EIF4E2

Summary

EIF4E2 (eukaryotic translation initiation factor 4E family member 2, HGNC:3293) is a protein-coding gene on chromosome 2q37.1, encoding Eukaryotic translation initiation factor 4E type 2 (O60573). Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation. It is a selective cancer dependency (DepMap: 14.7% of cell lines).

Enables RNA 7-methylguanosine cap binding activity; mRNA cap binding activity; and ubiquitin protein ligase binding activity. Involved in negative regulation of translational initiation; negative regulation of type I interferon-mediated signaling pathway; and rescue of stalled ribosome. Acts upstream of with a positive effect on miRNA-mediated gene silencing by inhibition of translation. Acts upstream of or within negative regulation of translation. Located in P-body.

Source: NCBI Gene 9470 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 33 total
• Cancer dependency (DepMap): dependent in 14.7% of screened cell lines
• MANE Select transcript: NM_004846

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3293
Approved symbol	EIF4E2
Name	eukaryotic translation initiation factor 4E family member 2
Location	2q37.1
Locus type	gene with protein product
Status	Approved
Aliases	IF4e, 4EHP
Ensembl gene	ENSG00000135930
Ensembl biotype	protein_coding
OMIM	605895
Entrez	9470

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000258416, ENST00000409098, ENST00000409167, ENST00000409322, ENST00000409394, ENST00000409495, ENST00000409514, ENST00000444113, ENST00000454501, ENST00000459714, ENST00000463074, ENST00000478878, ENST00000479834, ENST00000498242, ENST00000687222, ENST00000689278, ENST00000690794, ENST00000868568, ENST00000931065, ENST00000931066, ENST00000931067

RefSeq mRNA: 7 — MANE Select: NM_004846 NM_001276336, NM_001276337, NM_001282958, NM_001330201, NM_001330202, NM_001330203, NM_004846

CCDS: CCDS2496, CCDS63158, CCDS63159, CCDS74671, CCDS82579, CCDS92971

Canonical transcript exons

ENST00000258416 — 7 exons

Exon	Start	End
ENSE00000572172	232557884	232558018
ENSE00000786783	232564247	232564351
ENSE00001073151	232566829	232566981
ENSE00001073152	232568945	232569210
ENSE00001552964	232550689	232550744
ENSE00003466471	232567078	232567214
ENSE00003614778	232556416	232556530

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 98.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 92.8841 / max 5584.2685, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25995	91.4429	1825
25997	1.4073	989
25996	0.0340	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	98.28	gold quality
sural nerve	UBERON:0015488	98.02	gold quality
mononuclear cell	CL:0000842	97.94	gold quality
calcaneal tendon	UBERON:0003701	97.94	gold quality
leukocyte	CL:0000738	97.83	gold quality
cervix squamous epithelium	UBERON:0006922	97.53	gold quality
gastrocnemius	UBERON:0001388	97.37	gold quality
muscle of leg	UBERON:0001383	97.31	gold quality
rectum	UBERON:0001052	97.15	gold quality
esophagus squamous epithelium	UBERON:0006920	97.06	gold quality
squamous epithelium	UBERON:0006914	97.05	gold quality
gingival epithelium	UBERON:0001949	96.91	gold quality
mucosa of transverse colon	UBERON:0004991	96.69	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.68	gold quality
islet of Langerhans	UBERON:0000006	96.56	gold quality
amniotic fluid	UBERON:0000173	96.50	gold quality
sperm	CL:0000019	96.47	gold quality
tendon	UBERON:0000043	96.35	gold quality
stromal cell of endometrium	CL:0002255	96.29	gold quality
epithelium of esophagus	UBERON:0001976	96.19	gold quality
gingiva	UBERON:0001828	96.08	gold quality
granulocyte	CL:0000094	95.96	gold quality
tongue squamous epithelium	UBERON:0006919	95.84	gold quality
transverse colon	UBERON:0001157	95.65	gold quality
adrenal tissue	UBERON:0018303	95.61	gold quality
esophagus mucosa	UBERON:0002469	95.46	gold quality
endometrium	UBERON:0001295	95.43	gold quality
smooth muscle tissue	UBERON:0001135	95.37	gold quality
right lobe of liver	UBERON:0001114	95.33	gold quality
ganglionic eminence	UBERON:0004023	95.31	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.67
E-CURD-97	no	685.90

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting EIF4E2, 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-767-5P	99.95	70.85	993
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-6787-3P	97.75	66.17	1233
HSA-MIR-585-5P	97.54	69.02	955
HSA-MIR-4695-3P	96.71	67.21	836
HSA-MIR-1266-3P	96.23	66.36	778

