EPS8L3

Summary

EPS8L3 (EPS8 signaling adaptor L3, HGNC:21297) is a protein-coding gene on chromosome 1p13.3, encoding Epidermal growth factor receptor kinase substrate 8-like protein 3 (Q8TE67).

This gene encodes a protein that is related to epidermal growth factor receptor pathway substrate 8 (EPS8), a substrate for the epidermal growth factor receptor. The function of this protein is unknown. Alternatively spliced transcript variants encoding different isoforms exist.

Source: NCBI Gene 79574 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Marie Unna hereditary hypotrichosis (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 106 total — 1 pathogenic
• Phenotypes (HPO): 15
• MANE Select transcript: NM_133181

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21297
Approved symbol	EPS8L3
Name	EPS8 signaling adaptor L3
Location	1p13.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21522, MGC16817
Ensembl gene	ENSG00000198758
Ensembl biotype	protein_coding
OMIM	614989
Entrez	79574

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 19 protein_coding, 6 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000361852, ENST00000361965, ENST00000369805, ENST00000472325, ENST00000475725, ENST00000477568, ENST00000482453, ENST00000489465, ENST00000494151, ENST00000498743, ENST00000888973, ENST00000888974, ENST00000888975, ENST00000888976, ENST00000888977, ENST00000888978, ENST00000888979, ENST00000888980, ENST00000888981, ENST00000888982, ENST00000888983, ENST00000888984, ENST00000888985, ENST00000952210, ENST00000952211, ENST00000952212

RefSeq mRNA: 4 — MANE Select: NM_133181 NM_001319952, NM_024526, NM_133181, NM_139053

CCDS: CCDS813, CCDS814, CCDS815

Canonical transcript exons

ENST00000361965 — 19 exons

Exon	Start	End
ENSE00001024586	109757944	109758058
ENSE00001024592	109757481	109757555
ENSE00001024595	109757017	109757165
ENSE00001024599	109751278	109751351
ENSE00001024606	109757802	109757863
ENSE00001024608	109759238	109759387
ENSE00001024610	109758316	109758431
ENSE00001024617	109753117	109753198
ENSE00001024618	109752686	109752720
ENSE00001024620	109751654	109751782
ENSE00001024621	109759678	109759836
ENSE00001153277	109750080	109750402
ENSE00001281983	109751995	109752193
ENSE00001436073	109758524	109758663
ENSE00001866232	109763822	109763923
ENSE00003489522	109750660	109750792
ENSE00003532155	109761719	109761773
ENSE00003583762	109759062	109759117
ENSE00003740644	109761495	109761559

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 99.19.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.3539 / max 444.0889, expressed in 63 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13721	1.0792	57
13722	0.2748	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	99.19	gold quality
rectum	UBERON:0001052	99.09	gold quality
ileal mucosa	UBERON:0000331	97.97	gold quality
gall bladder	UBERON:0002110	97.91	gold quality
jejunal mucosa	UBERON:0000399	96.61	gold quality
duodenum	UBERON:0002114	96.18	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.44	gold quality
colonic mucosa	UBERON:0000317	94.97	gold quality
small intestine	UBERON:0002108	94.79	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.53	gold quality
mucosa of stomach	UBERON:0001199	92.61	gold quality
transverse colon	UBERON:0001157	92.13	gold quality
pancreatic ductal cell	CL:0002079	91.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.01	gold quality
vermiform appendix	UBERON:0001154	88.14	gold quality
type B pancreatic cell	CL:0000169	87.09	gold quality
olfactory bulb	UBERON:0002264	86.71	gold quality
caecum	UBERON:0001153	86.66	gold quality
body of stomach	UBERON:0001161	86.36	gold quality
intestine	UBERON:0000160	86.16	gold quality
jejunum	UBERON:0002115	85.33	gold quality
pylorus	UBERON:0001166	85.15	gold quality
stomach	UBERON:0000945	85.07	gold quality
large intestine	UBERON:0000059	83.36	gold quality
colonic epithelium	UBERON:0000397	82.84	gold quality
colon	UBERON:0001155	82.80	gold quality
male germ cell	CL:0000015	82.55	silver quality
sperm	CL:0000019	81.98	silver quality
fundus of stomach	UBERON:0001160	77.54	gold quality
epithelial cell of pancreas	CL:0000083	77.44	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	19.99
E-ENAD-27	yes	0.86

