EPS15

Summary

EPS15 (epidermal growth factor receptor pathway substrate 15, HGNC:3419) is a protein-coding gene on chromosome 1p32.3, encoding Epidermal growth factor receptor substrate 15 (P42566). Involved in cell growth regulation.

This gene encodes a protein that is part of the EGFR pathway. The protein is present at clatherin-coated pits and is involved in receptor-mediated endocytosis of EGF. Notably, this gene is rearranged with the HRX/ALL/MLL gene in acute myelogeneous leukemias. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 2060 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 144 total
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_001981

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3419
Approved symbol	EPS15
Name	epidermal growth factor receptor pathway substrate 15
Location	1p32.3
Locus type	gene with protein product
Status	Approved
Aliases	AF-1P, MLLT5
Ensembl gene	ENSG00000085832
Ensembl biotype	protein_coding
OMIM	600051
Entrez	2060

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 33 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000371727, ENST00000371730, ENST00000371733, ENST00000464478, ENST00000465467, ENST00000471391, ENST00000478657, ENST00000486505, ENST00000493793, ENST00000706287, ENST00000706288, ENST00000706289, ENST00000706290, ENST00000706291, ENST00000706292, ENST00000706293, ENST00000889375, ENST00000889376, ENST00000889377, ENST00000889378, ENST00000889379, ENST00000889380, ENST00000889381, ENST00000889382, ENST00000889383, ENST00000889384, ENST00000889385, ENST00000889386, ENST00000889387, ENST00000889388, ENST00000889389, ENST00000889390, ENST00000926816, ENST00000926817, ENST00000926818, ENST00000926819, ENST00000956027, ENST00000956028, ENST00000956029, ENST00000956030, ENST00000956031, ENST00000956032, ENST00000956033

RefSeq mRNA: 4 — MANE Select: NM_001981 NM_001159969, NM_001410796, NM_001410797, NM_001981

CCDS: CCDS557, CCDS90955, CCDS90956, CCDS90957

Canonical transcript exons

ENST00000371733 — 25 exons

Exon	Start	End
ENSE00001064519	51421786	51421858
ENSE00001064520	51440347	51440432
ENSE00001064521	51446960	51447105
ENSE00001064525	51448046	51448135
ENSE00001064528	51444889	51445045
ENSE00001222072	51519199	51519266
ENSE00001874328	51403419	51403532
ENSE00003467796	51463673	51463798
ENSE00003480486	51409535	51409696
ENSE00003482796	51481273	51481314
ENSE00003564732	51405905	51406108
ENSE00003565626	51461091	51461150
ENSE00003569590	51472859	51472948
ENSE00003582577	51408135	51408332
ENSE00003636933	51468473	51468568
ENSE00003671780	51471690	51471737
ENSE00003686550	51465261	51465326
ENSE00003995415	51399032	51399165
ENSE00003995422	51363866	51364028
ENSE00003995428	51361171	51361355
ENSE00003995429	51400918	51400953
ENSE00003995432	51365953	51366029
ENSE00003995434	51402435	51402525
ENSE00003995445	51394381	51394447
ENSE00003995447	51354263	51356846

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.7539 / max 1205.7036, expressed in 1811 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12315	31.0650	1806
12309	4.5284	424
12316	0.7755	509
12318	0.7735	435
12317	0.4566	236
12308	0.1549	55

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.60	gold quality
sperm	CL:0000019	99.29	gold quality
male germ cell	CL:0000015	98.90	gold quality
medial globus pallidus	UBERON:0002477	98.82	gold quality
frontal pole	UBERON:0002795	98.55	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.55	gold quality
globus pallidus	UBERON:0001875	98.46	gold quality
middle temporal gyrus	UBERON:0002771	98.36	gold quality
substantia nigra pars compacta	UBERON:0001965	98.34	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.20	gold quality
corpus callosum	UBERON:0002336	98.18	gold quality
pons	UBERON:0000988	98.13	gold quality
orbitofrontal cortex	UBERON:0004167	98.12	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.94	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.89	gold quality
occipital lobe	UBERON:0002021	97.82	gold quality
subthalamic nucleus	UBERON:0001906	97.78	gold quality
superior frontal gyrus	UBERON:0002661	97.78	gold quality
postcentral gyrus	UBERON:0002581	97.77	gold quality
primary visual cortex	UBERON:0002436	97.74	gold quality
parietal lobe	UBERON:0001872	97.68	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.67	gold quality
superior vestibular nucleus	UBERON:0007227	97.66	gold quality
CA1 field of hippocampus	UBERON:0003881	97.60	gold quality
cerebellar vermis	UBERON:0004720	97.52	gold quality
colonic epithelium	UBERON:0000397	97.47	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.30	gold quality
medulla oblongata	UBERON:0001896	97.29	gold quality
inferior vagus X ganglion	UBERON:0005363	97.22	gold quality
vastus lateralis	UBERON:0001379	97.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.96
E-CURD-88	yes	4.20