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 14.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 21)

• 4EHP over-expression instigates a negative feedback loop that inhibits upstream signaling to 4E-BP1 and ribosomal protein S6 kinase 1 (S6K1) whereas the 4E-BP1-binding-deficient mutant of 4EHP(W95A) was unable to trigger this feedback loop (PMID:15094042)
• ISGylation of 4EHP may play an important role in cap structure-dependent translation control in immune responses. (PMID:17289916)
• 4EHP plays a physiological role utilizing both cap-binding and protein-binding functions but which is distinct from eIF4E. (PMID:17368478)
• 4EHP binds cap analogs m(7)GpppG and m(7)GTP with low affinity (PMID:17369309)
• GIGYF2 and the zinc finger protein 598 (ZNF598) are identified as components of the 4EHP complex. (PMID:22751931)
• provide evidence that eIF4E2 binds 4E-T in the yeast two hybrid assay, as well as in pull-down assays and by recruitment to P-bodies in mammalian cells (PMID:23991149)
• Activation of eIF4E2-directed translation is essential for cancer cells. (PMID:24408918)
• DNA damage induces an increase in ARIH1 protein levels and association of ARIH1 with 4EHP. In turn, this causes 4EHP recruitment to the mRNA cap, where it is known to compete with eIF4E. (PMID:25624349)
• Tristetraprolin recruits eukaryotic initiation factor 4E2 (eIF4E2) to repress target mRNA translation. (PMID:26370510)
• Following heat shock, eIF4E2 is found in both processing bodies and stress granules, whereas eIF4E3_A relocates only to stress granules. (PMID:27578149)
• cap-binding activity contributes to the translational silencing by miRNAs through the CCR4-NOT complex (PMID:28487484)
• miRNA enhances eIF4E2 association with the target mRNA (PMID:28755203)
• We performed bioinformatics analyses of ESTs and the 3’UTRs of the main transcript splice variants of the translational initiation factor eIF4E1 and its family members, eIF4E2 and eIF4E3. We propose to elucidate the minor splice variants of eIF4E2 and eIF4E3 in great detail because they might produce proteins with modified features that fulfill different cellular roles from their major counterparts. (PMID:28942592)
• cadherin-22 is upregulated in hypoxia via mTORC1-independent translational control by the initiation factor eIF4E2 functioning as a hypoxia-specific cell-surface molecule involved in cancer cell migration, invasion and adhesion. (PMID:28991229)
• The authors that the Dusp6 mRNA, which encodes an ERK1/2 phosphatase, is translationally repressed by 4EHP and a specific miRNA, miR-145. (PMID:29412140)
• GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control. (PMID:32726578)
• 4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay. (PMID:33053355)
• microRNA-induced translational control of antiviral immunity by the cap-binding protein 4EHP. (PMID:33581076)
• High EIF4E2 expression is an independent prognostic risk factor for poor overall survival and recurrence-free survival in uveal melanoma. (PMID:33785306)
• Translational repression of NMD targets by GIGYF2 and EIF4E2. (PMID:34665823)
• METTL16 promotes translation and lung tumorigenesis by sequestering cytoplasmic eIF4E2. (PMID:36840945)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif4e2	ENSDARG00000038585
mus_musculus	Eif4e2	ENSMUSG00000026254
rattus_norvegicus	Chrng	ENSRNOG00000019634
drosophila_melanogaster	eIF4E1	FBGN0015218
drosophila_melanogaster	eIF4E4	FBGN0035709
drosophila_melanogaster	eIF4E5	FBGN0035823
drosophila_melanogaster	eIF4E6	FBGN0039622
drosophila_melanogaster	eIF4E7	FBGN0040368
drosophila_melanogaster	eIF4EHP	FBGN0053100
drosophila_melanogaster	eIF4E3	FBGN0265089
caenorhabditis_elegans		WBGENE00002059
caenorhabditis_elegans		WBGENE00002062
caenorhabditis_elegans		WBGENE00002063

Paralogs (3): EIF4E (ENSG00000151247), EIF4E3 (ENSG00000163412), EIF4E1B (ENSG00000175766)

Protein

Protein identifiers

Eukaryotic translation initiation factor 4E type 2 — O60573 (reviewed: O60573)

Alternative names: Eukaryotic translation initiation factor 4E homologous protein, Eukaryotic translation initiation factor 4E-like 3, eIF4E-like protein 4E-LP, mRNA cap-binding protein 4EHP, mRNA cap-binding protein type 3

All UniProt accessions (11): A0A8I5KSA5, A0A8I5KT16, B4E1E4, B8ZZ50, B8ZZL3, B9A023, B9A044, C9JEL3, O60573, H7BZH2, Q53RG0

UniProt curated annotations — full annotation on UniProt →

Function. Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation. Acts as a repressor of translation initiation. In contrast to EIF4E, it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3), suggesting that it acts by competing with EIF4E and block assembly of eIF4F at the cap. In P-bodies, component of a complex that promotes miRNA-mediated translational repression. Involved in virus-induced host response by mediating miRNA MIR34A-induced translational silencing which controls IFNB1 production by a negative feedback mechanism. Component of the 4EHP-GYF2 complex, a multiprotein complex that acts as a repressor of translation initiation. In association with GIGYF2, assists ribosome-associated quality control (RQC) by sequestering the mRNA cap, blocking ribosome initiation and decreasing the translational load on problematic messages. Part of a pathway that works in parallel to RQC-mediated degradation of the stalled nascent polypeptide. GIGYF2 and EIF4E2 work downstream and independently of ZNF598, which seems to work as a scaffold that can recruit them to faulty mRNA even if alternative recruitment mechanisms may exist. (Microbial infection) Upon SARS coronavirus-2/SARS-CoV-2 infection, the interaction with non-structural protein 2 (nsp2) with GIGYF2 enhances GIGYF2 binding to EIF4E2 and increases repression of translation initiation of genes involved in antiviral innate immune response such as IFNB1.

Subunit / interactions. Interacts with EIF4EBP1, EIF4EBP2 and EIF4EBP3. Does not interact with eIF4G (EIF4G1, EIF4G2 or EIF4G3). Component of the 4EHP-GYF2 complex, at least composed of EIF4E2, GIGYF2 and ZNF598. Interacts with GIGYF2 (via the 4EHP-binding motif); the interaction is direct. Interacts with EIF4ENIF1/4E-T (via YXXXXLphi motif); increasing affinity for the 7-methylguanosine-containing mRNA cap.

Subcellular location. Cytoplasm. P-body.

Post-translational modifications. Ubiquitinated by ARIH1. The consequences of ubiquitination are however unclear: according to a report, EIF4E2 ubiquitination leads to promote EIF4E2 cap-binding and protein translation arrest. According to another report ubiquitination leads to its subsequent degradation. ISGylation enhances its cap structure-binding activity and translation-inhibition activity.

Similarity. Belongs to the eukaryotic initiation factor 4E family.

Isoforms (2)

UniProt ID	Names	Canonical?
O60573-1	1	yes
O60573-2	2

RefSeq proteins (7): NP_001263265, NP_001263266, NP_001269887, NP_001317130, NP_001317131, NP_001317132, NP_004837* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001040	TIF_eIF_4E	Family
IPR019770	TIF_eIF_4E_CS	Conserved_site
IPR023398	TIF_eIF4e-like	Homologous_superfamily

Pfam: PF01652

UniProt features (48 total): mutagenesis site 15, strand 7, helix 6, binding site 5, region of interest 4, modified residue 2, cross-link 2, splice variant 2, turn 2, chain 1, sequence conflict 1, compositionally biased region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
2JGB	X-RAY DIFFRACTION	1.7
5NVN	X-RAY DIFFRACTION	1.9
5XLN	X-RAY DIFFRACTION	1.9
5NVM	X-RAY DIFFRACTION	2
5NVL	X-RAY DIFFRACTION	2.3
2JGC	X-RAY DIFFRACTION	2.4
5NVK	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60573-F1	80.42	0.62

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 (5): 222–224; 78–79; 110; 124–125; 174–179

Post-translational modifications (4): 13, 134, 134, 222

Mutagenesis-validated functional residues (15):

Position	Phenotype
63	unable to bind capped mrna.
95	ability to bind capped mrna reduced to 40% of wild-type.
121	does not affect ubiquitination by arih1; when associated with r-130; r-134 and r-222.
124–126	unable to bind capped mrna.
124	ability to bind capped mrna reduced to less than 10% of wild-type.
124	ability to bind capped mrna reduced to 13% of wild-type.
125	ability to bind capped mrna reduced to less than 10% of wild-type.
126	slight reduction in ability to bind capped mrna.
130	does not affect ubiquitination by arih1; when associated with r-121; r-134 and r-222.
134	does not affect ubiquitination by arih1; when associated with r-121; r-130 and r-222.
135	unable to bind capped mrna.
148	unable to bind capped mrna.
183	ability to bind capped mrna reduced to less than 10% of wild-type.
183	unable to bind capped mrna.
222	does not affect ubiquitination by arih1; when associated with r-121; r-130 and r-134.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism

MSigDB gene sets: 218 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, MORF_MBD4, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, ENK_UV_RESPONSE_KERATINOCYTE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_TRANSLATIONAL_INITIATION, GOMF_TRANSLATION_INITIATION_FACTOR_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, GOBP_NEGATIVE_REGULATION_OF_TRANSLATIONAL_INITIATION, GOBP_TRANSLATION

GO Biological Process (10): translational initiation (GO:0006413), negative regulation of translation (GO:0017148), miRNA-mediated gene silencing by inhibition of translation (GO:0035278), negative regulation of translational initiation (GO:0045947), negative regulation of type I interferon-mediated signaling pathway (GO:0060339), rescue of stalled cytosolic ribosome (GO:0072344), translation (GO:0006412), regulation of translation (GO:0006417), regulatory ncRNA-mediated gene silencing (GO:0031047), type I interferon-mediated signaling pathway (GO:0060337)

GO Molecular Function (8): RNA cap binding (GO:0000339), RNA 7-methylguanosine cap binding (GO:0000340), RNA binding (GO:0003723), translation initiation factor activity (GO:0003743), translation factor activity, RNA binding (GO:0008135), ubiquitin protein ligase binding (GO:0031625), mRNA cap binding (GO:0098808), protein binding (GO:0005515)

GO Cellular Component (4): P-body (GO:0000932), cytoplasm (GO:0005737), cytosol (GO:0005829), eukaryotic translation initiation factor 4F complex (GO:0016281)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Antimicrobial mechanism of IFN-stimulated genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translation	4
translational initiation	3
negative regulation of gene expression	2
negative regulation of translation	2
RNA binding	2
RNA cap binding	2
translation factor activity	2
cellular anatomical structure	2
cytoplasm	2
formation of translation initiation ternary complex	1
metabolic process	1
regulation of translation	1
negative regulation of protein metabolic process	1
miRNA-mediated post-transcriptional gene silencing	1
regulation of translational initiation	1
negative regulation of cytokine-mediated signaling pathway	1
negative regulation of innate immune response	1
type I interferon-mediated signaling pathway	1
regulation of type I interferon-mediated signaling pathway	1
cytoplasmic translational elongation	1
ribosome disassembly	1
peptidyltransferase activity	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
cellular response to type I interferon	1
interferon-mediated signaling pathway	1
nucleic acid binding	1
ubiquitin-like protein ligase binding	1
mRNA binding	1
binding	1
cytoplasmic ribonucleoprotein granule	1
intracellular anatomical structure	1
RNA cap binding complex	1

Protein interactions and networks

STRING

1986 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF4E2	RBM4	Q9BWF3	993
EIF4E2	GIGYF2	Q6Y7W6	984
EIF4E2	EIF4G3	O43432	950
EIF4E2	EIF4A1	P04765	945
EIF4E2	EPAS1	Q99814	940
EIF4E2	EIF4A2	Q14240	875
EIF4E2	ZNF598	Q86UK7	854
EIF4E2	GIGYF1	O75420	851
EIF4E2	ARIH1	Q9Y4X5	794
EIF4E2	EIF4G1	Q04637	772
EIF4E2	EIF5B	O60841	714
EIF4E2	EIF4ENIF1	Q9NRA8	607
EIF4E2	NGDN	Q8NEJ9	584
EIF4E2	EIF5	P55010	526
EIF4E2	ELAVL1	Q15717	523

IntAct

261 interactions, top by confidence:

A	B	Type	Score
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
EIF4E2	MYOG	psi-mi:“MI:0915”(physical association)	0.670
EIF4E2	ZBTB9	psi-mi:“MI:0915”(physical association)	0.670
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
KRT13	EIF4E2	psi-mi:“MI:0915”(physical association)	0.560
NECAB2	EIF4E2	psi-mi:“MI:0915”(physical association)	0.560
SPRY2	EIF4E2	psi-mi:“MI:0915”(physical association)	0.560
EIF4E2	TADA2A	psi-mi:“MI:0915”(physical association)	0.560
KRT19	EIF4E2	psi-mi:“MI:0915”(physical association)	0.560
EIF4E2	TRIM27	psi-mi:“MI:0915”(physical association)	0.560
EIF4E2	TCF4	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-5	EIF4E2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	EIF4E2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-9	EIF4E2	psi-mi:“MI:0915”(physical association)	0.560
CDR2	EIF4E2	psi-mi:“MI:0915”(physical association)	0.560
REL	EIF4E2	psi-mi:“MI:0915”(physical association)	0.560
EIF4E2	TLE5	psi-mi:“MI:0915”(physical association)	0.560
EIF4E2	KRT31	psi-mi:“MI:0915”(physical association)	0.560
UBXN11	EIF4E2	psi-mi:“MI:0915”(physical association)	0.560
EIF4E2	KRT40	psi-mi:“MI:0915”(physical association)	0.560
EIF4E2	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.560
EIF4E2	USP54	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	EIF4E2	psi-mi:“MI:0915”(physical association)	0.560
TMCC2	EIF4E2	psi-mi:“MI:0915”(physical association)	0.560
HOMEZ	EIF4E2	psi-mi:“MI:0915”(physical association)	0.560
EIF4E2	USHBP1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (332): EIF4E2 (Affinity Capture-MS), EIF4E2 (Two-hybrid), EIF4E2 (Two-hybrid), EIF4E2 (Two-hybrid), EIF4E2 (Two-hybrid), EIF4E2 (Two-hybrid), EIF4E2 (Two-hybrid), EIF4E2 (Two-hybrid), EIF4E2 (Two-hybrid), EIF4E2 (Two-hybrid), EIF4E2 (Two-hybrid), MAGED1 (Two-hybrid), TMCC2 (Two-hybrid), SPRY2 (Two-hybrid), SPAG5 (Two-hybrid)

ESM2 similar proteins: A0A075QQ08, A0A0P0V4R0, A0A1D8EJF9, A0A1U8F5V2, A0A1U8GR65, A0A2J6L8Y7, A0A3Q7FGP1, A0A3Q7I7R4, A0A445AGS0, A2X0Q3, A7KWF8, C6ZJZ3, C7SG33, D3UW26, K0P2S0, M1J8U6, M1JJT8, O23252, O60573, O77210, O81481, O81482, P0DXI0, P0DXI5, P10687, P10894, P29557, P48599, P48600, Q03389, Q0GRC4, Q3UTA9, Q4QXS7, Q4VQY1, Q4VQY3, Q5ZLV4, Q66UV4, Q66WU1, Q6YXZ7, Q8BMB3

Diamond homologs: A0A075QQ08, A0A1D8EJF9, A0A1U8F5V2, A0A1U8GR65, A0A2J6L8Y7, A0A3Q7FGP1, A0A3Q7I7R4, A0A445AGS0, A3RCV9, A6NMX2, A7KWF8, C6ZJZ3, C7SG33, D3UW26, K0P2S0, M1J8U6, M1JJT8, O04663, O23252, O45551, O60573, O61955, O74743, O77210, O81481, O81482, P06730, P07260, P0DXI0, P0DXI5, P29338, P29557, P48597, P48598, P48599, P48600, P56570, P63073, P63074, P78954

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
EIF4E2	“form complex”	“EIF4E2/GIGYF2 complex”	binding
EIF4E2	“form complex”	“EIF4E2/GIGYF1 complex”	binding
ARIH1	“down-regulates quantity by destabilization”	EIF4E2	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 137 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
CDC42 GTPase cycle	8	6.7×	5e-03
RHO GTPase cycle	8	5.5×	6e-03
Keratinization	8	5.1×	9e-03
Signaling by Rho GTPases	11	4.3×	5e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	11	4.2×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

988 predictions. Top by Δscore:

Variant	Effect	Δscore
2:232550740:GACGC:G	donor_gain	1.0000
2:232550743:GC:G	donor_gain	1.0000
2:232550745:G:GG	donor_gain	1.0000
2:232556410:A:AG	acceptor_gain	1.0000
2:232556411:T:G	acceptor_gain	1.0000
2:232556411:TTCA:T	acceptor_loss	1.0000
2:232556412:TCA:T	acceptor_loss	1.0000
2:232556413:CA:C	acceptor_loss	1.0000
2:232556414:A:AG	acceptor_gain	1.0000
2:232556414:AGTTT:A	acceptor_gain	1.0000
2:232556415:G:GG	acceptor_gain	1.0000
2:232556415:GT:G	acceptor_gain	1.0000
2:232556415:GTT:G	acceptor_gain	1.0000
2:232556415:GTTT:G	acceptor_gain	1.0000
2:232556415:GTTTG:G	acceptor_gain	1.0000
2:232556530:GGT:G	donor_loss	1.0000
2:232556531:GT:G	donor_loss	1.0000
2:232557880:CCAG:C	acceptor_loss	1.0000
2:232557881:CAG:C	acceptor_loss	1.0000
2:232557882:A:AT	acceptor_loss	1.0000
2:232557883:GGCT:G	acceptor_gain	1.0000
2:232557979:C:G	donor_gain	1.0000
2:232558019:G:GG	donor_gain	1.0000
2:232564244:CAGG:C	acceptor_loss	1.0000
2:232564245:A:AG	acceptor_gain	1.0000
2:232564245:A:G	acceptor_loss	1.0000
2:232564246:G:GA	acceptor_loss	1.0000
2:232564246:G:GG	acceptor_gain	1.0000
2:232564332:G:GT	donor_gain	1.0000
2:232564347:GGGAG:G	donor_gain	1.0000

AlphaMissense

1648 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:232557915:T:A	L56Q	1.000
2:232557915:T:C	L56P	1.000
2:232557926:T:G	Y60D	1.000
2:232557935:T:A	W63R	1.000
2:232557935:T:C	W63R	1.000
2:232557938:T:G	Y64D	1.000
2:232557941:T:C	S65P	1.000
2:232557980:T:C	Y78H	1.000
2:232557981:A:G	Y78C	1.000
2:232558004:G:C	G86R	1.000
2:232558005:G:A	G86D	1.000
2:232558016:T:C	S90P	1.000
2:232558017:C:T	S90F	1.000
2:232564256:T:C	F94L	1.000
2:232564257:T:C	F94S	1.000
2:232564258:C:A	F94L	1.000
2:232564258:C:G	F94L	1.000
2:232564259:T:A	W95R	1.000
2:232564259:T:C	W95R	1.000
2:232564287:C:A	P104H	1.000
2:232564287:C:G	P104R	1.000
2:232564296:T:C	L107P	1.000
2:232564310:G:C	D112H	1.000
2:232564310:G:T	D112Y	1.000
2:232564311:A:G	D112G	1.000
2:232564311:A:T	D112V	1.000
2:232564316:C:G	H114D	1.000
2:232564320:T:C	L115P	1.000
2:232564322:T:A	F116I	1.000
2:232564322:T:C	F116L	1.000

dbSNP variants (sampled 300 via entrez): RS1000108315 (2:232554484 T>C), RS1000310952 (2:232550728 A>G), RS1000378392 (2:232550562 C>A), RS1000401672 (2:232571854 A>G), RS1000558378 (2:232565126 A>G), RS1000598414 (2:232560425 G>A), RS1000721434 (2:232551660 G>A), RS1000755864 (2:232564958 T>A), RS1000827363 (2:232557829 A>G,T), RS1000863276 (2:232576117 T>A), RS1000935316 (2:232570293 C>T), RS1000985941 (2:232559171 A>G), RS1001072517 (2:232582648 G>A,C,T), RS1001082277 (2:232580735 T>G), RS1001140454 (2:232570472 G>A)

Disease associations

OMIM: gene MIM:605895 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000871_1	Non-small cell lung cancer (survival)	8.000000e-08
GCST002647_9	Height	1.000000e-17
GCST010002_411	Refractive error	1.000000e-123

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1656402	EIF4E2, TIGD1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment, decreases methylation, decreases expression	4
Valproic Acid	affects expression, decreases expression, decreases methylation	3
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	increases expression, affects methylation	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
salinomycin	decreases expression	1
beta-lapachone	decreases expression	1
K 7174	decreases expression	1
abrine	decreases expression	1
bisphenol S	affects cotreatment, decreases methylation, increases methylation	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Leflunomide	decreases expression	1
Acetaminophen	affects response to substance	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	increases expression	1
Chelating Agents	affects binding, decreases expression	1
Cisplatin	affects binding, increases reaction	1
Copper	affects binding, decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Lead	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Ozone	affects expression, increases abundance	1
Piroxicam	decreases expression	1
Quercetin	decreases expression	1
Smoke	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7P9	Ubigene A-549 EIF4E2 KO	Cancer cell line	Male
CVCL_SL76	HAP1 EIF4E2 (-) 1	Cancer cell line	Male
CVCL_SL77	HAP1 EIF4E2 (-) 2	Cancer cell line	Male
CVCL_SL78	HAP1 EIF4E2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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