EIF6

Summary

EIF6 (eukaryotic translation initiation factor 6, HGNC:6159) is a protein-coding gene on chromosome 20q11.22, encoding Eukaryotic translation initiation factor 6 (P56537). Binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit to form the 80S initiation complex in the cytoplasm. It is a common-essential gene (DepMap: required in 98.3% of cancer cell lines).

Hemidesmosomes are structures which link the basal lamina to the intermediate filament cytoskeleton. An important functional component of hemidesmosomes is the integrin beta-4 subunit (ITGB4), a protein containing two fibronectin type III domains. The protein encoded by this gene binds to the fibronectin type III domains of ITGB4 and may help link ITGB4 to the intermediate filament cytoskeleton. The encoded protein, which is insoluble and found both in the nucleus and in the cytoplasm, can function as a translation initiation factor and prevent the association of the 40S and 60S ribosomal subunits. Multiple non-protein coding transcript variants and variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 3692 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Shwachman-Diamond syndrome (Limited, GenCC)
• GWAS associations: 22
• Clinical variants (ClinVar): 270 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 98.3% of screened cell lines (common-essential)
• MANE Select transcript: NM_002212

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6159
Approved symbol	EIF6
Name	eukaryotic translation initiation factor 6
Location	20q11.22
Locus type	gene with protein product
Status	Approved
Aliases	p27BBP, b(2)gcn
Ensembl gene	ENSG00000242372
Ensembl biotype	protein_coding
OMIM	602912
Entrez	3692

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 20 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000374436, ENST00000374443, ENST00000374450, ENST00000415116, ENST00000440766, ENST00000447927, ENST00000456600, ENST00000462894, ENST00000675032, ENST00000866865, ENST00000866866, ENST00000866867, ENST00000866868, ENST00000914125, ENST00000914126, ENST00000914127, ENST00000914128, ENST00000914129, ENST00000914130, ENST00000914131, ENST00000914132, ENST00000914133, ENST00000955583, ENST00000955584

RefSeq mRNA: 4 — MANE Select: NM_002212 NM_001267810, NM_002212, NM_181466, NM_181468

CCDS: CCDS13249, CCDS13250

Canonical transcript exons

ENST00000374450 — 7 exons

Exon	Start	End
ENSE00001463574	35284381	35284492
ENSE00001900601	35284726	35284772
ENSE00003474602	35280654	35280829
ENSE00003490734	35279566	35279747
ENSE00003571846	35284176	35284261
ENSE00003609618	35279942	35280118
ENSE00003847706	35278918	35279206

Expression profiles

Bgee: expression breadth ubiquitous, 151 present calls, max score 98.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 91.8663 / max 411.1196, expressed in 1828 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111669	91.8663	1828
187037	46.6814	1821
187035	7.4981	1644
187036	1.8351	1143

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus mucosa	UBERON:0002469	98.90	gold quality
mucosa of transverse colon	UBERON:0004991	98.89	gold quality
lower esophagus mucosa	UBERON:0035834	98.84	gold quality
skin of leg	UBERON:0001511	98.68	gold quality
zone of skin	UBERON:0000014	98.63	gold quality
skin of abdomen	UBERON:0001416	98.59	gold quality
duodenum	UBERON:0002114	98.33	gold quality
rectum	UBERON:0001052	98.14	gold quality
esophagus	UBERON:0001043	98.00	gold quality
transverse colon	UBERON:0001157	97.95	gold quality
vagina	UBERON:0000996	97.92	gold quality
adult mammalian kidney	UBERON:0000082	97.85	gold quality
smooth muscle tissue	UBERON:0001135	97.80	gold quality
right lobe of liver	UBERON:0001114	97.66	gold quality
right adrenal gland	UBERON:0001233	97.64	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.63	gold quality
metanephros cortex	UBERON:0010533	97.54	gold quality
right adrenal gland cortex	UBERON:0035827	97.52	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.51	gold quality
epithelium of bronchus	UBERON:0002031	97.50	gold quality
small intestine	UBERON:0002108	97.47	gold quality
left adrenal gland	UBERON:0001234	97.44	gold quality
stromal cell of endometrium	CL:0002255	97.43	gold quality
body of stomach	UBERON:0001161	97.39	gold quality
fallopian tube	UBERON:0003889	97.38	gold quality
colon	UBERON:0001155	97.36	gold quality
left adrenal gland cortex	UBERON:0035825	97.32	gold quality
islet of Langerhans	UBERON:0000006	97.26	gold quality
intestine	UBERON:0000160	97.24	gold quality
thoracic aorta	UBERON:0001515	97.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-5	no	2.24
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT3

miRNA regulators (miRDB)

