDB2, Q23500, Q2A1K3, Q3KM54, Q42560, Q42669, Q4QME6, Q54X73, Q59938, Q5PB42, Q5ZLQ4, Q62751, Q63270, Q6NTP2

Diamond homologs: A0JMA0, A0QX20, A4YF02, A5MZ75, A7IA28, B3VKQ2, C3MKR6, C3MUB4, C3N1A2, C3N992, C3NMW1, C4KKU5, D9X0I3, D9XF46, O04916, O08451, O53166, P09339, P21399, P25516, P28271, P37032, P48200, P49608, P63433, P63434, P70920, P99148, Q01059, Q0RDK8, Q0VCU1, Q16DI8, Q1RKD5, Q23500, Q2A1K3, Q42560, Q42669, Q4JC10, Q4JVM4, Q4UK20

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
CDK1	down-regulates	IREB2	phosphorylation
CyclinB/CDK1	down-regulates	IREB2	phosphorylation
CDC14A	“up-regulates activity”	IREB2	dephosphorylation
VHL	“down-regulates quantity by destabilization”	IREB2	ubiquitination
FBXL5	“down-regulates quantity by destabilization”	IREB2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	149
Likely benign	103
Benign	23

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
633460	NM_004136.4(IREB2):c.1255C>T (p.Arg419Ter)	Likely pathogenic
633461	NM_004136.4(IREB2):c.1069G>T (p.Gly357Ter)	Likely pathogenic

SpliceAI

3263 predictions. Top by Δscore:

Variant	Effect	Δscore
15:78439793:A:AG	acceptor_gain	1.0000
15:78439794:G:GG	acceptor_gain	1.0000
15:78439877:G:GG	donor_gain	1.0000
15:78462918:TCA:T	acceptor_loss	1.0000
15:78462919:CAGA:C	acceptor_loss	1.0000
15:78462920:A:AG	acceptor_gain	1.0000
15:78462920:AGAT:A	acceptor_gain	1.0000
15:78462921:G:A	acceptor_loss	1.0000
15:78462921:G:GA	acceptor_gain	1.0000
15:78462921:GAT:G	acceptor_gain	1.0000
15:78462921:GATG:G	acceptor_gain	1.0000
15:78462941:AC:A	acceptor_gain	1.0000
15:78462941:ACG:A	acceptor_gain	1.0000
15:78462942:C:CA	acceptor_gain	1.0000
15:78462943:G:A	acceptor_gain	1.0000
15:78463042:TTG:T	donor_gain	1.0000
15:78463083:TTTAC:T	donor_gain	1.0000
15:78463084:TTAC:T	donor_gain	1.0000
15:78463085:TAC:T	donor_gain	1.0000
15:78463086:AC:A	donor_gain	1.0000
15:78463087:CG:C	donor_loss	1.0000
15:78463088:G:GG	donor_gain	1.0000
15:78463090:G:GG	donor_loss	1.0000
15:78463092:G:GG	donor_gain	1.0000
15:78465249:A:AG	acceptor_gain	1.0000
15:78465250:G:GG	acceptor_gain	1.0000
15:78465321:A:T	donor_gain	1.0000
15:78465355:T:G	donor_gain	1.0000
15:78465382:G:GG	donor_gain	1.0000
15:78465426:T:G	donor_gain	1.0000

AlphaMissense

6256 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:78494238:T:A	W857R	0.999
15:78494238:T:C	W857R	0.999
15:78490749:T:C	L771S	0.998
15:78463066:G:C	R84P	0.997
15:78471864:A:C	S275R	0.997
15:78471866:T:A	S275R	0.997
15:78471866:T:G	S275R	0.997
15:78476267:G:C	R368P	0.997
15:78476311:A:C	S383R	0.997
15:78476313:C:A	S383R	0.997
15:78476313:C:G	S383R	0.997
15:78490737:C:A	A767D	0.997
15:78494002:T:A	N806K	0.997
15:78494002:T:G	N806K	0.997
15:78471741:T:A	W234R	0.996
15:78471741:T:C	W234R	0.996
15:78493925:T:C	F781L	0.996
15:78493927:C:A	F781L	0.996
15:78493927:C:G	F781L	0.996
15:78493944:G:C	R787P	0.996
15:78494249:A:C	K860N	0.996
15:78494249:A:T	K860N	0.996
15:78494250:G:A	G861R	0.996
15:78494250:G:C	G861R	0.996
15:78476222:T:A	V353D	0.995
15:78490476:T:A	W711R	0.995
15:78490476:T:C	W711R	0.995
15:78490730:A:C	S765R	0.995
15:78490732:T:A	S765R	0.995
15:78490732:T:G	S765R	0.995