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting EPS8L3, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-6513-5P	99.43	67.81	1071
HSA-MIR-4506	99.34	67.47	526
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-887-5P	98.82	65.90	1347
HSA-MIR-432-5P	98.00	68.13	989
HSA-MIR-4769-3P	97.95	68.17	1002
HSA-MIR-6817-5P	97.95	67.86	1026
HSA-MIR-6748-3P	97.20	65.66	836
HSA-MIR-6822-3P	96.60	66.06	680
HSA-MIR-6742-5P	96.32	64.01	869
HSA-MIR-6802-5P	94.94	65.95	366
HSA-MIR-503-3P	92.89	66.09	537
HSA-MIR-4508	90.37	59.62	240

Literature-anchored findings (GeneRIF, showing 4)

• The results suggest that EPS8L3 is a causative gene for Marie Unna hereditary hypotrichosis. (PMID:23099647)
• EPS8L3 might promote proliferation by hyperactivating the AKT signaling pathway and subsequently inhibiting the FOXO1 transcriptional activity in hepatocellular carcinoma (PMID:29940761)
• The results revealed that EPS8L3 expression was significantly upregulated in liver cancer tissues and cell lines (P<0.01), and that the expression of EPS8L3 was closely associated with grade (P=0.024) and mortality (P=0.011). (PMID:31322213)
• Sorted-Cell Sequencing on HCC Specimens Reveals EPS8L3 as a Key Player in CD24/CD13/EpCAM-Triple Positive, Stemness-Related HCC Cells. (PMID:38750898)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	eps8l3b	ENSDARG00000005704
danio_rerio	eps8l3a	ENSDARG00000101979
mus_musculus	Eps8l3	ENSMUSG00000040600
rattus_norvegicus	Eps8l3	ENSRNOG00000048209
drosophila_melanogaster	aru	FBGN0029095
drosophila_melanogaster	CG8907	FBGN0038466
caenorhabditis_elegans		WBGENE00001330

Paralogs (3): EPS8L1 (ENSG00000131037), EPS8 (ENSG00000151491), EPS8L2 (ENSG00000177106)

Protein

Protein identifiers

Epidermal growth factor receptor kinase substrate 8-like protein 3 — Q8TE67 (reviewed: Q8TE67)

Alternative names: Epidermal growth factor receptor pathway substrate 8-related protein 3

All UniProt accessions (2): Q8TE67, A0A087X104

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Interacts with ABI1. Part of a complex that contains SOS1, ABI1 and EPS8L2. Interacts with FASLG.

Subcellular location. Cytoplasm.

Disease relevance. Hypotrichosis 5 (HYPT5) [MIM:612841] A form of hypotrichosis, a condition characterized by the presence of less than the normal amount of hair and abnormal hair follicles and shafts, which are thin and atrophic. The extent of scalp and body hair involvement can be very variable, within as well as between families. HYPT5 is an autosomal dominant form characterized by little or no scalp hair at birth, wiry and irregular scalp hair in childhood, and sparse or no forehead and parietal hair at puberty. Eyebrows and eyelashes are thin, and pubic and axillary hair fails to develop. Scarring alopecia is modest, and vertex hair is normal. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the EPS8 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TE67-1	1	yes
Q8TE67-2	2
Q8TE67-3	3, A

RefSeq proteins (4): NP_001306881, NP_078802, NP_573444, NP_620641 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013625	PTB	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR033928	EPS8_PTB	Domain
IPR035462	Eps8_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR039801	EPS8-like	Family
IPR041418	SAM_3	Domain
IPR055093	EPS8_2nd	Domain

Pfam: PF00018, PF08416, PF18016, PF22975

UniProt features (23 total): sequence variant 6, strand 5, region of interest 3, domain 2, splice variant 2, compositionally biased region 2, chain 1, helix 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1WXT	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TE67-F1	72.46	0.29

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 (1): 231

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 116 (showing top): GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_RUFFLE_ASSEMBLY, GOCC_RUFFLE, GOBP_REGULATION_OF_HAIR_CYCLE, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, PATIL_LIVER_CANCER, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, TGANTCA_AP1_C, GOBP_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MOLTING_CYCLE, GOMF_ACTIN_BINDING, GOBP_CELL_PROJECTION_ORGANIZATION, GOBP_REGULATION_OF_CELL_PROJECTION_ASSEMBLY

GO Biological Process (4): Rho protein signal transduction (GO:0007266), regulation of Rho protein signal transduction (GO:0035023), regulation of hair cycle (GO:0042634), positive regulation of ruffle assembly (GO:1900029)

GO Molecular Function (3): actin binding (GO:0003779), guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), plasma membrane (GO:0005886), ruffle membrane (GO:0032587)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
small GTPase-mediated signal transduction	1
Rho protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
hair cycle	1
regulation of multicellular organismal process	1
ruffle assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
regulation of ruffle assembly	1
cytoskeletal protein binding	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
membrane	1
cell periphery	1
ruffle	1
cell projection membrane	1
leading edge membrane	1