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

113 targeting EPS15, 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-4795-3P	100.00	74.62	4024
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
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-1468-3P	99.96	72.74	3797
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130B-3P	99.90	73.27	1850

Literature-anchored findings (GeneRIF, showing 23)

• Eps15 regulates clathrin coat assembly in vivo, and interactions between Eps15 homology domains and NPF motifs are involved in clathrin-coated vesicle formation during synaptic vesicle recycling (PMID:12807910)
• JC virus binding to human glial cells induces an intracellular signal that is critical for entry and infection by a ligand-inducible clathrin and eps15-dependent mechanism. (PMID:14671106)
• However, GFP-EH21 (a mutant Eps15) expression caused a 50% reduction in released enveloped virions, decreased formation of satellite plaques, and delayed virus spread, indicating an important role for receptor-mediated endocytosis. (PMID:15767409)
• Our results suggest that spartin might be involved in endocytosis, vesicle trafficking, or mitogenic activity, and that impairment in one of these processes may underlie the long axonopathy in patients with Troyer syndrome. (PMID:16036216)
• Data show that the first ubiquitin-interacting motif of Eps15 (UIM1) interacts directly with the UBL domain of ubiquilin, whereas it does not bind to ubiquitinated proteins. (PMID:16159959)
• SGIP1alpha plays an essential role in clathrin-mediated endocytosis by interacting with phospholipids and Eps15. (PMID:17626015)
• These results indicate that Eps15b is an endosomally localized isoform of Eps15 that is present in the Hrs complex via direct Hrs interaction and important for the sorting function of this complex. (PMID:18362181)
• EPS15 and EPS15R mediated internalization of activated EGF receptor to result in receptor recycling as to reinforce the proliferative response to EGF. (PMID:18395097)
• Distinct recruitment of Eps15 via Its coiled-coil domain is required for efficient down-regulation of the met receptor tyrosine kinase. (PMID:19109251)
• parkin Ubld uses differential surfaces to recruit UIM regions from the S5a proteasomal subunit compared with Eps15 involved in cell signaling. (PMID:19875440)
• analysis of the selective interaction of C-terminal Eps15 homology domain proteins with specific Asn-Pro-Phe-containing partners (PMID:20106972)
• distinct forms of Eps15 direct EGFR to either the late endosome/lysosome for degradation (Eps15) or to the recycling endosome for transit back to the cell surface (Eps15S) (PMID:21832070)
• MLL-EPS15 translocation and individual genomic copy number alterations in monozygotic infant twins are associated with acute lymphoblastic leukemia. (PMID:22581003)
• Results indicate that phosphorylation of epidermal growth factor receptor pathway substrate 15 (Eps15) at Ser-796 is catalyzed by p38 directly. (PMID:24269888)
• Ubiquitin is sufficient for Eps15 recruitment to endosomes. (PMID:25260758)
• over-expression of EPS15 is a potential favorable prognostic marker in breast cancer. (PMID:26289382)
• identify USP9X as a novel regulator of EGFR endocytosis (PMID:26748853)
• Together, the data indicate that a CUL3-SPOPL E3 ubiquitin ligase complex regulates endocytic trafficking and formation of multivesicular bodies by ubiquitinating and degrading EPS15 at endosomes. (PMID:27008177)
• Fcho1/2Eps15/RAP-2 ternary complexes to facilitate conformational activation of AP-2 by the Fcho1/2 interdomain linker to promote AP-2 cargo engagement. (PMID:27237791)
• RAB11FIP3 combines with Eps15 homology domain 1 to promote the endocytosis recycling of phosphorylation of epithelial growth factor receptor. (PMID:28215104)
• An interaction of Eps15 and pS227-FIP2 at the appropriate time and location in polarizing cells is necessary for proper establishment of epithelial polarity. (PMID:28228550)
• EPS15-NTRK1: a novel NTRK1 oncogenic fusion in patient with lung adenocarcinoma. (PMID:33037466)
• Modified iPOND revealed the role of mutant p53 in promoting helicase function and telomere maintenance. (PMID:37827695)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	eps15	ENSDARG00000078216
mus_musculus	Eps15	ENSMUSG00000028552
rattus_norvegicus	Eps15	ENSRNOG00000010299
drosophila_melanogaster	Dap160	FBGN0023388
drosophila_melanogaster	Eps-15	FBGN0035060
caenorhabditis_elegans		WBGENE00001224
caenorhabditis_elegans		WBGENE00006405

Paralogs (10): EHD3 (ENSG00000013016), EHD2 (ENSG00000024422), EHD4 (ENSG00000103966), EHD1 (ENSG00000110047), EPS15L1 (ENSG00000127527), REPS1 (ENSG00000135597), REPS2 (ENSG00000169891), SRL (ENSG00000185739), ITSN2 (ENSG00000198399), ITSN1 (ENSG00000205726)

Protein

Protein identifiers

Epidermal growth factor receptor substrate 15 — P42566 (reviewed: P42566)

Alternative names: Protein AF-1p

All UniProt accessions (8): P42566, A0A994J5A3, A0A994J5J3, A0A994J5W4, A0A994J7R8, A0A994J841, B1AUU8, S4R3U1

UniProt curated annotations — full annotation on UniProt →

Function. Involved in cell growth regulation. May be involved in the regulation of mitogenic signals and control of cell proliferation. Involved in the internalization of ligand-inducible receptors of the receptor tyrosine kinase (RTK) type, in particular EGFR. Plays a role in the assembly of clathrin-coated pits (CCPs). Acts as a clathrin adapter required for post-Golgi trafficking. Seems to be involved in CCPs maturation including invagination or budding. Involved in endocytosis of integrin beta-1 (ITGB1) and transferrin receptor (TFR); internalization of ITGB1 as DAB2-dependent cargo but not TFR seems to require association with DAB2.

Subunit / interactions. Interacts with SGIP1. Interacts with HGS; the interaction bridges the interaction of STAM or STAM2 with EPS15. Isoform 2 interacts with HGS and AP2A2. Part of a complex at least composed of EPS15, HGS, and either STAM or STAM2. Binds AP2A2. Interacts with AP2B1; clathrin competes with EPS15. Binds STON2. Interacts (via its SH3-binding sites) with CRK. Interacts with SH3BP4/TTP. Interacts with ERBB2. Interacts with FCHO1. Interacts with FCHO2. Interacts (via EH domains) with DAB2. Interacts (via UIM repeats) with CORO7 (when ubiquitinated at ‘Lys-472’). Interacts (via UIM domains) with UBQLN1 (via ubiquitin-like domain) and can interact with both the ubiquitinated and the non-ubiquitinated forms of UBQLN1. Interacts with UBQLN2. Interacts with REPS2; the interaction is direct. Interacts with EPN1; the interaction is direct. (Microbial infection) Interacts with vaccinia virus protein A36.

Subcellular location. Cytoplasm. Cell membrane. Membrane. Clathrin-coated pit Early endosome membrane.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Phosphorylation on Tyr-849 is involved in the internalization of EGFR. Not required for membrane translocation after EGF treatment or for targeting to coated pits, but essential for a subsequent step in EGFR endocytosis. Phosphorylated on serine upon DNA damage, probably by ATM or ATR. Ubiquitinated.

Disease relevance. A chromosomal aberration involving EPS15 is found in acute leukemias. Translocation t(1;11)(p32;q23) with KMT2A/MLL1. The result is a rogue activator protein.

Domain organisation. The EH domain interacts with Asn-Pro-Phe (NPF) motifs of target proteins. The UIM (ubiquitin-interacting motif) repeats specifically bind ‘Lys-33’-linked ubiquitin.

Isoforms (2)

UniProt ID	Names	Canonical?
P42566-1	1	yes
P42566-2	2, Eps15b

RefSeq proteins (4): NP_001153441, NP_001397725, NP_001397726, NP_001972* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000261	EH_dom	Domain
IPR002048	EF_hand_dom	Domain
IPR003903	UIM_dom	Conserved_site
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site

Pfam: PF12763

UniProt features (86 total): modified residue 17, repeat 15, helix 10, domain 9, binding site 9, turn 7, strand 5, region of interest 4, splice variant 2, mutagenesis site 2, initiator methionine 1, chain 1, short sequence motif 1, compositionally biased region 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
4RHG	X-RAY DIFFRACTION	1.58
4RH9	X-RAY DIFFRACTION	1.6
4RH5	X-RAY DIFFRACTION	1.6
4S0G	X-RAY DIFFRACTION	1.72
2IV9	X-RAY DIFFRACTION	1.9
5JP2	X-RAY DIFFRACTION	2.4
5AWU	X-RAY DIFFRACTION	2.7
5AWT	X-RAY DIFFRACTION	2.7
1C07	SOLUTION NMR
1EH2	SOLUTION NMR
1F8H	SOLUTION NMR
1FF1	SOLUTION NMR
2JXC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42566-F1	67.60	0.27

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 (9): 173; 175; 177; 179; 184; 236; 238; 240; 247

Post-translational modifications (17): 2, 108, 140, 323, 324, 467, 470, 485, 562, 563, 746, 777, 779, 790, 796, 814, 849

Mutagenesis-validated functional residues (2):

Position	Phenotype
154	loss of interaction with ston2 npf motifs.
169	loss of interaction with ston2 npf motifs.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-182971	EGFR downregulation
R-HSA-6807004	Negative regulation of MET activity
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-8875360	InlB-mediated entry of Listeria monocytogenes into host cell
R-HSA-9766229	Degradation of CDH1

MSigDB gene sets: 337 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, RRAGTTGT_UNKNOWN, ACTACCT_MIR196A_MIR196B, ZHAN_MULTIPLE_MYELOMA_PR_DN, GOBP_VESICLE_ORGANIZATION, ATACCTC_MIR202, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_CLATHRIN_COAT_ASSEMBLY, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, BORLAK_LIVER_CANCER_EGF_UP, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, WANG_RESPONSE_TO_BEXAROTENE_DN

GO Biological Process (14): positive regulation of receptor recycling (GO:0001921), Golgi to endosome transport (GO:0006895), endocytosis (GO:0006897), vesicle organization (GO:0016050), endosomal transport (GO:0016197), receptor-mediated endocytosis of virus by host cell (GO:0019065), endocytic recycling (GO:0032456), regulation of protein localization (GO:0032880), regulation of cell population proliferation (GO:0042127), symbiont entry into host cell (GO:0046718), clathrin coat assembly (GO:0048268), ubiquitin-dependent endocytosis (GO:0070086), postsynaptic neurotransmitter receptor internalization (GO:0098884), protein transport (GO:0015031)

GO Molecular Function (9): calcium ion binding (GO:0005509), SH3 domain binding (GO:0017124), protein-macromolecule adaptor activity (GO:0030674), polyubiquitin modification-dependent protein binding (GO:0031593), identical protein binding (GO:0042802), ubiquitin binding (GO:0043130), cadherin binding (GO:0045296), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (18): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), clathrin-coated pit (GO:0005905), basal plasma membrane (GO:0009925), membrane (GO:0016020), aggresome (GO:0016235), apical plasma membrane (GO:0016324), AP-2 adaptor complex (GO:0030122), clathrin coat of coated pit (GO:0030132), early endosome membrane (GO:0031901), ciliary membrane (GO:0060170), postsynaptic endocytic zone (GO:0098843), glutamatergic synapse (GO:0098978), endosome (GO:0005768), early endosome (GO:0005769), clathrin-coated vesicle (GO:0030136), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by EGFR	1
Signaling by MET	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
Listeria monocytogenes entry into host cells	1
Regulation of CDH1 Function	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
vesicle-mediated transport	2
intracellular protein localization	2
protein binding	2
membrane	2
endomembrane system	2
plasma membrane region	2
plasma membrane protein complex	2
clathrin coat	2
receptor recycling	1
regulation of receptor recycling	1
positive regulation of macromolecule metabolic process	1
positive regulation of signaling	1
post-Golgi vesicle-mediated transport	1
intercellular transport	1
cytosolic transport	1
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
organelle organization	1
intracellular transport	1
receptor-mediated endocytosis	1
symbiont entry into host cell	1
endocytosis involved in viral entry into host cell	1
endosomal transport	1
vesicle-mediated transport to the plasma membrane	1
regulation of localization	1
cell population proliferation	1
regulation of cellular process	1
viral life cycle	1
symbiont entry into host	1
protein-containing complex assembly	1
endocytosis	1
protein transport	1
protein localization to organelle	1
establishment of protein localization to organelle	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
neurotransmitter receptor internalization	1
postsynaptic endocytosis	1
transport	1

Protein interactions and networks

STRING

2800 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPS15	FCHO1	O14526	998
EPS15	EPN2	O95208	997
EPS15	EPN3	Q9H201	995
EPS15	STON2	Q8WXE9	994
EPS15	NUMBL	Q9Y6R0	986
EPS15	ITSN2	Q9NZM3	986
EPS15	ITSN1	Q15811	983
EPS15	EPN1	Q9Y6I3	980
EPS15	NUMB	P49757	973
EPS15	FCHO2	Q0JRZ9	967
EPS15	SPART	Q8N0X7	933
EPS15	EGFR	P00533	906
EPS15	AMPH	P49418	876
EPS15	SYNJ1	O43426	863
EPS15	SGIP1	Q9BQI5	859

IntAct

256 interactions, top by confidence:

A	B	Type	Score
SPC25	NDC80	psi-mi:“MI:0914”(association)	0.940
INO80E	YY1	psi-mi:“MI:0914”(association)	0.900
EPS15	STON2	psi-mi:“MI:0407”(direct interaction)	0.840
RUFY4	NDC80	psi-mi:“MI:0914”(association)	0.830
EPS15	NUMB	psi-mi:“MI:0407”(direct interaction)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
FCHO2	EPS15	psi-mi:“MI:0403”(colocalization)	0.700
FCHO2	EPS15	psi-mi:“MI:0915”(physical association)	0.700
STAMBPL1	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
AP2S1	AP2A2	psi-mi:“MI:0914”(association)	0.640
EPS15	EPN1	psi-mi:“MI:0407”(direct interaction)	0.620
EPS15	SH3BP4	psi-mi:“MI:0407”(direct interaction)	0.610
EPS15	PICALM	psi-mi:“MI:0407”(direct interaction)	0.590
EPS15	ITSN1	psi-mi:“MI:0915”(physical association)	0.560
PLK1	C1orf226	psi-mi:“MI:0914”(association)	0.560
Fcho2	EPS15	psi-mi:“MI:0403”(colocalization)	0.560
EPS15	Fcho2	psi-mi:“MI:0407”(direct interaction)	0.560
SLC25A41	NUDT19	psi-mi:“MI:0914”(association)	0.530
CCDC172	EPS15	psi-mi:“MI:0914”(association)	0.530
OXCT1	EPS15	psi-mi:“MI:0914”(association)	0.530
CRK	ARHGAP42	psi-mi:“MI:0914”(association)	0.530

BioGRID (405): EPS15 (Protein-peptide), EPS15 (Reconstituted Complex), EPS15 (Biochemical Activity), AGFG2 (Phenotypic Enhancement), EPS15 (Co-fractionation), EPS15 (Co-fractionation), EPS15 (Affinity Capture-MS), EPS15 (Affinity Capture-MS), EPS15 (Affinity Capture-MS), EPS15 (Affinity Capture-MS), EPS15 (Affinity Capture-MS), Numb (Affinity Capture-Western), Numb (Co-localization), EPS15 (Affinity Capture-MS), EPS15 (Co-fractionation)

ESM2 similar proteins: A0JNJ3, A0M8T5, A0PJT0, A2BIJ3, D3ZTQ1, O35867, O94876, P42566, P42567, P97578, Q00PJ1, Q02225, Q09YI1, Q09YK4, Q09YM8, Q16643, Q2IBF8, Q2QL82, Q2QLA2, Q2QLG9, Q2T9N1, Q3SX22, Q3UQU0, Q3USH5, Q5BJ78, Q5RDH2, Q5T1M5, Q5U3K5, Q5ZIK6, Q68EF0, Q69ZZ6, Q6INU2, Q6NTW1, Q6P9Q6, Q6TYB5, Q6ZPJ0, Q80Y55, Q8IWB9, Q8IWE2, Q8N0X7