dbSNP variants (sampled 300 via entrez): RS1000018682 (15:78438541 T>A,C), RS1000072520 (15:78475006 G>C), RS1000320418 (15:78469816 T>A,C,G), RS1000371154 (15:78444483 C>T), RS1000379954 (15:78460391 C>G), RS1000391779 (15:78445590 T>C), RS1000409741 (15:78460091 A>T), RS1000416986 (15:78469302 G>T), RS1000478779 (15:78493873 A>C,G), RS1000493476 (15:78501543 G>A), RS1000502022 (15:78451902 A>G), RS1000505688 (15:78478191 A>G), RS1000512379 (15:78468144 G>C), RS1000553957 (15:78451630 C>A), RS1000582227 (15:78466877 A>AT)

Disease associations

OMIM: gene MIM:147582 | disease phenotypes: MIM:618451

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia	Strong	Autosomal recessive

Mondo (2): neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia (MONDO:0032758), lung adenocarcinoma (MONDO:0005061)

Orphanet (1): NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000322	Short philtrum
HP:0000369	Low-set ears
HP:0000508	Ptosis
HP:0000817	Reduced eye contact
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001276	Hypertonia
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001931	Hypochromic anemia
HP:0001935	Microcytic anemia
HP:0002072	Chorea
HP:0002310	Orofacial dyskinesia
HP:0002353	EEG abnormality
HP:0002421	Poor head control
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0008936	Axial hypotonia
HP:0011800	Midface retrusion
HP:0011968	Feeding difficulties
HP:0012448	Delayed myelination
HP:0012736	Profound global developmental delay
HP:0012762	Cerebral white matter atrophy
HP:0025190	Bilateral tonic-clonic seizure with generalized onset
HP:0034295	Reduced cerebral white matter volume

GWAS associations

174 associations (top):

Study	Trait	p-value
GCST000603_3	Chronic obstructive pulmonary disease	2.000000e-08
GCST001321_4	Chronic obstructive pulmonary disease	1.000000e-06
GCST001762_362	Obesity-related traits	9.000000e-06
GCST002539_77	Schizophrenia	2.000000e-13
GCST002624_3	Chronic obstructive pulmonary disease	5.000000e-08
GCST002625_6	Chronic bronchitis and chronic obstructive pulmonary disease	3.000000e-06
GCST002797_1	Pulmonary artery enlargement in chronic obstructive pulmonary disease	2.000000e-08
GCST002798_1	Pulmonary artery enlargement and chronic obstructive pulmonary disease	7.000000e-10
GCST003262_108	Post bronchodilator FEV1	8.000000e-11
GCST003262_116	Post bronchodilator FEV1	1.000000e-07
GCST003262_117	Post bronchodilator FEV1	2.000000e-07
GCST003262_118	Post bronchodilator FEV1	2.000000e-07
GCST003262_120	Post bronchodilator FEV1	2.000000e-07
GCST003262_148	Post bronchodilator FEV1	2.000000e-12
GCST003262_149	Post bronchodilator FEV1	2.000000e-12
GCST003262_163	Post bronchodilator FEV1	4.000000e-08
GCST003262_187	Post bronchodilator FEV1	1.000000e-07
GCST003262_208	Post bronchodilator FEV1	1.000000e-10
GCST003262_228	Post bronchodilator FEV1	1.000000e-13
GCST003262_230	Post bronchodilator FEV1	1.000000e-13
GCST003262_4	Post bronchodilator FEV1	8.000000e-08
GCST003262_401	Post bronchodilator FEV1	3.000000e-12
GCST003262_402	Post bronchodilator FEV1	3.000000e-12
GCST003262_403	Post bronchodilator FEV1	3.000000e-12
GCST003262_404	Post bronchodilator FEV1	4.000000e-12
GCST003262_42	Post bronchodilator FEV1	7.000000e-09
GCST003262_43	Post bronchodilator FEV1	7.000000e-09
GCST003262_44	Post bronchodilator FEV1	7.000000e-09
GCST003262_444	Post bronchodilator FEV1	2.000000e-14
GCST003262_648	Post bronchodilator FEV1	1.000000e-12