Protein interactions and networks

STRING

618 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPS8L3	ESPN	B1AK53	590
EPS8L3	SNRPE	P08578	497
EPS8L3	DSG4	Q86SJ6	482
EPS8L3	RPL21	P46778	472
EPS8L3	MTSS2	Q765P7	452
EPS8L3	LPAR6	P43657	447
EPS8L3	FCSK	Q8N0W3	442
EPS8L3	STRIP1	Q5VSL9	438
EPS8L3	SLC45A4	Q5BKX6	435
EPS8L3	COG4	Q9H9E3	433
EPS8L3	AXDND1	Q5T1B0	428
EPS8L3	IGSF23	A1L1A6	424
EPS8L3	VAC14	Q08AM6	422
EPS8L3	APCDD1	Q8J025	422
EPS8L3	EZR	P15311	415

IntAct

5 interactions, top by confidence:

A	B	Type	Score
EPS8L3	FASLG	psi-mi:“MI:0407”(direct interaction)	0.440
EPS8L3	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
CD3E	EPS8L3	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350

BioGRID (9): ABI1 (Affinity Capture-Western), EPS8L3 (Affinity Capture-MS), EPS8L3 (Affinity Capture-MS), EPS8L3 (Affinity Capture-MS), EPS8L3 (Protein-peptide), Nmd3 (Affinity Capture-MS), Nmd3 (Affinity Capture-Western), EPS8L3 (Affinity Capture-Western), EPS8L3 (Biochemical Activity)

ESM2 similar proteins: A1IGU3, A1IGU4, A1IGU5, A6QP29, B1AVH7, B2RUP2, B5DFA1, D2H0G5, D3ZFJ3, O15068, O55043, P00530, P07332, P14238, P16879, P55194, P98171, Q0GNC1, Q14155, Q15052, Q27J81, Q3U5C8, Q3UMR0, Q58EX7, Q5VV41, Q5XXR3, Q5ZLR6, Q60I26, Q63406, Q64096, Q6PFY1, Q6PGG2, Q70J99, Q7TNH6, Q80TT2, Q80VK6, Q86WN1, Q8C2K1, Q8C6B2, Q8CJ00

Diamond homologs: A1A5H8, A1DBH2, A6ZKU1, A7TKW4, B0Y9Q4, F1LM93, O13736, P00527, P07947, P09324, P09769, P10569, P13395, P14234, P19706, P27447, P32790, P34109, P62993, P62994, P87379, Q00647, Q02977, Q04736, Q05876, Q07883, Q08012, Q28923, Q4WC55, Q5ALV2, Q5R4J7, Q5ZJJ9, Q60631, Q62422, Q66II3, Q6CHN0, Q6EWH2, Q6GPJ9, Q6P686, Q6P6U0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	83
Likely benign	13
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2424031	NC_000001.10:g.(?108679275)(111674176_?)del	Pathogenic

SpliceAI

2807 predictions. Top by Δscore:

Variant	Effect	Δscore
1:109750668:T:TA	donor_gain	1.0000
1:109750788:CCGTG:C	acceptor_gain	1.0000
1:109750789:CGTGC:C	acceptor_gain	1.0000
1:109751277:CG:C	donor_gain	1.0000
1:109753110:C:A	donor_gain	1.0000
1:109753115:A:AC	donor_gain	1.0000
1:109753116:C:CC	donor_gain	1.0000
1:109753116:CTTGG:C	donor_gain	1.0000
1:109757415:T:A	donor_gain	1.0000
1:109757428:C:CA	donor_gain	1.0000
1:109758522:A:AC	donor_gain	1.0000
1:109758523:C:CT	donor_gain	1.0000
1:109758523:CT:C	donor_gain	1.0000
1:109758664:CTG:C	acceptor_gain	1.0000
1:109758667:C:CC	acceptor_gain	1.0000
1:109758675:A:C	acceptor_gain	1.0000
1:109759236:ACCC:A	donor_gain	1.0000
1:109759237:CCCC:C	donor_gain	1.0000
1:109759245:T:TA	donor_gain	1.0000
1:109759394:C:CT	acceptor_gain	1.0000
1:109761490:CTCA:C	donor_loss	1.0000
1:109761491:TCA:T	donor_loss	1.0000
1:109761492:CACC:C	donor_loss	1.0000
1:109761494:C:A	donor_loss	1.0000
1:109763816:CCTTA:C	donor_loss	1.0000
1:109763817:CTTA:C	donor_loss	1.0000
1:109763818:TTAC:T	donor_loss	1.0000
1:109763819:TA:T	donor_loss	1.0000
1:109750626:C:CA	donor_gain	0.9900
1:109750791:TG:T	acceptor_gain	0.9900

