EIF4EBP3

Summary

EIF4EBP3 (eukaryotic translation initiation factor 4E binding protein 3, HGNC:3290) is a protein-coding gene on chromosome 5q31.3, encoding Eukaryotic translation initiation factor 4E-binding protein 3 (O60516). Repressor of translation initiation that regulates EIF4E activity by preventing its assembly into the eIF4F complex: the hypophosphorylated form competes with EIF4G1/EIF4G3 and strongly binds to EIF4E, leading to repression of translation.

This gene encodes a member of the EIF4EBP family, which consists of proteins that bind to eukaryotic translation initiation factor 4E and regulate its assembly into EIF4F, the multi-subunit translation initiation factor that recognizes the mRNA cap structure. Read-through transcription from the neighboring upstream gene (MASK or ANKHD1) generates a transcript (MASK-BP3) that encodes a protein comprised of the MASK protein sequence for the majority of the protein and a different C-terminus due to an alternate reading frame for the EIF4EBP3 segments.

Source: NCBI Gene 8637 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 1 total
• MANE Select transcript: NM_003732

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3290
Approved symbol	EIF4EBP3
Name	eukaryotic translation initiation factor 4E binding protein 3
Location	5q31.3
Locus type	gene with protein product
Status	Approved
Aliases	4E-BP3
Ensembl gene	ENSG00000243056
Ensembl biotype	protein_coding
OMIM	603483
Entrez	8637

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000310331

RefSeq mRNA: 1 — MANE Select: NM_003732 NM_003732

CCDS: CCDS4226

Canonical transcript exons

ENST00000310331 — 3 exons

Exon	Start	End
ENSE00001196668	140547662	140547840
ENSE00003584215	140548906	140549076
ENSE00003621850	140549234	140549576

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 96.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.6569 / max 253.0624, expressed in 1531 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
58907	15.6412	1516
58908	0.6156	326
58906	0.4001	191

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	96.42	gold quality
gastrocnemius	UBERON:0001388	95.36	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.19	gold quality
muscle of leg	UBERON:0001383	94.46	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.34	gold quality
lower esophagus mucosa	UBERON:0035834	93.95	gold quality
right adrenal gland cortex	UBERON:0035827	93.72	gold quality
body of stomach	UBERON:0001161	93.51	gold quality
right adrenal gland	UBERON:0001233	93.42	gold quality
left adrenal gland cortex	UBERON:0035825	93.36	gold quality
minor salivary gland	UBERON:0001830	93.20	gold quality
saliva-secreting gland	UBERON:0001044	93.17	gold quality
left adrenal gland	UBERON:0001234	92.96	gold quality
fundus of stomach	UBERON:0001160	92.46	gold quality
skin of leg	UBERON:0001511	92.39	gold quality
skeletal muscle tissue	UBERON:0001134	92.10	gold quality
zone of skin	UBERON:0000014	92.07	gold quality
skin of abdomen	UBERON:0001416	92.04	gold quality
body of pancreas	UBERON:0001150	91.75	gold quality
right lobe of liver	UBERON:0001114	91.73	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.73	gold quality
mucosa of stomach	UBERON:0001199	91.66	gold quality
thoracic mammary gland	UBERON:0005200	91.42	gold quality
mucosa of transverse colon	UBERON:0004991	91.13	gold quality
adipose tissue	UBERON:0001013	91.06	gold quality
transverse colon	UBERON:0001157	90.83	gold quality
fallopian tube	UBERON:0003889	90.63	gold quality
adrenal gland	UBERON:0002369	90.45	gold quality
apex of heart	UBERON:0002098	90.39	gold quality
omental fat pad	UBERON:0010414	90.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting EIF4EBP3, 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-22-3P	99.93	68.13	917
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-488-5P	99.28	68.12	821
HSA-MIR-5693	99.24	66.67	1106
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-4274	98.59	66.10	630
HSA-MIR-210-5P	98.57	64.37	832
HSA-MIR-6792-5P	98.39	68.16	1330
HSA-MIR-4494	97.86	64.93	850
HSA-MIR-2276-5P	96.27	65.85	937
HSA-MIR-601	95.98	67.59	421

Literature-anchored findings (GeneRIF, showing 8)