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0005116	urinary metabolite measurement
EFO:0006347	pulmonary artery enlargement
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0005850	emphysema pattern measurement
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0008354	cognitive function measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, increases expression	3
graphene oxide	increases expression	2
sodium arsenite	decreases reaction, increases abundance, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cadmium Chloride	increases abundance, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine	decreases expression, decreases reaction	1
FR900359	decreases phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
bisphenol A	increases methylation	1
zinc chloride	increases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
salvianolic acid A	decreases reaction, increases abundance, increases expression	1
2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone	increases activity	1
monomethylarsonous acid	increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
ferrostatin-1	increases expression, decreases reaction, increases abundance	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02399566	PHASE4	UNKNOWN	Clinical Trial of Erlotinib and Pemetrexed for Maintenance Treatment in Lung Adenocarcinoma
NCT02804646	PHASE4	UNKNOWN	Endostar Durative Transfusion Combined With Chemotherapy in the Treatment of Advanced Lung Adenocarcinoma
NCT00002852	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Stage I Non-small Cell Lung Cancer
NCT00005838	PHASE3	COMPLETED	Combination Chemotherapy Plus Radiation Therapy With or Without AE-941 in Treating Patients With Stage III Non-small Cell Lung Cancer That Cannot Be Removed By Surgery
NCT00020709	PHASE3	COMPLETED	Combination Chemotherapy and Radiation Therapy With or Without Gefitinib in Treating Patients With Stage III Non-Small Cell Lung Cancer That Cannot Be Removed By Surgery
NCT00049543	PHASE3	COMPLETED	Gefitinib in Treating Patients With Stage IB, II, or IIIA Non-small Cell Lung Cancer That Was Completely Removed by Surgery
NCT00946712	PHASE3	TERMINATED	S0819: Carboplatin and Paclitaxel With or Without Bevacizumab and/or Cetuximab in Treating Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer
NCT01798485	PHASE3	TERMINATED	A Phase 3 Study of Ganetespib in Combination With Docetaxel Versus Docetaxel Alone in Patients With Advanced NSCLC
NCT02011997	PHASE3	UNKNOWN	Comparison of cVATS Segmentectomy Versus Lobectomy for Lung Adenocarcinoma in Situ and With Microinvasion
NCT03391869	PHASE3	ACTIVE_NOT_RECRUITING	Nivolumab and Ipilimumab With or Without Local Consolidation Therapy in Treating Patients With Stage IV Non-Small Cell Lung Cancer
NCT03676192	PHASE3	COMPLETED	To Compare Efficacy and Safety of CT-P16 and European Union-Approved Avastin as First-Line Treatment for Metastatic or Recurrent Non-Squamous Non-Small Cell Lung Cancer
NCT04339218	PHASE3	RECRUITING	Cryoablation in Combination (or Not) With Pembrolizumab and Pemetrexed-carboplatin in 1st-line Treatment for Patients With Metastatic Lung Adenocarcinoma
NCT05204758	PHASE3	COMPLETED	Prophylactic TCM for Mitigation of EGFR-TKI Related Dermatological Adverse Effect
NCT05717803	PHASE3	RECRUITING	Segmentectomy for Ground Glass-dominant Invasive Lung Cancer (ECTOP-1012)
NCT05943795	PHASE3	ACTIVE_NOT_RECRUITING	A Clinical Study of SI-B001 Combined With Docetaxel in the Treatment of Non-small Cell Lung Adenocarcinoma and Lung Squamous Cell Carcinoma
