ENTREP3

Summary

ENTREP3 (endosomal transmembrane epsin interactor 3, HGNC:1233) is a protein-coding gene on chromosome 1q22, encoding Protein ENTREP3 (P81408).

This gene is located near the gene for the lysosomal enzyme glucosylceramidase; a deficiency in this enzyme is associated with Gaucher disease. The encoded protein has been identified as a potential binding partner of a WW domain-containing protein which is involved in apoptosis and tumor suppression. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10712 — RefSeq curated summary.

At a glance

• GWAS associations: 17
• Clinical variants (ClinVar): 123 total
• MANE Select transcript: NM_006589

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1233
Approved symbol	ENTREP3
Name	endosomal transmembrane epsin interactor 3
Location	1q22
Locus type	gene with protein product
Status	Approved
Aliases	cote1
Ensembl gene	ENSG00000160767
Ensembl biotype	protein_coding
OMIM	619447
Entrez	10712

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 24 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000350210, ENST00000361361, ENST00000368366, ENST00000368368, ENST00000472550, ENST00000481822, ENST00000487649, ENST00000491082, ENST00000497941, ENST00000706772, ENST00000706773, ENST00000706774, ENST00000851432, ENST00000851433, ENST00000851434, ENST00000851435, ENST00000851436, ENST00000851437, ENST00000851438, ENST00000851439, ENST00000851440, ENST00000851441, ENST00000927590, ENST00000927591, ENST00000927592, ENST00000927593, ENST00000927594, ENST00000927595, ENST00000927596, ENST00000927597, ENST00000927598, ENST00000965815

RefSeq mRNA: 3 — MANE Select: NM_006589 NM_001267608, NM_006589, NM_198264

CCDS: CCDS1103, CCDS1104, CCDS58035

Canonical transcript exons

ENST00000361361 — 12 exons

Exon	Start	End
ENSE00001225815	155250276	155250821
ENSE00001841249	155247205	155247955
ENSE00003462917	155251095	155251164
ENSE00003532182	155248050	155248303
ENSE00003538787	155251502	155251601
ENSE00003555746	155251733	155251905
ENSE00003598379	155253625	155253732
ENSE00003614003	155248405	155248473
ENSE00003643914	155254400	155254456
ENSE00003680590	155253859	155253978
ENSE00003684016	155254084	155254194
ENSE00003751957	155254653	155255483

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 91.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.6119 / max 189.9289, expressed in 1810 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14942	33.4917	1810
14941	0.2831	121
14937	0.2553	122
14940	0.2060	71
14939	0.1598	61
201749	0.1271	35
14938	0.0568	11
14943	0.0322	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	91.38	gold quality
cerebellar hemisphere	UBERON:0002245	90.99	gold quality
cerebellar cortex	UBERON:0002129	90.94	gold quality
cerebellum	UBERON:0002037	90.93	gold quality
lower esophagus mucosa	UBERON:0035834	90.58	gold quality
right frontal lobe	UBERON:0002810	89.60	gold quality
apex of heart	UBERON:0002098	89.07	gold quality
gastrocnemius	UBERON:0001388	89.02	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.82	gold quality
lower esophagus	UBERON:0013473	88.80	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.79	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.70	gold quality
stromal cell of endometrium	CL:0002255	88.43	gold quality
frontal cortex	UBERON:0001870	88.34	gold quality
anterior cingulate cortex	UBERON:0009835	88.11	gold quality
right adrenal gland cortex	UBERON:0035827	88.09	gold quality
primary visual cortex	UBERON:0002436	88.06	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.92	gold quality
right adrenal gland	UBERON:0001233	87.86	gold quality
prefrontal cortex	UBERON:0000451	87.76	gold quality
cerebral cortex	UBERON:0000956	87.75	gold quality
right coronary artery	UBERON:0001625	87.74	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.62	gold quality
muscle of leg	UBERON:0001383	87.59	gold quality
superior frontal gyrus	UBERON:0002661	87.54	gold quality
mucosa of stomach	UBERON:0001199	87.42	gold quality
fundus of stomach	UBERON:0001160	87.36	gold quality
brain	UBERON:0000955	87.15	gold quality
popliteal artery	UBERON:0002250	87.13	gold quality
tibial artery	UBERON:0007610	87.12	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

54 targeting ENTREP3, 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-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-543	99.52	69.03	2595

Literature-anchored findings (GeneRIF, showing 5)

• Overexpression of COTE1 promotes cellular invasion of hepatocellular carcinoma. (PMID:23317259)
• our findings suggest that the cytoplasmic protein COTE1 contributes to hepatocellular carcinoma tumorigenesis by regulating cell proliferation through the modulation of WWOX signaling (PMID:24899407)
• High FAM189B Expression and Its Prognostic Value in Patients with Gastric Cancer. (PMID:34124264)
• COTE-1 promotes the proliferation and invasion of small cell lung cancer by regulating autophagy activity via the AMPK/mTOR signaling pathway. (PMID:37454876)
• COTE1 Facilitates Intrahepatic Cholangiocarcinoma Progression via Beclin1-Dependent Autophagy Inhibition. (PMID:37780485)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fam189b	ENSDARG00000079008
mus_musculus	Entrep3	ENSMUSG00000032657
rattus_norvegicus	Entrep3	ENSRNOG00000020518

Paralogs (2): ENTREP2 (ENSG00000104059), ENTREP1 (ENSG00000135063)

Protein

Protein identifiers

Protein ENTREP3 — P81408 (reviewed: P81408)

Alternative names: Endosomal transmembrane epsin interactor 3, Protein COTE1

All UniProt accessions (3): P81408, D6RD59, Q96AD8

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. May interact with WWOX.

Subcellular location. Membrane.

Tissue specificity. Widely expressed.

Similarity. Belongs to the ENTREP family.

Isoforms (4)

UniProt ID	Names	Canonical?
P81408-1	A	yes
P81408-2	B
P81408-3	2
P81408-4	3

RefSeq proteins (3): NP_001254537, NP_006580, NP_937995 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007237	CD20-like_TM	Domain
IPR030431	ENTREP1-3	Family

Pfam: PF04103

UniProt features (23 total): region of interest 5, transmembrane region 4, modified residue 4, splice variant 3, sequence variant 3, compositionally biased region 2, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P81408-F1	53.93	0.10

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 (4): 358, 389, 493, 574

Glycosylation sites (1): 160

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 162 (showing top): MORF_RAGE, GCANCTGNY_MYOD_Q6, MAZ_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, PATIL_LIVER_CANCER, MORF_FANCG, chr1q22, DASU_IL6_SIGNALING_UP, DODD_NASOPHARYNGEAL_CARCINOMA_UP, MORF_PML, MORF_IKBKG, MORF_MT4, MORF_ORC1L, TCCCRNNRTGC_UNKNOWN, MARSON_BOUND_BY_E2F4_UNSTIMULATED

GO Biological Process (0):

GO Molecular Function (2): WW domain binding (GO:0050699), protein binding (GO:0005515)

GO Cellular Component (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein domain specific binding	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

634 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ENTREP3	MTX1	Q13505	505
ENTREP3	SCAMP3	O14828	489
ENTREP3	THBS3	P49746	478
ENTREP3	N4BP1	O75113	426
ENTREP3	SYNRG	Q9UMZ2	412
ENTREP3	SLC50A1	Q9BRV3	410
ENTREP3	JAGN1	Q8N5M9	409
ENTREP3	HCN3	Q9P1Z3	408
ENTREP3	KRTCAP2	Q8N6L1	402
ENTREP3	NDFIP2	Q9NV92	389
ENTREP3	DCST2	Q5T1A1	370
ENTREP3	GBA1	P04062	359
ENTREP3	SCAMP1	O15126	359
ENTREP3	LENEP	Q9Y5L5	357
ENTREP3	NDFIP1	Q9BT67	350

IntAct

63 interactions, top by confidence:

A	B	Type	Score
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
WWOX	ENTREP3	psi-mi:“MI:0914”(association)	0.720
ENTREP3	WWOX	psi-mi:“MI:0915”(physical association)	0.720
WWOX	ENTREP3	psi-mi:“MI:0915”(physical association)	0.720
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
FSHR	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
SPINT2	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
TSPAN17	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
KCNS3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
CHRND	TPST2	psi-mi:“MI:0914”(association)	0.530
ENTREP3	NEDD4	psi-mi:“MI:0914”(association)	0.530
CHRNA4	FZD6	psi-mi:“MI:0914”(association)	0.530
HFE	ADAM10	psi-mi:“MI:0914”(association)	0.530
YAP1	ENTREP3	psi-mi:“MI:0407”(direct interaction)	0.440
SCRIB	ENTREP3	psi-mi:“MI:0915”(physical association)	0.400
ORF5	TFRC	psi-mi:“MI:0914”(association)	0.350
TTMP	TMEM223	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
CHRNA4	TMEM223	psi-mi:“MI:0914”(association)	0.350
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CLEC2D	TMEM120B	psi-mi:“MI:0914”(association)	0.350
TEX28	NBAS	psi-mi:“MI:0914”(association)	0.350
ZDHHC12	NBAS	psi-mi:“MI:0914”(association)	0.350
MPPE1	FAM234B	psi-mi:“MI:0914”(association)	0.350
CLRN2	FAM234B	psi-mi:“MI:0914”(association)	0.350
LRP3	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (179): FAM189B (Two-hybrid), HSPA8 (Affinity Capture-MS), WWOX (Affinity Capture-MS), NEDD4 (Affinity Capture-MS), ITCH (Affinity Capture-MS), NEDD4L (Affinity Capture-MS), WWP1 (Affinity Capture-MS), ACP2 (Affinity Capture-MS), ANKRD13A (Affinity Capture-MS), ANKRD13D (Affinity Capture-MS), HERC3 (Affinity Capture-MS), HECW2 (Affinity Capture-MS), TPM2 (Affinity Capture-MS), CFAP74 (Affinity Capture-MS), CYHR1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RQ45, A0A1B0GWB2, A2A9T0, A6QPA0, A7MCY6, D3ZFB6, E9PUL5, E9Q0B3, F5GYI3, F5H4A9, J3QNX5, O70142, P0C1G7, P81408, P97764, P98077, Q148V8, Q15654, Q2KI80, Q3SX26, Q3SZL6, Q4V9L6, Q5FVJ4, Q5FW56, Q5RAC1, Q5T7N3, Q6DG50, Q6PAJ3, Q6PJ61, Q6ZMQ8, Q6ZNR0, Q6ZRV2, Q75VX8, Q7Z6L0, Q86UK7, Q86VE0, Q8BGW2, Q8BRJ3, Q8BX43, Q8C0R7

Diamond homologs: O60320, P81408, Q15884, Q4FZH1, Q5HZJ5, Q6A044

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 86 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
R-HSA-425393	5	12.5×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of intracellular pH	5	41.8×	6e-05
transmembrane transport	7	16.4×	6e-05
transport across blood-brain barrier	5	12.4×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	108
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1482 predictions. Top by Δscore:

Variant	Effect	Δscore
1:155248044:TCCTA:T	donor_loss	1.0000
1:155248045:CCTA:C	donor_loss	1.0000
1:155248046:CTA:C	donor_loss	1.0000
1:155248047:TA:T	donor_loss	1.0000
1:155248049:CC:C	donor_loss	1.0000
1:155248049:CCTG:C	donor_gain	1.0000
1:155248301:GCCCT:G	acceptor_loss	1.0000
1:155248302:CC:C	acceptor_gain	1.0000
1:155248303:CC:C	acceptor_gain	1.0000
1:155248304:C:CC	acceptor_gain	1.0000
1:155248304:CT:C	acceptor_loss	1.0000
1:155248305:T:A	acceptor_loss	1.0000
1:155248400:CTGA:C	donor_loss	1.0000
1:155248402:GACCT:G	donor_loss	1.0000
1:155248404:C:CG	donor_loss	1.0000
1:155248437:T:TA	donor_gain	1.0000
1:155248469:GTCAG:G	acceptor_gain	1.0000
1:155248470:TCAG:T	acceptor_gain	1.0000
1:155248471:CAG:C	acceptor_gain	1.0000
1:155248471:CAGC:C	acceptor_gain	1.0000
1:155248472:AG:A	acceptor_gain	1.0000
1:155248474:C:CC	acceptor_gain	1.0000
1:155248475:T:C	acceptor_loss	1.0000
1:155250623:T:TA	donor_gain	1.0000
1:155251082:ACGC:A	donor_gain	1.0000
1:155251083:CGCC:C	donor_gain	1.0000
1:155251085:C:CA	donor_gain	1.0000
1:155251089:GCTCA:G	donor_loss	1.0000
1:155251090:CTCA:C	donor_loss	1.0000
1:155251091:TCA:T	donor_loss	1.0000