• 4E-BP3 is associated with eIF4E in the cell nucleus and cytoplasm (PMID:12482586)
• PHAS-II, but not PHAS-III, contributes to the control of protein synthesis by insulin (PMID:14507920)
• there are overlapping reading frames in the mouse and human genes for 4E-BP3 and MASK (PMID:14557257)
• potential prognostic factor for survival in patients with lung adenocarcinoma (PMID:20621385)
• 4E-BP3 regulates eIF4E-mediated nuclear mRNA export and interacts with replication protein A2 (PMID:22684010)
• The data reveal that 4E-BP3 expression is controlled by the transcription factor TFE3 through a cis-regulatory element in the EIF4EBP3 gene promoter. (PMID:27319316)
• Role of the eIF4EBP3 gene in miR-22-3p-mediated cervical squamous carcinoma cell growth (PMID:29333098)
• eIF4EBP3 was downregulated by methylation and acted as a tumor suppressor by targeting eIF4E/beta-catenin in gastric cancer. (PMID:31853750)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif4ebp3l	ENSDARG00000041607
danio_rerio	eif4ebp3	ENSDARG00000054916
mus_musculus	Eif4ebp3	ENSMUSG00000090264
rattus_norvegicus	Ankhd1	ENSRNOG00000030247
drosophila_melanogaster	Thor	FBGN0261560

Paralogs (2): EIF4EBP2 (ENSG00000148730), EIF4EBP1 (ENSG00000187840)

Protein

Protein identifiers

Eukaryotic translation initiation factor 4E-binding protein 3 — O60516 (reviewed: O60516)

All UniProt accessions (1): O60516

UniProt curated annotations — full annotation on UniProt →

Function. Repressor of translation initiation that regulates EIF4E activity by preventing its assembly into the eIF4F complex: the hypophosphorylated form competes with EIF4G1/EIF4G3 and strongly binds to EIF4E, leading to repression of translation. In contrast, the hyperphosphorylated form dissociates from EIF4E, allowing interaction between EIF4G1/EIF4G3 and EIF4E, leading to initiation of translation. Inhibits EIF4E-mediated mRNA nuclear export.

Subunit / interactions. Interacts with EIF4E. Interacts with RPA2 (in unphosphorylated form via N-terminus); the interaction enhances EIF4EBP3-mediated inhibition of EIF4E-mediated mRNA nuclear export.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expression is highest in skeletal muscle, heart, kidney, and pancreas, whereas there is very little expression in brain and thymus.

Post-translational modifications. Phosphorylated.

Similarity. Belongs to the eIF4E-binding protein family.

RefSeq proteins (1): NP_003723* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008606	EIF4EBP	Family

Pfam: PF05456

UniProt features (7 total): short sequence motif 2, mutagenesis site 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60516-F1	75.88	0.30

Functional residue map

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

Mutagenesis-validated functional residues (2):

Position	Phenotype
40	loss of interaction with eif4e.
45	loss of interaction with eif4e.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 46 (showing top): GOBP_TRANSLATIONAL_INITIATION, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, GOBP_NEGATIVE_REGULATION_OF_TRANSLATIONAL_INITIATION, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOMF_TRANSLATION_REGULATOR_ACTIVITY, ONKEN_UVEAL_MELANOMA_UP, NF1_Q6_01, WTGAAAT_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, GOCC_RNA_CAP_BINDING_COMPLEX, GOBP_REGULATION_OF_TRANSLATION, BROWNE_HCMV_INFECTION_14HR_UP, GOBP_REGULATION_OF_TRANSLATIONAL_INITIATION, chr5q31

GO Biological Process (3): negative regulation of translational initiation (GO:0045947), regulation of translation (GO:0006417), negative regulation of translation (GO:0017148)

GO Molecular Function (3): eukaryotic initiation factor 4E binding (GO:0008190), translation repressor activity (GO:0030371), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), membrane (GO:0016020), eukaryotic translation initiation factor 4F complex (GO:0016281), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of translation	2
translation	2
cellular anatomical structure	2
translational initiation	1
regulation of translational initiation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
translation initiation factor binding	1
translation regulator activity	1
binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
RNA cap binding complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

