NFE2

Summary

NFE2 (nuclear factor, erythroid 2, HGNC:7780) is a protein-coding gene on chromosome 12q13.13, encoding Transcription factor NF-E2 45 kDa subunit (Q16621). Component of the NF-E2 complex essential for regulating erythroid and megakaryocytic maturation and differentiation.

Enables WW domain binding activity; identical protein binding activity; and sequence-specific double-stranded DNA binding activity. Contributes to cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including labyrinthine layer blood vessel development; negative regulation of bone mineralization; and positive regulation of peptidyl-lysine acetylation. Part of RNA polymerase II transcription regulator complex and protein-DNA complex.

Source: NCBI Gene 4778 — RefSeq curated summary.

At a glance

• Gene–disease (curated): thrombocytopenia (Limited, ClinGen)
• GWAS associations: 16
• Clinical variants (ClinVar): 42 total
• Druggable target: yes
• Transcription factor: yes — 27 downstream targets (CollecTRI)
• MANE Select transcript: NM_001136023

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7780
Approved symbol	NFE2
Name	nuclear factor, erythroid 2
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Aliases	NF-E2
Ensembl gene	ENSG00000123405
Ensembl biotype	protein_coding
OMIM	601490
Entrez	4778

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 14 protein_coding

ENST00000312156, ENST00000435572, ENST00000540264, ENST00000553070, ENST00000553198, ENST00000896009, ENST00000896010, ENST00000896011, ENST00000896012, ENST00000928745, ENST00000928746, ENST00000928747, ENST00000941275, ENST00000941276

RefSeq mRNA: 5 — MANE Select: NM_001136023 NM_001136023, NM_001261461, NM_001400365, NM_001400372, NM_006163

CCDS: CCDS8876

Canonical transcript exons

ENST00000435572 — 3 exons

Exon	Start	End
ENSE00000838349	54292111	54293381
ENSE00001254313	54295135	54295304
ENSE00001630389	54300801	54301015

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 97.67.

FANTOM5 (CAGE): breadth broad, TPM avg 27.9240 / max 2152.9945, expressed in 646 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131323	12.5133	482
131320	6.0816	269
131324	5.9177	309
131316	1.1398	91
131322	0.8498	161
131317	0.5522	77
131321	0.3968	101
131318	0.3590	72
131319	0.1139	44

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	97.67	gold quality
monocyte	CL:0000576	97.21	gold quality
leukocyte	CL:0000738	96.58	gold quality
mononuclear cell	CL:0000842	96.56	gold quality
granulocyte	CL:0000094	95.82	gold quality
trabecular bone tissue	UBERON:0002483	95.47	gold quality
bone marrow	UBERON:0002371	93.61	gold quality
bone marrow cell	CL:0002092	90.13	gold quality
spleen	UBERON:0002106	87.20	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.50	gold quality
right lung	UBERON:0002167	79.86	gold quality
upper lobe of left lung	UBERON:0008952	78.93	gold quality
upper lobe of lung	UBERON:0008948	76.12	gold quality
periodontal ligament	UBERON:0008266	73.22	gold quality
skin of leg	UBERON:0001511	68.84	gold quality
hindlimb stylopod muscle	UBERON:0004252	68.10	gold quality
omental fat pad	UBERON:0010414	67.82	gold quality
peritoneum	UBERON:0002358	67.75	gold quality
vermiform appendix	UBERON:0001154	67.63	gold quality
adipose tissue of abdominal region	UBERON:0007808	67.58	gold quality
right lobe of liver	UBERON:0001114	64.92	gold quality
lung	UBERON:0002048	64.77	gold quality
gastrocnemius	UBERON:0001388	64.28	gold quality
zone of skin	UBERON:0000014	63.65	gold quality
skin of abdomen	UBERON:0001416	63.49	gold quality
caecum	UBERON:0001153	63.30	gold quality
apex of heart	UBERON:0002098	63.00	gold quality
muscle of leg	UBERON:0001383	62.91	gold quality
gall bladder	UBERON:0002110	61.87	gold quality
adrenal tissue	UBERON:0018303	61.80	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	826.06
E-MTAB-9067	yes	704.75
E-GEOD-130473	yes	300.35
E-HCAD-6	yes	43.63
E-CURD-112	yes	41.79
E-MTAB-10042	yes	32.97
E-ANND-3	yes	17.07
E-HCAD-10	yes	16.85
E-MTAB-6701	yes	12.22
E-MTAB-9221	yes	11.36
E-HCAD-9	yes	6.39
E-MTAB-9801	yes	5.30
E-MTAB-6678	yes	4.41
E-MTAB-9467	no	2.43

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

27 targets.

Target	Regulation
ABCC6	Unknown
ADAM2
AHSP	Unknown
AKR1C2
ALAS2
ANK1	Activation
ASIP
CD74
GCLC	Unknown
GCM1	Unknown
GSS	Unknown
HBA1
HBB	Activation
HBD	Activation
HBE1	Unknown
HBG1	Activation
HBG2	Activation
HDC	Activation
HMBS	Activation
NOTCH1
OGA
SLC7A11	Activation
SPTA1
TBXA2R	Unknown
TBXAS1	Unknown
TRIB3
TYMS	Activation

JASPAR motifs

Motif	Name	Family
MA0501.1	MAF::NFE2	Maf-related::Jun-related
MA0501.2	MAF::NFE2	Maf-related::Jun-related
MA0841.1	NFE2	Jun-related
MA0841.2	NFE2	Jun-related

JASPAR matrix evidence (PMIDs): PMID:9166829, PMID:10498903

Upstream regulators (CollecTRI, top): GATA1, GATA2, LDB1, LMO2, MYC, NFE2L2, NRF1, RUNX1, TAL1, TCF3, TFCP2, ZFPM1

miRNA regulators (miRDB)

16 targeting NFE2, 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-1252-5P	100.00	69.80	2774
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-361-5P	98.95	70.16	1340
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-374A-3P	98.87	67.82	1531
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-744-3P	97.99	67.76	637
HSA-MIR-5196-3P	97.57	65.98	979
HSA-MIR-6501-5P	97.41	68.24	712
HSA-MIR-3663-5P	97.01	64.84	713
HSA-MIR-601	95.98	67.59	421

Literature-anchored findings (GeneRIF, showing 40)

• with GATA1, mediates expression of alpha-spectrin gene promoter in erythroid cells in vitro (PMID:12196550)
• MafF/NFE2 hetrodimers act as weak transcriptional activators, and, in particular, are able to stimulate activity of the GCS1 promoter. (PMID:12490281)
• interaction in the beta-globin locus control regions before chromatin remodeling (PMID:12509425)
• IL-1beta up-regulates expression in megakaryocytic cells (PMID:14966463)
• model of mammalian beta-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells (PMID:16287851)
• Scl acts up-stream of NF-E2 expression to control megakaryocyte development and platelet release in settings of thrombopoietic stress (PMID:16763211)
• This is the first in vivo evidence for the interaction between p45/NF-E2 and the E3 ubiquitin ligase Itch, and the subsequent ubiquitination of p45/NF-E2 by Itch. (PMID:18718448)
• p45 dominates over Nrf2 to enhance megakaryocytic maturation by promoting ROS accumulation. (PMID:19901266)
• Data suggest that the posttranslational modifications and turnover of p45/NF-E2, as mediated by P-JNK, contribute to the control of its homeostatic concentration and consequently, its regulatory functions. (PMID:19966288)
• USF and NF-E2 cooperate to regulate the recruitment and activity of RNA polymerase II in the beta-globin gene locus. (PMID:20236933)
• data identify NF-E2 as a novel AML1 target gene and delineate a role for aberrant AML1 expression in mediating elevated NF-E2 expression in patients with myeloproliferative neoplasms (PMID:20339092)
• NLS-dependent nuclear import of p45 NF-E2 is important for platelet development (PMID:20854373)
• NF-E2 may play an important role in AHSP gene regulation, providing new insights into the molecular mechanisms underlying the erythroid-specific expression of AHSP as well as new possibilities for beta-thalassemia treatment (PMID:21232177)
• p45/NF-E2 knockdown inhibited the transcription of the gamma-globin genes, hypersensitive site formation in the LCR and chromatin loop formation of the beta-globin locus. (PMID:21609963)
• Nfe2 modulates JunD binding to the Gcm1 promoter via acetylation (PMID:22174410)
• These data establish a role for NF-E2 in the pathophysiology of MPNs and provide a molecular rationale for investigating epigenetic alterations as novel targets for rationally designed MPN therapies. (PMID:22231305)
• These findings demonstrate that a combination of p45NF-E2, Maf G, and Maf K is a key determinant of both megakaryopoiesis and thrombopoiesis. (PMID:22855609)
• A tissue-specific chromatin loop brings NF-E2 and ANK1E into close proximity preventing gene silencing and mutagenesis leading to hereditary spherocytosis. (PMID:22968456)
• NF-E2 overexpression is both required and sufficient for Epo independence and hematopoietic stem cells/myeloid progenitor cell expansion in polycythemia vera. (PMID:23341442)
• NFE-2 transgene mediates the expression of interleukin 8 in myeloproliferative neoplasms, thereby contributing to myeloproliferative neoplasm pathology. (PMID:23445878)
• the role of increased NF-E2 activity in the pathophysiology of myeloproliferative neoplasms, is reported. (PMID:23589569)
• Here we demonstrate that NF-E2 is mislocalized in prefibrotic primary myelofibrosis cells and that aberrant NF-E2 localization discriminates statistically highly significantly between essential thrombocytthemia and that disease. (PMID:23670178)
• NF-E2 immunohistochemistry and analysis of the proportion of nuclear positive erythroblasts of all erythroid precursor cells can help to distinguish between ET and PMF even in early stages of the diseases. (PMID:24196613)
• RUNX1 and NF-E2 are overexpressed in polycythemic patients of diverse phenotypes and molecular causes (PMID:24297870)
• IFN-gamma modulates NF-kappaB/c-Jun to antagonize activin A-mediated NF-E2 transcriptional activity on erythroid cell globin gene expression. (PMID:24336657)
• Findings suggest a model whereby ROCK inhibition drives polyploidization, DMS growth and proplatelet formation late in megakaryocyte maturation through downregulation of MYC and NFE2 expression. (PMID:24383889)
• the RUNX1 target NF-E2 is part of the molecular network by which RUNX1 regulates platelet biogenesis and function in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia (PMID:24606315)
• A functional link among the erythroid transcription factors GATA-1/NF-E2, miR-199b-5p in erythropoiesis. (PMID:24608802)
• The genes BCL6, NFE2, POU4F2 and ELF4 are primary 1,25(OH)2D3 targets in THP-1 cells (PMID:25482012)
• assessment of NF-E2 and NGFR expression may provide additional support in reaching a correct diagnosis in discriminating polycythemia vera from prefibrotic/fibrotic primary myelofibrosis and essential thrombocythemia (PMID:26093937)
• NF-E2, TAL1 and KLF1, all activators play a primary role in HSs formation in the LCR (PMID:27026582)
• Our data presented herein support the hypothesis that cytoplasmically located NF-E2 may have a function in the elimination of internal organelles. The mild autophagy defect observed in our mice may be due to the requirement for additional proteins in the formation of larger complexes to exert this function. (PMID:27479815)
• results suggest that p45 NF-E2 negatively regulates differentiation and apoptosis activation of human syncytiotrophoblast by modulating GCM1 acetylation and sumoylation. (PMID:28383551)
• under the obese condition, activation of the hepatic NFE2/miR-423-5p axis plays important roles in the progression of type 2 diabetes and NAFLD by repressing the FAM3A-ATP-Akt signaling pathway. (PMID:28411267)
• NF-E2 silencing in hematopoietic stem and progenitor cells (HSPCs) did not affect their myeloid and B cell differentiation in vivo, it almost abrogated T cell production in primary hosts, as confirmed by in vitro studies. This effect is at least partly due to Notch1 downregulation in NF-E2-silenced HSPCs. (PMID:28648895)
• We detected that cigarette smoke significantly increased p45 NFE2 levels in DJ-1 KO mice compared to wild-type mice. Our results indicate that p45 NFE2 expression is induced by exposure to cigarette smoke, has a cytoprotective activity against cell injury, and its downregulation in human primary ATII cells may contribute to emphysema pathogenesis (PMID:29476075)
• mutations in NFE2 predispose to the acquisition of secondary changes promoting the development of myelosarcoma and/or AML (PMID:30755419)
• The NFE2-miR-423-5p-TFF1 axis is a novel molecular mechanism and provides a new direction for the study and treatment of diabetic retinopathy. (PMID:31455213)
• data confirm that NFE2 mutations are rare, heterogenous mutations with a prevalence of frameshift and deletion, and are slightly enriched in PV. (PMID:31659782)
• Nuclear factor erythroid 2 (NF-E2) p45-related factor 2 interferes with homeodomain-interacting protein kinase 2/p53 activity to impair solid tumors chemosensitivity. (PMID:32593231)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nfe2	ENSDARG00000020606
mus_musculus	Nfe2	ENSMUSG00000058794
rattus_norvegicus	Nfe2	ENSRNOG00000036837

Paralogs (3): NFE2L3 (ENSG00000050344), NFE2L1 (ENSG00000082641), NFE2L2 (ENSG00000116044)

Protein

Protein identifiers

Transcription factor NF-E2 45 kDa subunit — Q16621 (reviewed: Q16621)

Alternative names: Leucine zipper protein NF-E2, Nuclear factor, erythroid-derived 2 45 kDa subunit, p45 NF-E2

All UniProt accessions (3): A8K3E0, Q16621, F8W1N9

UniProt curated annotations — full annotation on UniProt →

Function. Component of the NF-E2 complex essential for regulating erythroid and megakaryocytic maturation and differentiation. Binds to the hypersensitive site 2 (HS2) of the beta-globin control region (LCR). This subunit (NFE2) recognizes the TCAT/C sequence of the AP-1-like core palindrome present in a number of erythroid and megakaryocytic gene promoters. Requires MAFK or other small MAF proteins for binding to the NF-E2 motif. May play a role in all aspects of hemoglobin production from globin and heme synthesis to procurement of iron.

Subunit / interactions. Homodimer; can bind DNA as a homodimer. Erythroid transcription activator nuclear factor erythroid-derived 2 (NF-E2), composed of a heterodimer of NFE2 and MAFK, possesses transactivation activity on beta-globin. Also forms high affinity heterodimer with MAFG; the interaction promotes erythropoiesis. Interacts (via the PXY motif 1) with ITCH (via the WW 1 domain); the interaction promotes ‘Lys63’-linked ubiquitination of NFE2, translocates it to the cytoplasm and inhibits its transactivation activity. Interacts with KMT2D/MLL2; the interaction promotes transactivation of the beta-globin locus. Interacts with MAPK8 (phosphorylated form); the interaction leads to phosphorylation of NFE2 in undifferentiated cells.

Subcellular location. Nucleus. PML body. Cytoplasm.

Tissue specificity. Expressed in hematopoietic cells and also in colon and testis.

Post-translational modifications. Phosphorylated on serine residues. In undifferentiated erythrocytes, phosphorylated by MAPK8 which then leads to ubiquitination and protein degradation. Sumoylated. Sumoylation is required for translocation to nuclear bodies PODs, anchoring to the gene loci, and transactivation of the beta-globin gene. Ubiquitinated mainly by ‘Lys63’-linked ubiquitin. Polyubiquitination with ‘Lys63’-linked ubiquitin by ITCH retains NFE2 in the cytoplasm preventing its transactivation activity. In undifferentiated erythrocyte, ubiquitinated after MAPK8-mediatd phosphorylation leading to protein degradation.

Domain organisation. The PXY motifs are required for binding WW domains. PXY1 is required to promote transactivation of beta-globin and for hyperacetylation of histone H3, but not for binding to the HS2 promoter site.

Similarity. Belongs to the bZIP family. CNC subfamily.

RefSeq proteins (5): NP_001129495, NP_001248390, NP_001387294, NP_001387301, NP_006154 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004826	bZIP_Maf	Domain
IPR004827	bZIP	Domain
IPR008917	TF_DNA-bd_sf	Homologous_superfamily
IPR046347	bZIP_sf	Homologous_superfamily
IPR047167	NFE2-like	Family

Pfam: PF03131

UniProt features (19 total): region of interest 6, helix 4, modified residue 2, short sequence motif 2, chain 1, domain 1, cross-link 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2KZ5	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16621-F1	67.50	0.31

Functional residue map

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

Post-translational modifications (3): 157, 170, 368

Mutagenesis-validated functional residues (1):

Position	Phenotype
368	60% loss of dna-binding and 5-fold loss of transactivation activity. almost no colocalization with nuclear bodies.

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-983231	Factors involved in megakaryocyte development and platelet production

MSigDB gene sets: 228 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, MULLIGHAN_NPM1_SIGNATURE_3_UP, CMYB_01, AREB6_03, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GNF2_ANK1, HOFMANN_MYELODYSPLASTIC_SYNDROM_RISK_DN, GNF2_SPTA1, GATA1_04, WELCH_GATA1_TARGETS, SCHLOSSER_SERUM_RESPONSE_DN, GATA1_03, HAHTOLA_SEZARY_SYNDROM_UP, GOBP_HEMOSTASIS

GO Biological Process (6): nucleosome disassembly (GO:0006337), regulation of transcription by RNA polymerase II (GO:0006357), hemostasis (GO:0007599), positive regulation of DNA-templated transcription (GO:0045893), integrated stress response signaling (GO:0140467), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (10): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), identical protein binding (GO:0042802), sequence-specific DNA binding (GO:0043565), WW domain binding (GO:0050699), sequence-specific double-stranded DNA binding (GO:1990837), cis-regulatory region sequence-specific DNA binding (GO:0000987), protein binding (GO:0005515)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), PML body (GO:0016605), protein-DNA complex (GO:0032993), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Transcriptional regulation by RUNX1	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
cellular anatomical structure	3
DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
transcription cis-regulatory region binding	2
protein-DNA complex disassembly	1
nucleosome organization	1
transcription by RNA polymerase II	1
regulation of body fluid levels	1
positive regulation of RNA biosynthetic process	1
cellular response to stress	1
intracellular signaling cassette	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription regulator activity	1
protein binding	1
DNA binding	1
protein domain specific binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
nuclear body	1
protein-containing complex	1
transcription regulator complex	1
nuclear protein-containing complex	1

Protein interactions and networks

STRING

1606 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NFE2	MAFG	O15525	993
NFE2	MAF	O75444	984
NFE2	MAFK	O60675	973
NFE2	MAFF	Q9ULX9	933
NFE2	GATA1	P15976	904
NFE2	KEAP1	Q14145	780
NFE2	ZFPM1	Q8IX07	738
NFE2	GCLC	P48506	710
NFE2	HMBS	P08396	693
NFE2	TFCP2	Q12800	691
NFE2	HMOX1	P09601	679
NFE2	KLF1	Q13351	665
NFE2	FECH	P22830	657
NFE2	HHAT	Q5VTY9	645
NFE2	FOS	P01100	629

IntAct

44 interactions, top by confidence:

A	B	Type	Score
NFE2	NFE2	psi-mi:“MI:0407”(direct interaction)	0.620
NFE2	NFE2L3	psi-mi:“MI:0407”(direct interaction)	0.620
NFE2L3	NFE2	psi-mi:“MI:0407”(direct interaction)	0.620
NFE2	BTRC	psi-mi:“MI:0915”(physical association)	0.560
BTRC	NFE2	psi-mi:“MI:0915”(physical association)	0.560
NFE2	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
NFE2	GLE1	psi-mi:“MI:0915”(physical association)	0.560
NFE2	GSN	psi-mi:“MI:0915”(physical association)	0.560
NFE2		psi-mi:“MI:0915”(physical association)	0.560
NFE2	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
MDV005	NFE2	psi-mi:“MI:0407”(direct interaction)	0.440
NFE2	CREBZF	psi-mi:“MI:0407”(direct interaction)	0.440
NFE2	ATF7	psi-mi:“MI:0407”(direct interaction)	0.440
NFE2	MAFG	psi-mi:“MI:0407”(direct interaction)	0.440
NFE2	NFE2L1	psi-mi:“MI:0407”(direct interaction)	0.440
NFE2	MDV005	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (30): BTRC (Two-hybrid), CREBBP (Reconstituted Complex), NFE2 (Affinity Capture-Western), NFE2 (Biochemical Activity), NFE2 (Reconstituted Complex), GALT (Affinity Capture-MS), NFE2 (Reconstituted Complex), NFE2 (Biochemical Activity), NFE2 (Biochemical Activity), ITCH (Affinity Capture-Western), NFE2L1 (Negative Genetic), NFE2 (Two-hybrid), NFE2 (Two-hybrid), SSX5 (Two-hybrid), SCAND1 (Two-hybrid)

ESM2 similar proteins: A1L224, A2A699, A2AI08, A8MVW0, D3ZDX9, F6VAN0, G3N1S4, G3V909, O15534, O35451, O35973, O43889, O77728, O94983, P10166, P18850, P23999, Q00322, Q03484, Q07279, Q08CW8, Q16621, Q1HGE8, Q4FZU8, Q5EAD3, Q5FVM5, Q5UEM7, Q5XHX2, Q61817, Q6AYT2, Q6ZS17, Q80Y50, Q8BG26, Q8CHI5, Q8IZL8, Q8K3T3, Q8N1G0, Q8SQ19, Q91XE9, Q96PV7

Diamond homologs: A5D7E9, O14867, O54968, P20482, P34707, P97302, P97303, Q07279, Q14494, Q16236, Q16621, Q5EAD3, Q5NUA6, Q5RA25, Q5ZL67, Q60795, Q61985, Q6AYT2, Q9BYV9, Q9Y4A8, A0JN76, A1L2U9, A1YPR0, B1WAZ8, B1WBU4, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, E1B932, F1LZF0, O15062, O15156, O15209

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
ITCH	“down-regulates activity”	NFE2	ubiquitination
NFE2	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
NFE2	“up-regulates quantity by expression”	HBG2	“transcriptional regulation”
NFE2	“up-regulates quantity by expression”	HBG1	“transcriptional regulation”
NFE2	“up-regulates quantity by expression”	HBE1	“transcriptional regulation”
NFE2	“up-regulates quantity by expression”	HBD	“transcriptional regulation”
MAPK8	“down-regulates quantity by destabilization”	NFE2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	39
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

326 predictions. Top by Δscore:

Variant	Effect	Δscore
12:54293380:CC:C	acceptor_gain	1.0000
12:54293381:CC:C	acceptor_gain	1.0000
12:54295132:CAC:C	donor_loss	1.0000
12:54295133:A:AC	donor_gain	1.0000
12:54295133:ACC:A	donor_loss	1.0000
12:54295134:C:A	donor_loss	1.0000
12:54295134:C:CC	donor_gain	1.0000
12:54295134:CCTG:C	donor_gain	1.0000
12:54293378:GACC:G	acceptor_gain	0.9900
12:54293379:ACCC:A	acceptor_loss	0.9900
12:54293382:C:A	acceptor_loss	0.9900
12:54293382:C:CC	acceptor_gain	0.9900
12:54293383:T:C	acceptor_loss	0.9900
12:54295133:AC:A	donor_gain	0.9900
12:54295133:ACCTG:A	donor_gain	0.9900
12:54295134:CC:C	donor_gain	0.9900
12:54295134:CCTGC:C	donor_gain	0.9900
12:54295592:C:A	donor_gain	0.9900
12:54295605:T:A	donor_gain	0.9900
12:54293377:AGACC:A	acceptor_gain	0.9800
12:54295130:CTCA:C	donor_gain	0.9800
12:54295134:CCT:C	donor_gain	0.9800
12:54295591:C:CA	donor_gain	0.9800
12:54295698:T:A	donor_gain	0.9800
12:54295131:TCACC:T	donor_gain	0.9700
12:54293379:ACC:A	acceptor_gain	0.9600
12:54293380:CCC:C	acceptor_gain	0.9600
12:54295391:T:TA	donor_gain	0.9600
12:54295451:C:A	donor_gain	0.9600
12:54295430:A:AC	donor_gain	0.9500

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000117846 (12:54296011 C>T), RS1000665005 (12:54301273 A>G), RS1001104553 (12:54300958 A>T), RS1001312384 (12:54293943 T>A,C), RS1001570173 (12:54302957 T>C), RS1001572975 (12:54297173 G>A), RS1001619021 (12:54295069 T>A,C), RS1002001946 (12:54295398 A>C), RS1002519212 (12:54300900 G>T), RS1002623325 (12:54293495 C>T), RS1002981585 (12:54301011 C>G,T), RS1003245648 (12:54299313 T>C), RS1003392374 (12:54294254 G>A), RS1003892576 (12:54298427 A>C), RS1003959286 (12:54300343 G>A,C)

Disease associations

OMIM: gene MIM:601490 | disease phenotypes:

GenCC curated gene-disease

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
thrombocytopenia	Limited	AR

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST001335_22	Mean platelet volume	2.000000e-14
GCST002184_1	Mean platelet volume	2.000000e-09
GCST004603_107	Platelet count	4.000000e-36
GCST004607_47	Plateletcrit	3.000000e-32
GCST005962_20	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	7.000000e-13
GCST005991_29	Platelet count	3.000000e-13
GCST006804_99	Red cell distribution width	3.000000e-21
GCST007576_171	Chronotype	5.000000e-11
GCST010143_26	Meat-related diet	2.000000e-09
GCST90002385_229	High light scatter reticulocyte count	8.000000e-10
GCST90002391_208	Mean corpuscular hemoglobin concentration	1.000000e-14
GCST90002397_205	Mean spheric corpuscular volume	1.000000e-34
GCST90002401_241	Platelet distribution width	1.000000e-11
GCST90002402_131	Platelet count	5.000000e-31
GCST90002405_305	Reticulocyte count	4.000000e-19
GCST90002406_337	Reticulocyte fraction of red cells	2.000000e-24

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009188	Red cell distribution width
EFO:0008328	chronotype measurement
EFO:0008111	diet measurement
EFO:0007986	reticulocyte count
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0007984	platelet component distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523303 (SINGLE PROTEIN)

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
7.15	IC50	71.2	nM	CHEMBL4555143
6.95	IC50	112.6	nM	CHEMBL4447685

PubChem BioAssay actives

2 with measured affinity, of 2 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
N-(3-tert-butyl-1-phenylpyrazol-5-yl)-2-(1-phenyltetrazol-5-yl)sulfanylacetamide	1601007: Inhibition of activated recombinant human His-tagged TrkB expressed in baculovirus expression system preincubated for 20 mins followed by ATP/SRCtide substarte addition further incubated for 2 hrs by caliper microfluidic mobility shift assay	ic50	0.0712	uM
[2-[(3-tert-butyl-1-phenylpyrazol-5-yl)amino]-2-oxoethyl] 4-(tetrazol-1-yl)benzoate	1601007: Inhibition of activated recombinant human His-tagged TrkB expressed in baculovirus expression system preincubated for 20 mins followed by ATP/SRCtide substarte addition further incubated for 2 hrs by caliper microfluidic mobility shift assay	ic50	0.1126	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Butyric Acid	decreases reaction, increases expression	3
sodium arsenite	decreases expression, increases expression	2
entinostat	affects cotreatment, increases expression	2
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	decreases expression	2
Estradiol	affects expression, affects cotreatment, decreases expression	2
Hemin	increases expression, increases reaction, decreases reaction	2
Silicon Dioxide	decreases expression, increases expression	2
Aflatoxin B1	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
OTX015	decreases expression	1
mivebresib	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
hydroxyhydroquinone	decreases reaction, increases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
pyrrolidine dithiocarbamic acid	decreases reaction, increases expression	1
hydroquinone	decreases reaction, increases expression	1
catechol	increases expression, increases reaction	1
tamibarotene	increases expression	1
tellimagrandin I	decreases reaction, increases expression, decreases expression	1
chebulinic acid	decreases reaction, increases expression, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
pomalidomide	decreases expression	1
abrine	decreases expression	1
ormosil	affects binding, decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4400009	Binding	Inhibition of activated recombinant human His-tagged TrkB expressed in baculovirus expression system preincubated for 20 mins followed by ATP/SRCtide substarte addition further incubated for 2 hrs by caliper microfluidic mobility shift assa	Type 2 inhibitor leads of human tropomyosin receptor kinase (hTrkA). — Bioorg Med Chem Lett

Cellosaurus cell lines

6 cell lines: 5 induced pluripotent stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A5IU	UKAi004-A	Induced pluripotent stem cell	Male
CVCL_A5IV	UKAi004-B	Induced pluripotent stem cell	Male
CVCL_A5IW	UKAi004-C	Induced pluripotent stem cell	Male
CVCL_A5IX	UKAi004-D	Induced pluripotent stem cell	Male
CVCL_A5IY	UKAi004-E	Induced pluripotent stem cell	Male
CVCL_GZ90	K562 eGFP-NFE2	Cancer cell line	Female

Clinical trials (associated diseases)

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