15 targeting EIF6, 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-4516	99.61	67.78	3390
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-12114	98.70	63.45	730
HSA-MIR-6516-5P	98.42	70.19	1551
HSA-MIR-4701-5P	96.45	68.41	1121
HSA-MIR-588	96.45	68.36	1127
HSA-MIR-6858-3P	96.37	64.41	771
HSA-MIR-4793-3P	94.87	65.85	896
HSA-MIR-1228-5P	93.60	63.91	91
HSA-MIR-1538	85.86	60.08	75
HSA-MIR-4745-3P	83.50	60.58	126

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 34)

• eIF6 release regulates ribosome subunit joining and RACK1 provides a physical and functional link between PKC signalling and ribosome activation (PMID:14654845)
• ITGB4BP is overexpressed in head and neck cancers and its metastases. (PMID:15122657)
• Human eIF6 promoter contains consensus sites for the GABP (GA-binding protein) transcription factor complex. (PMID:16530192)
• results uncover an evolutionarily conserved function of the ribosome anti-association factor eIF6 in miRNA-mediated post-transcriptional silencing (PMID:17507929)
• Nuclear matrix proteins such as mutant Pyst1 and nucleophosmin 1 were downregulated, whereas eIF6 and beta-tubulin were upregulated during cell differentiation in hepatocarcinoma cells. (PMID:17569113)
• definitive evidence that eIF6 and dicer are both upregulated in a significant proportion of ovarian serous carcinomas (PMID:18327211)
• P311 and ITGB4BP expression was elevated in non-small cell lung cancer, possibly indicative of a new signaling pathway. (PMID:21029697)
• Ca(2+)-activated calcineurin phosphatase binds to and promotes nuclear localization of eIF6.Nuclear export of eIF6 is regulated by phosphorylation at Ser-174 and Ser-175 by the nuclear isoform of CK1. (PMID:21084295)
• a direct role for SBDS and EFL1 in catalyzing the translational activation of ribosomes in all eukaryotes, and define SDS as a ribosomopathy caused by uncoupling GTP hydrolysis from eIF6 release (PMID:21536732)
• The benign prognosis of the Shwachman-Diamond syndrome patients with the int del (20)(q11.21q13.32) may be due to a gene/dosage effect for the EIF6 protein. (PMID:22295858)
• eIF6 is one of the downstream effectors of Notch-1 in the pathway that controls cell motility and invasiveness in tumor cell lines (PMID:22348144)
• The interactions between P311 and ITGB4BP may be very important in the process of tumor cell differentiation and metastasis. (PMID:22365962)
• Inhibiting the induction of two proteins involved in two of the most significantly upregulated cellular processes, ribosome biogenesis (eIF6) and hnRNA splicing (SF3B2/SF3B4), showed that human T cells can enter the cell cycle without growing in size. (PMID:22415777)
• SBDS protein facilitates the release of eIF6, a factor that prevents ribosome joining. (PMID:23115272)
• eIF6 is a node regulator of ribosomal function and predict that prioritizing its pharmacological targeting will be of benefit in cancer and Shwachman-Bodian-Diamond syndrome (PMID:25252159)
• EIF6 plays an important role in controlling cell motility and tumor metastasis. (PMID:25886394)
• Propose that eIF6 is necessary for malignant pleural mesothelioma growth. (PMID:26462016)
• Studies indicate that eukaryotic translation initiation factor 6 (eIF6) is a central regulator of metabolism independent from mTOR protein and myc proto-oncogene protein (Myc). (PMID:27913676)
• in human CD4(+) T cells, eIF6 levels rapidly increase upon T-cell receptor activation and drive the glycolytic switch and the acquisition of effector functions (PMID:28743432)
• Data suggest an important contribution of eukaryotic translation initiation factor 6 (eIF6) to the development and progression of non-small cell lung cancer (NSCLC) and a potential for new treatment strategies against NSCLC. (PMID:30077122)
• High Eukaryotic translation initiation factor 6 expression is associated with gastric cancer. (PMID:31586263)
• Discovery and Preliminary Characterization of Translational Modulators that Impair the Binding of eIF6 to 60S Ribosomal Subunits. (PMID:31936702)
• Heterozygous missense variant in EIF6 gene: A novel form of Shwachman-Diamond syndrome? (PMID:32657013)
• Regulation of eukaryotic translation initiation factor 6 dynamics through multisite phosphorylation by GSK3. (PMID:32703900)
• eIF6 promotes the malignant progression of human hepatocellular carcinoma via the mTOR signaling pathway. (PMID:34016142)
• Targeting of eIF6-driven translation induces a metabolic rewiring that reduces NAFLD and the consequent evolution to hepatocellular carcinoma. (PMID:34385447)
• Roles of HDAC2, eIF5, and eIF6 in Lung Cancer Tumorigenesis. (PMID:34403101)
• Somatic genetic rescue of a germline ribosome assembly defect. (PMID:34413298)
• Cytoplasmic eIF6 promotes OSCC malignant behavior through AKT pathway. (PMID:34922580)
• Eukaryotic initiation factor 6 regulates mechanical responses in endothelial cells. (PMID:35024764)
• Inhibition of eIF6 Activity Reduces Hepatocellular Carcinoma Growth: An In Vivo and In Vitro Study. (PMID:35887068)
• Dynamic states of eIF6 and SDS variants modulate interactions with uL14 of the 60S ribosomal subunit. (PMID:36651285)
• Circular RNA eukaryotic translation initiation factor 6 facilitates TPC-1 cell proliferation and invasion through the microRNA-138-5p/lipase H axis. (PMID:37776372)
• eIF6 Promotes Gastric Cancer Proliferation and Invasion by Regulating Cell Cycle. (PMID:38987443)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif6	ENSDARG00000020232
mus_musculus	Eif6	ENSMUSG00000027613
rattus_norvegicus	Eif6-ps1	ENSRNOG00000058513
drosophila_melanogaster	eIF6	FBGN0034915
caenorhabditis_elegans	eif-6	WBGENE00001234

Protein

Protein identifiers

Eukaryotic translation initiation factor 6 — P56537 (reviewed: P56537)

Alternative names: B(2)GCN homolog, B4 integrin interactor, CAB, p27(BBP)

All UniProt accessions (5): A0A0B4J1Y7, B7ZBH1, P56537, F8WD20, F8WDS6

UniProt curated annotations — full annotation on UniProt →

Function. Binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit to form the 80S initiation complex in the cytoplasm. Behaves as a stimulatory translation initiation factor downstream insulin/growth factors. Is also involved in ribosome biogenesis. Associates with pre-60S subunits in the nucleus and is involved in its nuclear export. Cytoplasmic release of TIF6 from 60S subunits and nuclear relocalization is promoted by a RACK1 (RACK1)-dependent protein kinase C activity. In tissues responsive to insulin, controls fatty acid synthesis and glycolysis by exerting translational control of adipogenic transcription factors such as CEBPB, CEBPD and ATF4 that have G/C rich or uORF in their 5’UTR. Required for ROS-dependent megakaryocyte maturation and platelets formation, controls the expression of mitochondrial respiratory chain genes involved in reactive oxygen species (ROS) synthesis. Involved in miRNA-mediated gene silencing by the RNA-induced silencing complex (RISC). Required for both miRNA-mediated translational repression and miRNA-mediated cleavage of complementary mRNAs by RISC. Modulates cell cycle progression and global translation of pre-B cells, its activation seems to be rate-limiting in tumorigenesis and tumor growth.

Subunit / interactions. Monomer. Associates with the 60S ribosomal subunit. Interacts with RACK1. Interacts with DICER1, AGO2, TARBP2, MOV10 and RPL7A; they form a large RNA-induced silencing complex (RISC).

Subcellular location. Cytoplasm. Nucleus. Nucleolus.

Tissue specificity. Expressed at very high levels in colon carcinoma with lower levels in normal colon and ileum and lowest levels in kidney and muscle (at protein level).

Post-translational modifications. Phosphorylation at Ser-174 and Ser-175 by CSNK1D/CK1 promotes nuclear export. Ufmylated by UFL1.

Similarity. Belongs to the eIF-6 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P56537-1	1	yes
P56537-2	2

RefSeq proteins (4): NP_001254739, NP_002203, NP_852131, NP_852133 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002769	eIF6	Family

Pfam: PF01912

UniProt features (11 total): modified residue 8, chain 1, sequence conflict 1, splice variant 1

Structure

Experimental structures (PDB)

49 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8A3D	ELECTRON MICROSCOPY	1.67
7OW7	ELECTRON MICROSCOPY	2.4
8FKV	ELECTRON MICROSCOPY	2.47
8FLE	ELECTRON MICROSCOPY	2.48
8FKW	ELECTRON MICROSCOPY	2.5
8FL3	ELECTRON MICROSCOPY	2.53
8FL7	ELECTRON MICROSCOPY	2.55
8FLB	ELECTRON MICROSCOPY	2.55
8FLD	ELECTRON MICROSCOPY	2.58
8FKX	ELECTRON MICROSCOPY	2.59
9GMO	ELECTRON MICROSCOPY	2.59
8FL6	ELECTRON MICROSCOPY	2.62
8FLA	ELECTRON MICROSCOPY	2.63
8FLF	ELECTRON MICROSCOPY	2.65
8FKY	ELECTRON MICROSCOPY	2.67
8FL2	ELECTRON MICROSCOPY	2.67
8FL9	ELECTRON MICROSCOPY	2.75
8FKQ	ELECTRON MICROSCOPY	2.76
8FLC	ELECTRON MICROSCOPY	2.76
8IDT	ELECTRON MICROSCOPY	2.8
8FKT	ELECTRON MICROSCOPY	2.81
8FKU	ELECTRON MICROSCOPY	2.82
8RL2	ELECTRON MICROSCOPY	2.84
8FKP	ELECTRON MICROSCOPY	2.85
8FKS	ELECTRON MICROSCOPY	2.88
8FKR	ELECTRON MICROSCOPY	2.89
8FL4	ELECTRON MICROSCOPY	2.89
8FL0	ELECTRON MICROSCOPY	2.91
9P9K	ELECTRON MICROSCOPY	2.96
8IDY	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56537-F1	91.12	0.85

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 (8): 113, 165, 166, 174, 175, 235, 239, 243

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 518 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CYTOPLASMIC_TRANSLATION, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_RIBOSOME_BIOGENESIS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GRUETZMANN_PANCREATIC_CANCER_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, ENK_UV_RESPONSE_KERATINOCYTE_UP, TTTGTAG_MIR520D, SHEPARD_CRASH_AND_BURN_MUTANT_UP, NIKOLSKY_BREAST_CANCER_20Q11_AMPLICON, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_UBE2I

GO Biological Process (17): ribosomal subunit export from nucleus (GO:0000054), maturation of 5.8S rRNA (GO:0000460), maturation of LSU-rRNA (GO:0000470), regulation of glycolytic process (GO:0006110), response to insulin (GO:0032868), miRNA-mediated post-transcriptional gene silencing (GO:0035195), miRNA-mediated gene silencing by inhibition of translation (GO:0035278), cytosolic ribosome assembly (GO:0042256), regulation of fatty acid biosynthetic process (GO:0042304), regulation of megakaryocyte differentiation (GO:0045652), positive regulation of translation (GO:0045727), assembly of large subunit precursor of preribosome (GO:1902626), regulation of reactive oxygen species metabolic process (GO:2000377), translation (GO:0006412), translational initiation (GO:0006413), ribosome biogenesis (GO:0042254), ribosomal large subunit biogenesis (GO:0042273)

GO Molecular Function (4): translation initiation factor activity (GO:0003743), ribosome binding (GO:0043022), ribosomal large subunit binding (GO:0043023), protein binding (GO:0005515)

GO Cellular Component (9): nucleus (GO:0005634), lamin filament (GO:0005638), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), synapse (GO:0045202), extracellular exosome (GO:0070062), intermediate filament (GO:0005882)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
ribosome biogenesis	2
rRNA processing	2
translation	2
translational initiation	2
ribonucleoprotein complex biogenesis	2
nuclear lumen	2
ribosome localization	1
nuclear export	1
establishment of organelle localization	1
ribosomal large subunit biogenesis	1
glycolytic process	1
regulation of purine nucleotide catabolic process	1
regulation of generation of precursor metabolites and energy	1
regulation of carbohydrate catabolic process	1
regulation of ATP metabolic process	1
response to peptide hormone	1
regulatory ncRNA-mediated post-transcriptional gene silencing	1
negative regulation of translation	1
miRNA-mediated post-transcriptional gene silencing	1
ribosome assembly	1
fatty acid biosynthetic process	1
regulation of fatty acid metabolic process	1
regulation of lipid biosynthetic process	1
megakaryocyte differentiation	1
regulation of myeloid cell differentiation	1
regulation of translation	1
positive regulation of gene expression	1
positive regulation of protein metabolic process	1
ribosomal large subunit assembly	1
protein-RNA complex assembly	1
regulation of metabolic process	1
reactive oxygen species metabolic process	1
peptidyltransferase activity	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
formation of translation initiation ternary complex	1

Protein interactions and networks

STRING

3326 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF6	RACK1	P25388	929
EIF6	EIF5	P55010	814
EIF6	EFL1	Q7Z2Z2	811
EIF6	AGO2	Q9UKV8	808
EIF6	EIF1	P41567	808
EIF6	SBDS	Q9Y3A5	793
EIF6	EIF3H	O15372	782
EIF6	MOV10	Q9HCE1	777
EIF6	ITGB4	P16144	753
EIF6	EIF5B	O60841	746
EIF6	EIF4G1	Q04637	735
EIF6	MRTO4	Q9UKD2	698
EIF6	EIF4H	Q15056	697
EIF6	EIF3B	P55884	694
EIF6	EIF4E	P06730	685

IntAct

191 interactions, top by confidence:

A	B	Type	Score
CNOT2	CNOT1	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
EIF6	NREP	psi-mi:“MI:0915”(physical association)	0.630
NREP	EIF6	psi-mi:“MI:0915”(physical association)	0.630
NREP	EIF6	psi-mi:“MI:0403”(colocalization)	0.630
EIF6	VAC14	psi-mi:“MI:0915”(physical association)	0.560
EIF6	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
EIF6	MSRB3	psi-mi:“MI:0915”(physical association)	0.560
BCCIP	EIF6	psi-mi:“MI:0914”(association)	0.560
VCAM1	PSMD11	psi-mi:“MI:0914”(association)	0.530
DHX58	NKRF	psi-mi:“MI:0914”(association)	0.500
EIF6	EIF2AK2	psi-mi:“MI:0915”(physical association)	0.500
OAS3	EIF6	psi-mi:“MI:0915”(physical association)	0.500
DHX58	EIF6	psi-mi:“MI:0915”(physical association)	0.500
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
EIF6	Prkcb	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
Prkcb	EIF6	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
EIF6	ZBTB26	psi-mi:“MI:0915”(physical association)	0.370
EIF6	CSNK2B	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (448): EIF6 (Affinity Capture-MS), EIF6 (Affinity Capture-MS), EIF6 (Affinity Capture-MS), EIF6 (Affinity Capture-MS), CHMP4A (Co-fractionation), CHMP4B (Co-fractionation), DDX27 (Co-fractionation), EIF6 (Co-fractionation), EIF6 (Co-fractionation), EIF6 (Co-fractionation), EIF6 (Co-fractionation), EIF6 (Co-fractionation), EIF6 (Co-fractionation), EIF6 (Co-fractionation), EIF6 (Co-fractionation)

ESM2 similar proteins: A2STI7, A3CWZ4, A4RSQ6, A4XRA9, A7ANL7, A7I9I6, B0EMY3, B8GEU6, B8MDN4, B9PVB9, C9SV08, D1ZG64, G7JT50, O22290, O27648, O28214, O55135, O62106, O81920, O94476, P13981, P56537, P56538, Q0W5H2, Q11G43, Q12522, Q12ZJ5, Q245F2, Q2FS97, Q2NGQ7, Q2SB21, Q2UTN7, Q3KRD8, Q46FA1, Q4E097, Q551M2, Q59L13, Q5ASA6, Q6GR45, Q6ZM19

Diamond homologs: A0RYC3, A1RXF3, A2BN57, A2STI7, A3CWZ4, A3DNH5, A4RSQ6, A5UL31, A7I9I6, A9A305, B0EMY3, B8MDN4, B9LUU8, C3MR78, C3MXG7, C3MZB3, C3N7D3, C3NGA1, C4KIJ1, C5A7H2, C9SV08, D1ZG64, O27648, O28214, O55135, O62106, O81920, O94476, P56537, P56538, Q0W5H2, Q12ZJ5, Q18EU8, Q245F2, Q2FS97, Q2NGQ7, Q2UTN7, Q3ITD5, Q3KRD8, Q4E097

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
PRKCA	unknown	EIF6	phosphorylation
EFL1	up-regulates	EIF6
SBDS	up-regulates	EIF6
PRKCB	“down-regulates activity”	EIF6	phosphorylation
EIF6	“down-regulates activity”	“60S cytosolic large ribosomal subunit”	binding
EIF6	“up-regulates quantity”	“60S cytosolic large ribosomal subunit”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 192 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
Formation of the ternary complex, and subsequently, the 43S complex	10	15.7×	2e-07
Translation initiation complex formation	10	13.9×	3e-07
Ribosomal scanning and start codon recognition	10	13.9×	3e-07
Eukaryotic Translation Elongation	6	12.2×	4e-04
Nonsense-Mediated Decay (NMD)	7	11.9×	1e-04
SPOP-mediated proteasomal degradation of PD-L1(CD274)	7	11.7×	1e-04
Eukaryotic Translation Initiation	5	11.3×	2e-03
Cap-dependent Translation Initiation	5	11.3×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
formation of cytoplasmic translation initiation complex	5	32.3×	2e-04
positive regulation of transcription by RNA polymerase I	5	18.6×	1e-03
translational initiation	8	16.5×	3e-05
cytoplasmic translation	9	9.6×	2e-04
negative regulation of translation	8	9.0×	9e-04
rRNA processing	9	7.3×	1e-03
translation	9	5.3×	6e-03
chromatin remodeling	11	4.6×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	189
Likely benign	13
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

804 predictions. Top by Δscore:

Variant	Effect	Δscore
20:35279105:C:A	donor_gain	1.0000
20:35279561:GGTAC:G	donor_loss	1.0000
20:35279562:GTACC:G	donor_loss	1.0000
20:35279563:TACCT:T	donor_loss	1.0000
20:35279564:A:T	donor_loss	1.0000
20:35279565:C:CG	donor_loss	1.0000
20:35279565:C:CT	donor_loss	1.0000
20:35279743:CCCGC:C	acceptor_gain	1.0000
20:35279744:CCGC:C	acceptor_gain	1.0000
20:35279744:CCGCC:C	acceptor_gain	1.0000
20:35279745:CGC:C	acceptor_gain	1.0000
20:35279745:CGCC:C	acceptor_gain	1.0000
20:35279746:GC:G	acceptor_gain	1.0000
20:35279746:GCCT:G	acceptor_loss	1.0000
20:35279747:CC:C	acceptor_gain	1.0000
20:35279748:C:CC	acceptor_gain	1.0000
20:35279748:CT:C	acceptor_loss	1.0000
20:35279752:C:CT	acceptor_gain	1.0000
20:35279752:C:T	acceptor_gain	1.0000
20:35279936:GCTTA:G	donor_loss	1.0000
20:35279937:CTTA:C	donor_loss	1.0000
20:35279938:TTA:T	donor_loss	1.0000
20:35279939:TA:T	donor_loss	1.0000
20:35279940:A:AC	donor_gain	1.0000
20:35279940:AC:A	donor_gain	1.0000
20:35279941:C:CC	donor_gain	1.0000
20:35279941:CC:C	donor_gain	1.0000
20:35279941:CCA:C	donor_gain	1.0000
20:35279941:CCACA:C	donor_gain	1.0000
20:35279975:AT:A	donor_gain	1.0000

AlphaMissense

1603 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:35279694:A:C	N200K	1.000
20:35279694:A:T	N200K	1.000
20:35279743:C:T	G184E	1.000
20:35279744:C:A	G184W	1.000
20:35280042:C:T	G149E	1.000
20:35280705:A:C	N106K	1.000
20:35280705:A:T	N106K	1.000
20:35284416:A:C	C24W	1.000
20:35279650:A:G	L215P	0.999
20:35279654:C:T	E214K	0.999
20:35279674:C:A	G207V	0.999
20:35279674:C:T	G207D	0.999
20:35279675:C:G	G207R	0.999
20:35279683:G:T	A204D	0.999
20:35279708:C:A	G196W	0.999
20:35279731:C:G	R188P	0.999
20:35279733:G:C	N187K	0.999
20:35279733:G:T	N187K	0.999
20:35279744:C:G	G184R	0.999
20:35279744:C:T	G184R	0.999
20:35279961:A:G	L176P	0.999
20:35279970:A:G	L173P	0.999
20:35280009:A:G	L160P	0.999
20:35280012:C:T	G159E	0.999
20:35280023:G:C	S155R	0.999
20:35280023:G:T	S155R	0.999
20:35280025:T:G	S155R	0.999
20:35280038:G:C	S150R	0.999
20:35280038:G:T	S150R	0.999
20:35280040:T:G	S150R	0.999

dbSNP variants (sampled 300 via entrez): RS1000150706 (20:35286300 C>T), RS1000306727 (20:35280587 A>G), RS1000739399 (20:35283328 G>A), RS1001906807 (20:35283032 C>T), RS1001977192 (20:35282039 AG>A), RS1002546688 (20:35280446 A>C), RS1002749965 (20:35285889 C>G,T), RS1003089548 (20:35278409 C>A), RS1003107334 (20:35286267 C>T), RS1003549902 (20:35278645 C>G), RS1003579678 (20:35281776 T>G), RS1003599476 (20:35283009 C>G,T), RS1003651683 (20:35283257 G>T), RS1003920525 (20:35285498 G>T), RS1004327689 (20:35282710 A>G)

Disease associations

OMIM: gene MIM:602912 | disease phenotypes: MIM:258040

GenCC curated gene-disease

Disease	Classification	Inheritance
Shwachman-Diamond syndrome	Limited	Autosomal dominant

Mondo (2): exstrophy-epispadias complex (MONDO:0017919), Shwachman-Diamond syndrome (MONDO:0009833)

Orphanet (2): Exstrophy-epispadias complex (Orphanet:322), Cloacal exstrophy (Orphanet:93929)

HPO phenotypes

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

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000175_30	Height	8.000000e-07
GCST004860_11	Alcoholic chronic pancreatitis	6.000000e-06
GCST004860_130	Alcoholic chronic pancreatitis	7.000000e-06
GCST004860_135	Alcoholic chronic pancreatitis	5.000000e-06
GCST004860_156	Alcoholic chronic pancreatitis	2.000000e-07
GCST004860_17	Alcoholic chronic pancreatitis	6.000000e-06
GCST004860_41	Alcoholic chronic pancreatitis	7.000000e-06
GCST005956_31	Waist-to-hip ratio adjusted for BMI	8.000000e-08
GCST005958_16	Waist-to-hip ratio adjusted for BMI (age >50)	6.000000e-06
GCST005962_40	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	3.000000e-08
GCST007294_22	Body fat distribution (trunk fat ratio)	4.000000e-48
GCST007294_41	Body fat distribution (trunk fat ratio)	6.000000e-38
GCST007295_10	Body fat distribution (leg fat ratio)	3.000000e-09
GCST007295_170	Body fat distribution (leg fat ratio)	3.000000e-43
GCST007295_4	Body fat distribution (leg fat ratio)	1.000000e-40
GCST009144_14	Disease progression in age-related macular degeneration (adjusted for baseline)	6.000000e-06
GCST010142_10	Fish- and plant-related diet	8.000000e-12
GCST90002385_534	High light scatter reticulocyte count	2.000000e-13
GCST90002386_514	High light scatter reticulocyte percentage of red cells	2.000000e-21
GCST90002387_164	Immature fraction of reticulocytes	3.000000e-15
GCST90002400_624	Plateletcrit	8.000000e-11
GCST90013442_16	Keratoconus	4.000000e-12

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004341	body fat distribution
EFO:0008336	disease progression measurement
EFO:0008111	diet measurement
EFO:0007986	reticulocyte count
EFO:0007985	platelet crit

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296020 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

6 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10510050	Toxicity	3	Platinum compounds	Non-Small Cell Lung Carcinoma
rs1409314	Toxicity	3	Platinum compounds	Non-Small Cell Lung Carcinoma
rs3740556	Efficacy	3	carboplatin;cisplatin	Lung Neoplasms
rs4752219	Toxicity	3	Platinum compounds	Non-Small Cell Lung Carcinoma
rs4752220	Toxicity	3	Platinum compounds	Non-Small Cell Lung Carcinoma
rs7091672	Toxicity	3	Platinum compounds	Non-Small Cell Lung Carcinoma

PharmGKB variants

11 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1409314	EIF3A	3	2.75	1	Platinum compounds
rs2275112	EIF3A, SFXN4		0.00	0
rs3740556	EIF3A	3	3.75	1	carboplatin;cisplatin
rs4752219	EIF3A	3	2.25	1	Platinum compounds
rs4752220	EIF3A	3	2.25	1	Platinum compounds
rs4752269	EIF3A, GRK5		0.00	0
rs7091672	EIF3A	3	2.75	1	Platinum compounds
rs10510050	EIF3A	3	3.25	1	Platinum compounds
rs10787899	EIF3A		0.00	0
rs10886342	EIF3A		0.00	0
rs11198804	EIF3A, SFXN4		0.00	0

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.65	Kd	222.9	nM	CHEMBL5653589
6.65	ED50	222.9	nM	CHEMBL5653589
5.52	Kd	2999	nM	CHEMBL3752910
5.52	ED50	2999	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 6 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148313: Binding affinity to human EIF6 incubated for 45 mins by Kinobead based pull down assay	kd	0.2229	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148313: Binding affinity to human EIF6 incubated for 45 mins by Kinobead based pull down assay	kd	2.9994	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, affects cotreatment	3
Valproic Acid	increases expression, increases methylation, decreases expression	3
Particulate Matter	decreases reaction, increases expression, affects cotreatment, increases abundance	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
deoxynivalenol	increases expression	2
nivalenol	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
hexamethylene bisacetamide	increases expression	1
arsenite	affects binding, increases reaction	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
15-acetyldeoxynivalenol	increases expression	1
di-n-butylphosphoric acid	affects expression	1
chloropicrin	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	1
bisphenol S	increases expression	1
MT19c compound	decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	affects expression	1
Air Pollutants	increases abundance, affects expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118588	Binding	Binding affinity to EIF6 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04760028	PHASE4	COMPLETED	Study on the Influencing Factors of Electroencephalogram Parameters Under Anesthesia
NCT00004787	PHASE2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT03333486	PHASE2	TERMINATED	Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer
NCT04965597	PHASE2	COMPLETED	Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT00176852	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Hemoglobinopathy
NCT00176878	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Bone Marrow Failure Syndromes
NCT01966367	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	CD34+ (Non-Malignant) Stem Cell Selection for Patients Receiving Allogeneic Stem Cell Transplantation
NCT00027274	Not specified	RECRUITING	Cancer in Inherited Bone Marrow Failure Syndromes
NCT00499070	Not specified	COMPLETED	Assessing Immune Function in Young Patients With Cytopenia That Did Not Respond to Treatment
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT02011074	Not specified	COMPLETED	Perioperative Changes of Heart Rate Variability Related to Anxiety and Depressiveness in Patients Undergoing General Anesthesia
NCT02179359	Not specified	TERMINATED	Hematopoietic Stem Cell Transplant for High Risk Hemoglobinopathies
NCT04275479	Not specified	TERMINATED	Diabetes/ Endocrine Surveillance in SDS
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06056908	Not specified	RECRUITING	Shwachman Diamond Syndrome Registry and Study
NCT06999954	Not specified	RECRUITING	Shwachman-Diamond Syndrome Global Patient Survey and Partnering Platform
NCT06106425	Not specified	UNKNOWN	Diagnostic and Prognostic Criteria of EEG in Neonatal Convulsions at Assiut University Children Hospital