408 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF4EBP3	EIF4E	P06730	922
EIF4EBP3	H7C0V5	H7C0V5	900
EIF4EBP3	ANKHD1	Q8IWZ3	798
EIF4EBP3	RPTOR	Q8N122	710
EIF4EBP3	EIF4G1	Q04637	705
EIF4EBP3	RPS6	P08227	641
EIF4EBP3	RICTOR	Q6R327	636
EIF4EBP3	RPS6KB1	P23443	631
EIF4EBP3	EIF4A2	Q14240	616
EIF4EBP3	EIF4B	P23588	612
EIF4EBP3	EIF4A1	P04765	600
EIF4EBP3	NGDN	Q8NEJ9	590
EIF4EBP3	MLST8	Q9BVC4	584
EIF4EBP3	SLC4A9	Q96Q91	547
EIF4EBP3	DDIT4	Q9NX09	507

IntAct

21 interactions, top by confidence:

A	B	Type	Score
EIF4EBP3	EIF4E	psi-mi:“MI:0915”(physical association)	0.930
EIF4E	EIF4EBP3	psi-mi:“MI:0915”(physical association)	0.930
EIF4EBP3	EIF4E	psi-mi:“MI:0407”(direct interaction)	0.930
RPA2	EIF4EBP3	psi-mi:“MI:0915”(physical association)	0.600
EIF4EBP3	RPA2	psi-mi:“MI:0915”(physical association)	0.600
EIF4EBP3	RPA2	psi-mi:“MI:0407”(direct interaction)	0.600
EIF4EBP3	Eif4e2	psi-mi:“MI:0407”(direct interaction)	0.560
Eif4e2	EIF4EBP3	psi-mi:“MI:0407”(direct interaction)	0.560
EIF4EBP3	EIF4E2	psi-mi:“MI:0914”(association)	0.550
EIF4EBP3	EIF4E2	psi-mi:“MI:0915”(physical association)	0.550
EIF4E	EIF4EBP3	psi-mi:“MI:0915”(physical association)	0.370
Smad6	DDX1	psi-mi:“MI:0914”(association)	0.350
EIF4E	EIF4EBP3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (15): EIF4EBP3 (Two-hybrid), EIF4E2 (Two-hybrid), EIF4EBP3 (Two-hybrid), EIF4E2 (Affinity Capture-MS), KLHL18 (Affinity Capture-MS), EIF4E (Affinity Capture-MS), EIF4E (Affinity Capture-Western), EIF4E (Affinity Capture-Western), EIF4EBP3 (Affinity Capture-MS), EIF4EBP3 (Affinity Capture-MS), EIF4EBP3 (Two-hybrid), EIF4EBP3 (Affinity Capture-MS), EIF4EBP3 (Affinity Capture-MS), EIF4EBP3 (Affinity Capture-MS), EIF4EBP3 (Affinity Capture-MS)

ESM2 similar proteins: A2AQ25, A4IGU9, A7E300, A8E4V2, B5DF41, B5DGK1, F1N4M2, O15079, O55003, O60238, O60516, Q0IHF8, Q0P5A7, Q12983, Q13541, Q14DQ1, Q1LWL8, Q3B7T9, Q3T013, Q3UN70, Q3ZCB6, Q5PR01, Q5XG16, Q5XKK7, Q5ZLN7, Q60876, Q62622, Q62739, Q63744, Q68EF0, Q68FF7, Q6AYT4, Q6PBI2, Q6PFP3, Q6ZNC4, Q7Z309, Q80U23, Q80VV3, Q8AVU0, Q8LD26

Diamond homologs: O60516, P70445, Q0P5A7, Q13541, Q13542, Q54DU8, Q60876, Q62622, Q80VV3, Q98TT6, Q9XZ56

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MTOR	up-regulates	EIF4EBP3	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

418 predictions. Top by Δscore:

Variant	Effect	Δscore
5:140547838:G:GT	donor_gain	1.0000
5:140548902:ACAG:A	acceptor_loss	1.0000
5:140548903:CA:C	acceptor_loss	1.0000
5:140548903:CAGGC:C	acceptor_loss	1.0000
5:140548904:A:AG	acceptor_gain	1.0000
5:140548905:G:GG	acceptor_gain	1.0000
5:140549064:G:GT	donor_gain	1.0000
5:140549073:CCCGG:C	donor_loss	1.0000
5:140549074:CCGGT:C	donor_loss	1.0000
5:140549075:CGGTA:C	donor_loss	1.0000
5:140549076:GGT:G	donor_loss	1.0000
5:140549077:G:GG	donor_gain	1.0000
5:140549077:G:T	donor_loss	1.0000
5:140549077:GTAAG:G	donor_loss	1.0000
5:140549078:T:A	donor_loss	1.0000
5:140549083:A:T	donor_gain	1.0000
5:140549090:GAAT:G	donor_gain	1.0000
5:140547868:GC:G	donor_gain	0.9900
5:140547883:GCGC:G	donor_gain	0.9900
5:140547885:GC:G	donor_gain	0.9900
5:140547887:G:GG	donor_gain	0.9900
5:140548900:T:A	acceptor_gain	0.9900
5:140548904:AG:A	acceptor_gain	0.9900
5:140548905:GG:G	acceptor_gain	0.9900
5:140548905:GGC:G	acceptor_gain	0.9900
5:140548905:GGCA:G	acceptor_gain	0.9900
5:140548905:GGCAC:G	acceptor_gain	0.9900
5:140549232:A:AG	acceptor_gain	0.9900
5:140549233:G:GG	acceptor_gain	0.9900
5:140549082:G:GT	donor_gain	0.9800

AlphaMissense

634 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:140549245:T:C	F96L	0.999
5:140549247:T:A	F96L	0.999
5:140549247:T:G	F96L	0.999
5:140548932:T:C	F44L	0.998
5:140548934:C:A	F44L	0.998
5:140548934:C:G	F44L	0.998
5:140548913:G:C	R37S	0.996
5:140548913:G:T	R37S	0.996
5:140548915:T:G	I38S	0.996
5:140548936:T:C	L45P	0.996
5:140548963:C:A	A54D	0.996
5:140548906:G:A	G35D	0.995
5:140548920:T:C	Y40H	0.995
5:140548920:T:G	Y40D	0.995
5:140547838:G:A	G34E	0.994
5:140548915:T:C	I38T	0.994
5:140548927:G:C	R42P	0.994
5:140549246:T:C	F96S	0.994
5:140549246:T:G	F96C	0.994
5:140547814:G:A	G26D	0.993
5:140548906:G:T	G35V	0.993
5:140548915:T:A	I38N	0.993
5:140548933:T:C	F44S	0.993
5:140548936:T:A	L45Q	0.993
5:140548939:T:C	L46P	0.993
5:140548953:T:C	S51P	0.993
5:140547813:G:C	G26R	0.992
5:140547822:T:G	Y29D	0.992
5:140547840:G:C	G35R	0.992
5:140547814:G:T	G26V	0.991

dbSNP variants (sampled 300 via entrez): RS1000568048 (5:140545802 C>T), RS1000836199 (5:140546232 C>G), RS1001898044 (5:140546694 A>C,G), RS1002989574 (5:140548079 G>C), RS1005099325 (5:140549614 T>C), RS1005470708 (5:140546746 C>T), RS1005774255 (5:140546358 C>A), RS1005832451 (5:140547076 T>C), RS1005886719 (5:140547767 C>G,T), RS1006106334 (5:140548029 A>G), RS1006422121 (5:140548558 C>T), RS1006800770 (5:140547798 A>G), RS1006928176 (5:140547560 C>G,T), RS1007038568 (5:140545736 A>G,T), RS1008149949 (5:140547718 TGCTGCTCCTCCCGCTC>T)

Disease associations

OMIM: gene MIM:603483 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009391_1528	Metabolite levels	8.000000e-06
GCST010146_22	Serum immune biomarker levels	7.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009771	methionine measurement
EFO:0004872	inflammatory biomarker measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Quercetin	increases reaction, affects cotreatment, increases expression, decreases phosphorylation	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
arsenite	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
perfluoro-n-nonanoic acid	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
bisphenol Z	increases expression	1
jinfukang	decreases expression	1
momelotinib	increases expression	1
Sunitinib	increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Diethylhexyl Phthalate	increases phosphorylation	1
Gold	affects cotreatment, increases expression	1
Phthalic Acids	decreases methylation	1
Thiram	decreases expression	1
Urethane	increases expression	1
Valproic Acid	increases expression	1
Arachidonic Acid	decreases phosphorylation, increases reaction	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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