Diamond homologs: A1CD74, A1CPG1, A1D2B8, A1DC51, A1DDY6, A2QRG2, A2R180, A3LN86, A3M008, A4R8N4, A5DF78, A5DP36, A5DVD6, A5DXI9, A6R7X5, A6RFP4, A6S9N4, A6SIJ6, A7E7N7, A7EKZ0, B0XR88, B0YC95, B2AS96, B2AWS3, L7IIY8, O42287, O54916, O94685, P0CT09, P32521, P42566, P42567, Q0CPW4, Q0D0N9, Q1DQC1, Q1DUU2, Q2H2V8, Q2H922, Q2UCH0, Q2UDY8

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
PRKN	up-regulates	EPS15	ubiquitination
EGFR	up-regulates	EPS15	phosphorylation
MAPK14	up-regulates	EPS15	phosphorylation
USP9X	“down-regulates activity”	EPS15	deubiquitination
PRKN	“down-regulates activity”	EPS15	ubiquitination
“AP-2 complex”	“up-regulates activity”	EPS15	binding
EPS15	“down-regulates activity”	EGFR	binding
EPS15	“up-regulates quantity by stabilization”	“AP-2/clathrin vescicle”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 186 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
WNT5A-dependent internalization of FZD4	8	48.7×	2e-10
VLDLR internalisation and degradation	7	40.0×	2e-08
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	7	35.5×	3e-08
The role of Nef in HIV-1 replication and disease pathogenesis	7	35.5×	3e-08
LDL clearance	8	34.8×	4e-09
Trafficking of GluR2-containing AMPA receptors	5	26.9×	3e-05
Plasma lipoprotein clearance	6	22.8×	6e-06
Host Interactions of HIV factors	8	21.5×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
clathrin coat assembly	12	66.1×	1e-17
clathrin-dependent endocytosis	16	57.8×	2e-22
synaptic vesicle endocytosis	13	34.9×	1e-14
negative regulation of protein localization to plasma membrane	7	27.1×	1e-06
regulation of endocytosis	7	20.9×	6e-06
mitotic spindle organization	7	11.8×	3e-04
positive regulation of substrate adhesion-dependent cell spreading	5	11.6×	6e-03
epidermal growth factor receptor signaling pathway	6	9.2×	5e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — PRAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	109
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4880 predictions. Top by Δscore:

Variant	Effect	Δscore
1:51361165:ACTT:A	donor_loss	1.0000
1:51361167:TTA:T	donor_loss	1.0000
1:51361169:A:AC	donor_gain	1.0000
1:51361169:A:AG	donor_loss	1.0000
1:51361169:ACAG:A	donor_gain	1.0000
1:51361170:C:CA	donor_gain	1.0000
1:51361170:C:T	donor_loss	1.0000
1:51361170:CA:C	donor_gain	1.0000
1:51361170:CAG:C	donor_gain	1.0000
1:51361170:CAGC:C	donor_gain	1.0000
1:51361170:CAGCA:C	donor_gain	1.0000
1:51361354:CCCTG:C	acceptor_loss	1.0000
1:51361355:CCTG:C	acceptor_loss	1.0000
1:51361356:C:CA	acceptor_loss	1.0000
1:51361356:C:CC	acceptor_gain	1.0000
1:51361357:T:A	acceptor_loss	1.0000
1:51363856:A:AC	donor_gain	1.0000
1:51363857:C:CC	donor_gain	1.0000
1:51363857:CT:C	donor_gain	1.0000
1:51364028:CC:C	acceptor_loss	1.0000
1:51364028:CCTT:C	acceptor_gain	1.0000
1:51364029:C:CC	acceptor_gain	1.0000
1:51364031:T:C	acceptor_gain	1.0000
1:51364031:T:TC	acceptor_gain	1.0000
1:51364035:T:C	acceptor_gain	1.0000
1:51364035:T:TC	acceptor_gain	1.0000
1:51366025:TGTGG:T	acceptor_gain	1.0000
1:51366030:C:CC	acceptor_gain	1.0000
1:51394376:TTTAC:T	donor_loss	1.0000
1:51394377:TTA:T	donor_loss	1.0000

AlphaMissense

5958 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:51461147:A:G	W169R	1.000
1:51461147:A:T	W169R	1.000
1:51356728:A:G	L888P	0.999
1:51356732:C:G	A887P	0.999
1:51356738:C:G	A885P	0.999
1:51356740:A:G	L884P	0.999
1:51408238:A:G	L457P	0.999
1:51408247:A:G	L454P	0.999
1:51440353:A:G	L345P	0.999
1:51445013:A:G	L277P	0.999
1:51446961:A:G	W266R	0.999
1:51446961:A:T	W266R	0.999
1:51461098:A:G	F185S	0.999
1:51461113:A:G	L180P	0.999
1:51461113:A:T	L180H	0.999
1:51461136:A:C	S172R	0.999
1:51461136:A:T	S172R	0.999
1:51461138:T:G	S172R	0.999
1:51461145:C:A	W169C	0.999
1:51461145:C:G	W169C	0.999
1:51461149:A:T	V168D	0.999
1:51463695:A:G	L160S	0.999
1:51463710:A:G	L155S	0.999
1:51472896:A:G	L43P	0.999
1:51356816:C:G	A859P	0.998
1:51408322:A:G	L429P	0.998
1:51409692:A:G	L373P	0.998
1:51440383:A:G	L335P	0.998
1:51445013:A:T	L277H	0.998
1:51461097:A:C	F185L	0.998

dbSNP variants (sampled 300 via entrez): RS1000030446 (1:51366182 C>A), RS1000048607 (1:51390386 A>G), RS1000074831 (1:51512422 TAAGAG>T), RS1000084386 (1:51437223 A>G), RS1000092260 (1:51366405 A>G), RS1000117577 (1:51464334 G>A), RS1000124365 (1:51455696 A>G), RS1000127460 (1:51379444 G>A,C), RS1000129794 (1:51469605 T>G), RS1000131065 (1:51360486 C>T), RS1000155755 (1:51455416 C>A), RS1000180074 (1:51393145 G>A), RS1000183380 (1:51446583 A>C), RS1000219838 (1:51408646 G>C), RS1000245885 (1:51504343 G>A)

Disease associations

OMIM: gene MIM:600051 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001303_5	IgE grass sensitization	2.000000e-06
GCST007045_12	PR interval	1.000000e-08
GCST008062_114	Blood urea nitrogen levels	1.000000e-08
GCST010321_98	PR interval	1.000000e-25
GCST010796_3703	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-10
GCST010796_3704	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-10
GCST010796_3705	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-10
GCST010796_3706	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-09
GCST010796_3707	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_3708	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-10
GCST012227_1069	Hip circumference adjusted for BMI	4.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004462	PR interval
EFO:0004327	electrocardiography
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295760 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.43	Kd	370	nM	CHEMBL4526960

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
(5S,11S,14S,17S,20S,23S,26S,32S,35S,38R)-5-amino-26-(2-amino-2-oxoethyl)-35-benzyl-17-[3-(diaminomethylideneamino)propyl]-23-[(1R)-1-hydroxyethyl]-14-(1H-indol-3-ylmethyl)-20-methyl-6,12,15,18,21,24,27,33,36-nonaoxo-3,40-dithia-7,13,16,19,22,25,28,34,37-nonazatetracyclo[40.3.1.07,11.028,32]hexatetraconta-1(46),42,44-triene-38-carboxylic acid	1584430: Inhibition of stonin-2 binding to Eps15 (unknown origin)	kd	0.3700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation	3
Valproic Acid	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
biochanin A	decreases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	decreases methylation	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
coenzyme Q10	decreases reaction, increases expression	1
4-hydroxy-2-nonenal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	increases expression	1
K 7174	increases expression	1
(E)-4-((2-N-(4-methoxybenzenesulfonyl)amino)stilbazole)1-oxide	decreases expression	1
thifluzamide	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pyrachlostrobin	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol AF	increases expression	1
Gefitinib	increases expression	1
Resveratrol	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Carbamazepine	affects expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4186165	Binding	Binding affinity to GST-fused Eps15 EH2 domain (unknown origin) expressed in Escherichia coli BL21 cells under high salt condition by fluorescence polarization assay	Thioether-stapled macrocyclic inhibitors of the EH domain of EHD1. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SM27	HAP1 EPS15 (-) 1	Cancer cell line	Male
CVCL_XN48	HAP1 EPS15 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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