AlphaMissense

4223 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:155251764:A:G	Y255H	0.999
1:155254722:G:C	S52R	0.999
1:155254722:G:T	S52R	0.999
1:155254724:T:G	S52R	0.999
1:155251753:G:C	S258R	0.998
1:155251753:G:T	S258R	0.998
1:155251755:T:G	S258R	0.998
1:155251763:T:C	Y255C	0.998
1:155254745:C:G	G45R	0.998
1:155251574:G:C	S274R	0.997
1:155251574:G:T	S274R	0.997
1:155251576:T:G	S274R	0.997
1:155251779:A:C	Y250D	0.997
1:155251779:A:G	Y250H	0.997
1:155254667:A:G	W71R	0.997
1:155254667:A:T	W71R	0.997
1:155251804:A:C	F241L	0.996
1:155251804:A:T	F241L	0.996
1:155251806:A:G	F241L	0.996
1:155253718:G:C	S176R	0.996
1:155253718:G:T	S176R	0.996
1:155253720:T:G	S176R	0.996
1:155254443:C:T	G80E	0.996
1:155251537:A:C	Y287D	0.995
1:155251763:T:G	Y255S	0.995
1:155251764:A:C	Y255D	0.995
1:155254150:G:C	S109R	0.995
1:155254150:G:T	S109R	0.995
1:155254152:T:G	S109R	0.995
1:155254444:C:G	G80R	0.995

dbSNP variants (sampled 300 via entrez): RS1000434190 (1:155250699 G>A), RS1000466806 (1:155250371 G>A,T), RS1000646418 (1:155255256 G>A), RS1000765780 (1:155249515 G>A,T), RS1000796865 (1:155249206 G>C), RS1001015417 (1:155255542 G>A), RS1001045584 (1:155251381 A>G), RS1001980751 (1:155249603 G>A), RS1001982643 (1:155250137 T>C), RS1002045475 (1:155250821 A>G), RS1002293618 (1:155256154 A>T), RS1002346477 (1:155249799 T>C), RS1002406489 (1:155255894 C>A), RS1002649899 (1:155252259 G>A), RS1003026962 (1:155252495 G>A)

Disease associations

OMIM: gene MIM:619447 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST004131_70	Inflammatory bowel disease	6.000000e-08
GCST004132_44	Crohn’s disease	2.000000e-07
GCST007294_124	Body fat distribution (trunk fat ratio)	8.000000e-35
GCST007294_3	Body fat distribution (trunk fat ratio)	6.000000e-21
GCST007294_50	Body fat distribution (trunk fat ratio)	1.000000e-15
GCST007295_17	Body fat distribution (leg fat ratio)	3.000000e-13
GCST007295_37	Body fat distribution (leg fat ratio)	7.000000e-17
GCST007295_72	Body fat distribution (leg fat ratio)	1.000000e-28
GCST007324_63	Adventurousness	2.000000e-15
GCST010696_19	Cortical thickness (min-P)	2.000000e-10
GCST010697_10	Cortical surface area (min-P)	3.000000e-10
GCST010698_59	Subcortical volume (min-P)	9.000000e-10
GCST010699_20	Brain morphology (min-P)	7.000000e-10
GCST010700_5	Cortical thickness (MOSTest)	8.000000e-17
GCST010701_66	Cortical surface area (MOSTest)	1.000000e-09
GCST010702_43	Subcortical volume (MOSTest)	3.000000e-10
GCST010703_253	Brain morphology (MOSTest)	4.000000e-14

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0008579	risk-taking behaviour
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
bisphenol A	decreases methylation	1
terbufos	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
K 7174	decreases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects binding, decreases expression	1
Diazinon	increases methylation	1
Fonofos	increases methylation	1
Endosulfan	increases expression	1
Fluorouracil	affects response to substance	1
Lead	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Parathion	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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