AlphaMissense

3848 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:109752046:A:C	F461L	0.994
1:109752046:A:T	F461L	0.994
1:109752048:A:G	F461L	0.994
1:109759257:A:G	F129S	0.994
1:109757820:C:A	K292N	0.991
1:109757820:C:G	K292N	0.991
1:109751759:C:A	W486C	0.990
1:109751759:C:G	W486C	0.990
1:109757030:A:G	W369R	0.990
1:109757030:A:T	W369R	0.990
1:109751761:A:G	W486R	0.989
1:109751761:A:T	W486R	0.989
1:109757028:C:A	W369C	0.987
1:109757028:C:G	W369C	0.987
1:109759308:A:G	L112P	0.987
1:109759724:A:G	L70P	0.986
1:109759832:A:G	L34S	0.986
1:109759256:G:C	F129L	0.983
1:109759256:G:T	F129L	0.983
1:109759258:A:G	F129L	0.983
1:109751721:A:T	I499N	0.982
1:109759697:A:G	L79P	0.982
1:109759743:A:G	W64R	0.981
1:109759743:A:T	W64R	0.981
1:109759703:A:G	L77P	0.980
1:109759741:C:A	W64C	0.980
1:109759741:C:G	W64C	0.980
1:109752023:A:G	L469P	0.979
1:109757814:G:C	S294R	0.978
1:109757814:G:T	S294R	0.978

dbSNP variants (sampled 300 via entrez): RS1000196742 (1:109750103 G>C,T), RS1000331195 (1:109762239 G>T), RS1000385059 (1:109762533 A>G), RS1000551931 (1:109749901 T>G), RS1000629057 (1:109762232 C>T), RS1001275084 (1:109751564 A>C), RS1001333017 (1:109763434 G>T), RS1001496756 (1:109758786 C>T), RS1001615076 (1:109759009 C>T), RS1001674324 (1:109752877 GCACC>G), RS1002214827 (1:109760196 C>G,T), RS1002277177 (1:109751544 A>G), RS1002353869 (1:109763316 C>T), RS1002632931 (1:109751360 A>C,G), RS1002833334 (1:109760957 A>G)

Disease associations

OMIM: gene MIM:614989 | disease phenotypes: MIM:615686, MIM:615809, MIM:612841

GenCC curated gene-disease

Disease	Classification	Inheritance
Marie Unna hereditary hypotrichosis	Supportive	Autosomal dominant
hypotrichosis 5	Limited	Autosomal dominant

Mondo (4): hereditary spastic paraplegia 63 (MONDO:0014305), pontocerebellar hypoplasia type 9 (MONDO:0014351), hypotrichosis 5 (MONDO:0013017), Marie Unna hereditary hypotrichosis (MONDO:0018631)

Orphanet (3): Pontocerebellar hypoplasia type 9 (Orphanet:369920), Autosomal recessive spastic paraplegia type 63 (Orphanet:401805), Marie Unna hereditary hypotrichosis (Orphanet:444)

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000164	Abnormality of the dentition
HP:0000364	Hearing abnormality
HP:0000653	Sparse eyelashes
HP:0000971	Abnormal sweat gland morphology
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0002208	Coarse hair
HP:0002209	Sparse scalp hair
HP:0002221	Absent axillary hair
HP:0002555	Absent pubic hair
HP:0003577	Congenital onset
HP:0045074	Thin eyebrow
HP:0100840	Aplasia/Hypoplasia of the eyebrow
HP:0200102	Sparse or absent eyelashes

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002734_2	Fibrinogen levels (smoking status, alcohol consumption or body mass index interaction)	7.000000e-07
GCST006979_997	Heel bone mineral density	2.000000e-09
GCST009869_7	Colorectal cancer	4.000000e-08
GCST011955_7	Alcohol dependence	9.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004329	alcohol drinking
EFO:0009270	heel bone mineral density

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C567554	Hypotrichosis 5 (supp.)
C535912	Marie Unna congenital hypotrichosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	4
Cyclosporine	decreases expression, increases expression	3
Tetrachlorodibenzodioxin	increases expression	2
Aflatoxin B1	affects expression, increases methylation	2
methyleugenol	increases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	affects response to substance	1
3,4,8-trimethylimidazo(4,5-f)quinoxalin-2-amine	affects response to substance	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	affects response to substance	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	decreases expression	1
Caffeine	affects phosphorylation	1
Cisplatin	increases expression, affects cotreatment	1
Dactinomycin	increases expression	1
Methapyrilene	increases methylation	1
N-Nitrosopyrrolidine	increases expression	1
Niclosamide	increases expression	1
Valproic Acid	decreases expression	1
Oxyquinoline	increases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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