NCT06031181	PHASE3	RECRUITING	Sublobar Resection for Adenocarcinoma in Situ/Minimally Invasive Adenocarcinoma Diagnosed by Intraoperative Frozen Section (ECTOP-1019)
NCT06031246	PHASE3	RECRUITING	Selective Lymph Node Dissection for cT1N0M0 Invasive NSCLC With CTR>0.5 Located in the Apical Segment (ECTOP-1018)
NCT06634966	PHASE3	RECRUITING	Segmentectomy for Solid-dominant Lung Cancer
NCT07169903	PHASE3	NOT_YET_RECRUITING	Segmentectomy vs Lobectomy for 2 - 3cm IASLC Grade 1-2 Lung Adenocarcinoma: A Multi-center RCT
NCT07481786	PHASE3	RECRUITING	Bevacizumab Plus FSRT Versus Hippocampus-Avoidant WBRT in Lung Adenocarcinoma With Extensive Brain Metastases
NCT00040794	PHASE2	COMPLETED	Combination Chemotherapy, Radiation Therapy, and Gefitinib in Treating Patients With Stage III Non-Small Cell Lung Cancer
NCT00087412	PHASE2	COMPLETED	S0341: Erlotinib in Treating Patients With Advanced Primary Non-Small Cell Lung Cancer
NCT00118144	PHASE2	COMPLETED	Bortezomib in Treating Patients With Stage IIIB or Stage IV Lung Cancer
NCT00118183	PHASE2	COMPLETED	Docetaxel With Either Cetuximab or Bortezomib as First-Line Therapy in Treating Patients With Stage III or Stage IV Non-Small Cell Lung Cancer
NCT00126581	PHASE2	COMPLETED	Erlotinib Hydrochloride With or Without Carboplatin and Paclitaxel in Treating Patients With Stage III-IV Non-small Cell Lung Cancer
NCT00334815	PHASE2	ACTIVE_NOT_RECRUITING	Combination Chemotherapy, Radiation Therapy, and Bevacizumab in Treating Patients With Newly Diagnosed Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery
NCT00368992	PHASE2	COMPLETED	S0536: Cetuximab, Paclitaxel, Carboplatin, and Bevacizumab in Treating Patients With Advanced Non-Small Cell Lung Cancer
NCT00511485	PHASE2	COMPLETED	Study of Vintafolide (MK-8109, EC145) in Participants With Progressive Adenocarcinoma of the Lung (MK-8109-008, EC-FV-03)
NCT00950365	PHASE2	COMPLETED	Pemetrexed Disodium With or Without Erlotinib Hydrochloride in Treating Patients With Stage IIIB-IV or Recurrent Non-Small Cell Lung Cancer
NCT00955305	PHASE2	TERMINATED	Paclitaxel, Carboplatin, and Bevacizumab With or Without Cixutumumab in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer
NCT01218516	PHASE2	COMPLETED	A Safety and Efficacy Study of Farletuzumab in Participants With Adenocarcinoma of the Lung
NCT01294306	PHASE2	COMPLETED	MK2206 and Erlotinib Hydrochloride in Treating Patients With Advanced Non-Small Cell Lung Cancer Who Have Progressed After Previous Response to Erlotinib Hydrochloride Therapy
NCT01557959	PHASE2	COMPLETED	Docetaxel, Cisplatin, Pegfilgrastim, and Erlotinib Hydrochloride in Treating Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer
NCT01561456	PHASE2	COMPLETED	Study of AXL1717 Compared to Docetaxel to Treat Squamous Cell Carcinoma or Adenocarcinoma of the Lung
NCT01578551	PHASE2	TERMINATED	Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients With Adenocarcinoma.
NCT01578668	PHASE2	COMPLETED	Erlotinib Plus Pemetrexed to Treat Lung Adenocarcinoma With Brain Metastases
NCT01819428	PHASE2	TERMINATED	NOV120101 (Poziotinib) for 1st Line Monotherapy in Patients With Lung Adenocarcinoma
NCT01935336	PHASE2	COMPLETED	Study of Ponatinib in Patients With Lung Cancer Preselected Using Different Candidate Predictive Biomarkers
NCT02134912	PHASE2	TERMINATED	S1300: Pemetrexed Disodium With or Without Crizotinib in Treating Patients With Stage IV Non-Small Cell Lung Cancer That Has Progressed After Crizotinib
NCT02186847	PHASE2	COMPLETED	Chemotherapy and Radiation Therapy With or Without Metformin Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer