EREG

Summary

EREG (epiregulin, HGNC:3443) is a protein-coding gene on chromosome 4q13.3, encoding Proepiregulin (O14944). Ligand of the EGF receptor/EGFR and ERBB4. In precision oncology, EREG EXPRESSION confers sensitivity to Panitumumab in Colorectal Cancer (CIViC Level B); 1 further curated variant–drug associations are listed below.

This gene encodes a secreted peptide hormone and member of the epidermal growth factor (EGF) family of proteins. The encoded protein is a ligand of the epidermal growth factor receptor (EGFR) and the structurally related erb-b2 receptor tyrosine kinase 4 (ERBB4). The encoded protein may be involved in a wide range of biological processes including inflammation, wound healing, oocyte maturation, and cell proliferation. Additionally, the encoded protein may promote the progression of cancers of various human tissues.

Source: NCBI Gene 2069 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 24 total
• Druggable target: yes
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• MANE Select transcript: NM_001432

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3443
Approved symbol	EREG
Name	epiregulin
Location	4q13.3
Locus type	gene with protein product
Status	Approved
Aliases	ER
Ensembl gene	ENSG00000124882
Ensembl biotype	protein_coding
OMIM	602061
Entrez	2069

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 1 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000244869, ENST00000503689, ENST00000507603

RefSeq mRNA: 1 — MANE Select: NM_001432 NM_001432

CCDS: CCDS3564

Canonical transcript exons

ENST00000244869 — 5 exons

Exon	Start	End
ENSE00000851078	74381014	74381137
ENSE00000851079	74382645	74382794
ENSE00000851080	74384727	74388749
ENSE00001025095	74365145	74365375
ENSE00003558412	74379448	74379534

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 97.42.

FANTOM5 (CAGE): breadth broad, TPM avg 24.1879 / max 2147.5608, expressed in 654 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
48274	23.8463	645
48273	0.1806	81
48275	0.0970	45
48272	0.0640	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.42	gold quality
amniotic fluid	UBERON:0000173	90.08	gold quality
upper leg skin	UBERON:0004262	89.36	gold quality
tongue squamous epithelium	UBERON:0006919	88.95	silver quality
upper arm skin	UBERON:0004263	87.88	gold quality
penis	UBERON:0000989	87.55	gold quality
cervix epithelium	UBERON:0004801	85.67	gold quality
esophagus squamous epithelium	UBERON:0006920	85.58	gold quality
epithelium of esophagus	UBERON:0001976	84.49	gold quality
squamous epithelium	UBERON:0006914	83.26	gold quality
cervix squamous epithelium	UBERON:0006922	82.19	gold quality
oral cavity	UBERON:0000167	79.04	gold quality
bone marrow cell	CL:0002092	78.72	gold quality
esophagus mucosa	UBERON:0002469	78.52	gold quality
skin of leg	UBERON:0001511	78.35	gold quality
zone of skin	UBERON:0000014	78.26	gold quality
lower esophagus mucosa	UBERON:0035834	77.46	gold quality
skin of abdomen	UBERON:0001416	76.65	gold quality
gingiva	UBERON:0001828	76.21	gold quality
monocyte	CL:0000576	75.48	gold quality
gall bladder	UBERON:0002110	75.27	gold quality
skin of hip	UBERON:0001554	75.13	gold quality
mononuclear cell	CL:0000842	75.06	gold quality
mammalian vulva	UBERON:0000997	74.12	gold quality
rectum	UBERON:0001052	74.09	gold quality
leukocyte	CL:0000738	73.91	gold quality
right lung	UBERON:0002167	73.88	gold quality
mucosa of sigmoid colon	UBERON:0004993	73.74	gold quality
gingival epithelium	UBERON:0001949	73.21	gold quality
esophagus	UBERON:0001043	73.13	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-9841	yes	1380.53
E-MTAB-8495	yes	482.33
E-HCAD-1	yes	68.10
E-MTAB-8142	yes	41.07
E-MTAB-9467	yes	31.99
E-CURD-46	yes	21.11
E-CURD-88	yes	12.48
E-CURD-11	no	3273.66
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, BCL6, DNMT1, DNMT3B, EGR1, ETS1, FOXC1, KDM2A, MBD2, NFIL3, SP1, SP3, WT1

miRNA regulators (miRDB)

204 targeting EREG, 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-126-5P	100.00	72.71	3180
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4673	100.00	66.64	1490
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-190A-3P	100.00	80.35	5520
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-19A-3P	99.98	75.33	2762

Literature-anchored findings (GeneRIF, showing 40)

• Blockade of epiregulin reduced the growth of hTERT-BJ cells and colony formation of hTERT-transformed fibroblasts. Moreover, inhibition of epiregulin function in immortal hTERT-BJ cells triggered a senescence program. (PMID:12702554)
• Epiregulin might be a more important tumor growth regulator of malignant fibrous histiocytoma through autocrine or paracrine pathways, when compared with betacellulin. (PMID:15274392)
• upregulation of the epiregulin and amphiregulin expression is part of the signal transduction pathway which leads to ovulation and luteinization in the human ovary (PMID:15474502)
• findings demonstrated that PGE2 may mimic LH action at least in part by the activation of amphiregulin and epiregulin biosynthesis in human granulosa cells (PMID:16888076)
• epiregulin, COX2, and MMP1 and 2 collectively facilitate the assembly of new tumour blood vessels, the release of tumour cells into the circulation, and the breaching of lung capillaries by circulating tumour cells to seed pulmonary metastasis (PMID:17429393)
• 1st report of EREG expression in breast cancer (45.5% of breast cancers studied). It is preferentially expressed in breast tumors co-expressing HER2/HER4. (PMID:17962208)
• Epiregulin played an autocrine role in the proliferation of corneal epithelial cells presumably through cross-induction with other EGF family members. (PMID:18079685)
• hamartomatous TSC skin tumors are induced by paracrine factors released by two-hit cells in the dermis, and proliferation with mTOR activation of the overlying epidermis is an effect of epiregulin (PMID:18292222)
• Increased epiregulin is associated with oral squamous cell carcinomas (PMID:18497965)
• Epiregulin has a protective effect against apoptosis in the human corpus luteum. (PMID:18835871)
• The regulatory mechanism of epiregulin expression in Ki-ras-transformed 267B1 prostate epithelial cells was studied. (PMID:18948081)
• Epiregulin expression correlates with advanced disease, is EGFR dependent, and confers invasive properties on non-small cell lung cancer cells. (PMID:19138957)
• Data suggest that expression status of AR and EPI mRNAs might be evaluated as dynamic predictors of response in KRAS WT patients receiving any cetuximab-based therapy. (PMID:21161326)
• It is suggested that follow-up of the expression of Ep can serve as a reliable early indication of the development of ovarian cancer. (PMID:21769422)
• Epiregulin (EREG) variation is associated with susceptibility to tuberculosis. (PMID:22170233)
• EREG gene expression was low in 7 out of 11 gastric cancer cells and this downregulation was mediated by aberrant CpG methylation of the EREG promoter. (PMID:22508389)
• Data indicate that epiregulin (EREG) expression significantly correlated with KRAS expression or KRAS copy number in KRAS-mutant non-small-cell lung cancer (NSCLC) cell lines. (PMID:22964644)
• FBXL11 inhibited osteo/dentinogenic differentiation potential in MSC cells by associating with BCOR, then increasing histone K4/36 methylation in Epiregulin promoter to repress Epiregulin transcription. (PMID:23074094)
• EREG-AREG and NRG1, which are members of the epidermal growth factor (EGF) family, seem to modulate Bhecet’s Disease susceptibility through main effects and gene-gene interactions (PMID:23625463)
• Apical mistrafficking of EREG crystallizes an apical EGFR signaling complex that may be uncoupled from basolateral regulatory restraints leading to cell transformation. (PMID:23671122)
• keratinocyte hyperproliferation in cholesteatoma is promoted through overexpression of epiregulin by subepithelial fibroblasts via epithelial-mesenchymal interactions, which may play a crucial role in the pathogenesis of middle ear cholesteatoma (PMID:23826119)
• Depletion of Epiregulin with shRNA inhibited SCAP proliferation. (PMID:23829318)
• we did not find a correlation between the presence of a K-ras mutation and the presence of Epiregulin and Amphiregulin in colon cancer tissue. (PMID:23885463)
• Data suggest that EREG (epiregulin), AREG (amphiregulin), and BTC (betacellulin) induced prostaglandin E2 production by induction of COX-2 (prostaglandin-endoperoxide synthase 2) through MAP kinase signaling in granulosa cells. (PMID:24092824)
• EREG may contribute to glioma progression under the control of IRE1a. (PMID:24330607)
• In pre-treated K-ras wild-type status colorectal cancer, patients with high EREG gene expression appear to benefit more from cetuximab therapy compared with low expression. (PMID:24335920)
• These results suggested that EREG is one of the molecules involved in glioma malignancy (PMID:24470554)
• Epiregulin is a transcriptional target of TSC2 (tuberin). (PMID:24748662)
• Plasma HGF and EREG levels are associated with resistance to treatment with anti-EGFR antibodies in KRAS wild-type patients with metastatic colorectal cancer. (PMID:24800946)
• Epiregulin promotes the proliferation of liver progenitor cells and DNA synthesis by hepatocytes and is upregulated in the serum of patients with liver injury. (PMID:24812054)
• Data indicate that the effects of epiregulin (EREG) and V-ATPase (TCIRG1) single nucleotide polymorphism (SNP) on pulmonary tuberculosis susceptibility, to the extent that they exist, are dependent on gene-gene interactions in West African populations. (PMID:24898387)
• Patients homozygous for the minor allele A of EREG rs12641042 had a significantly higher 3-year survival rate than patients with allele C (HR 0.48; P=0.034), but significance was lost in multivariable analysis (PMID:25203737)
• Together, these studies lead to identification of a novel pathway involving EREG and MMP-1 that contributes to the formation of early stage breast cancer (PMID:26215578)
• three-dimensional structure of the EPR antibody (the 9E5(Fab) fragment) in the presence and absence of EPR (PMID:26627827)
• we showed that epidermal growth factor receptors (EGFR) were constitutively activated in metastatic lung subtypes of salivary adenoid cystic carcinoma cells, and that this activation was induced by autocrine expression of epiregulin (PMID:26958807)
• upregulation of EREG expression through promoter demethylation might be an important means of activating the EGFR pathway during the genesis of colorectal adenocarcinoma (CRC) and potentially other cancers. (PMID:27270421)
• EREG and AREG are strongly regulated by methylation, and their expression is associated with CIMP status and primary tumour site. (PMID:27272216)
• EREG and MMP-1 were found to be elevated in nasal polyp and uncinate tissues in patients with Chronic rhinosinusitis with nasal polyps. (PMID:28398769)
• Whole genome bisulfite sequencing revealed that integrin alpha6beta4 signaling promotes an overall hypomethylated state and site specific DNA demethylation of enhancer elements within the proximal promoters of AREG and EREG in pancreatic neoplasm cells as well as their expression. Additionally, base excision repair (BER) pathway is required to maintain the expression of AREG and EREG. (PMID:28733611)
• Study shows how the EGFR ligands epiregulin (EREG) and epigen (EPGN) stabilize different dimeric conformations of the EGFR extracellular region. Results reveal how responses to different EGFR ligands are defined by receptor dimerization strength and signaling dynamics. These findings have broad implications for understanding receptor tyrosine kinase (RTK) signaling specificity. (PMID:28988771)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ereg	ENSMUSG00000029377
rattus_norvegicus	Ereg	ENSRNOG00000002771

Paralogs (5): AREG (ENSG00000109321), HBEGF (ENSG00000113070), TGFA (ENSG00000163235), BTC (ENSG00000174808), EPGN (ENSG00000182585)

Protein

Protein identifiers

Proepiregulin — O14944 (reviewed: O14944)

All UniProt accessions (1): O14944

UniProt curated annotations — full annotation on UniProt →

Function. Ligand of the EGF receptor/EGFR and ERBB4. Stimulates EGFR and ERBB4 tyrosine phosphorylation. Contributes to inflammation, wound healing, tissue repair, and oocyte maturation by regulating angiogenesis and vascular remodeling and by stimulating cell proliferation.

Subunit / interactions. Interacts with EGFR and ERBB4.

Subcellular location. Secreted. Extracellular space Cell membrane.

Tissue specificity. In normal adults, expressed predominantly in the placenta and peripheral blood leukocytes. High levels were detected in carcinomas of the bladder, lung, kidney and colon.

RefSeq proteins (1): NP_001423* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain

UniProt features (22 total): strand 4, disulfide bond 3, chain 2, sequence variant 2, turn 2, propeptide 2, topological domain 2, signal peptide 1, helix 1, transmembrane region 1, domain 1, glycosylation site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
5E8D	X-RAY DIFFRACTION	2.5
7LEN	X-RAY DIFFRACTION	2.9
5WB7	X-RAY DIFFRACTION	2.94
7LFR	X-RAY DIFFRACTION	3.2
7LFS	X-RAY DIFFRACTION	3.5
8HGP	ELECTRON MICROSCOPY	4.53
1K36	SOLUTION NMR
1K37	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14944-F1	69.40	0.00

Antibody-complex structures (SAbDab): 1 — 5E8D

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (3): 68–81, 76–92, 94–103

Glycosylation sites (1): 47

Function

Pathways and Gene Ontology

Reactome pathways

28 pathways

ID	Pathway
R-HSA-1227986	Signaling by ERBB2
R-HSA-1236394	Signaling by ERBB4
R-HSA-1250196	SHC1 events in ERBB2 signaling
R-HSA-1250342	PI3K events in ERBB4 signaling
R-HSA-1250347	SHC1 events in ERBB4 signaling
R-HSA-1251985	Nuclear signaling by ERBB4
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-177929	Signaling by EGFR
R-HSA-179812	GRB2 events in EGFR signaling
R-HSA-180292	GAB1 signalosome
R-HSA-180336	SHC1 events in EGFR signaling
R-HSA-182971	EGFR downregulation
R-HSA-1963640	GRB2 events in ERBB2 signaling
R-HSA-1963642	PI3K events in ERBB2 signaling
R-HSA-212718	EGFR interacts with phospholipase C-gamma
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5638303	Inhibition of Signaling by Overexpressed EGFR
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6785631	ERBB2 Regulates Cell Motility
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8847993	ERBB2 Activates PTK6 Signaling
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-8863795	Downregulation of ERBB2 signaling
R-HSA-9009391	Extra-nuclear estrogen signaling
R-HSA-9634638	Estrogen-dependent nuclear events downstream of ESR-membrane signaling
R-HSA-9664565	Signaling by ERBB2 KD Mutants
R-HSA-9665686	Signaling by ERBB2 TMD/JMD mutants

MSigDB gene sets: 546 (showing top): GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, MODULE_92, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_GAB1_SIGNALOSOME, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_REGULATION_OF_NUCLEAR_DIVISION, MODULE_255, GOBP_RESPONSE_TO_PEPTIDE, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, NKX25_02, TGCACTT_MIR519C_MIR519B_MIR519A

GO Biological Process (38): angiogenesis (GO:0001525), ovarian cumulus expansion (GO:0001550), oocyte maturation (GO:0001556), positive regulation of cytokine production (GO:0001819), female meiotic nuclear division (GO:0007143), epidermal growth factor receptor signaling pathway (GO:0007173), cell-cell signaling (GO:0007267), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell population proliferation (GO:0008285), mRNA transcription (GO:0009299), anatomical structure morphogenesis (GO:0009653), animal organ morphogenesis (GO:0009887), cytokine-mediated signaling pathway (GO:0019221), keratinocyte differentiation (GO:0030216), ovulation (GO:0030728), positive regulation of interleukin-6 production (GO:0032755), ERBB2-EGFR signaling pathway (GO:0038134), ERBB2-ERBB4 signaling pathway (GO:0038135), ERBB4-ERBB4 signaling pathway (GO:0038138), wound healing (GO:0042060), positive regulation of phosphorylation (GO:0042327), luteinizing hormone signaling pathway (GO:0042700), response to peptide hormone (GO:0043434), keratinocyte proliferation (GO:0043616), positive regulation of innate immune response (GO:0045089), positive regulation of DNA replication (GO:0045740), positive regulation of mitotic nuclear division (GO:0045840), positive regulation of protein kinase activity (GO:0045860), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of fibroblast proliferation (GO:0048146), primary follicle stage (GO:0048160), positive regulation of smooth muscle cell proliferation (GO:0048661), negative regulation of epithelial cell proliferation (GO:0050680), negative regulation of smooth muscle cell differentiation (GO:0051151), positive regulation of cell division (GO:0051781), cell differentiation (GO:0030154), animal organ development (GO:0048513), positive regulation of multicellular organismal process (GO:0051240)

GO Molecular Function (5): epidermal growth factor receptor binding (GO:0005154), growth factor activity (GO:0008083), transmembrane receptor protein tyrosine kinase activator activity (GO:0030297), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), clathrin-coated endocytic vesicle membrane (GO:0030669), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Signaling by EGFR	5
Signaling by ERBB2	4
Signaling by Receptor Tyrosine Kinases	3
Signaling by ERBB4	3
Intracellular signaling by second messengers	1
PI3K/AKT Signaling in Cancer	1
Signaling by Overexpressed Wild-Type EGFR in Cancer	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
female gamete generation	2
cell population proliferation	2
regulation of cell population proliferation	2
ERBB2 signaling pathway	2
ERBB4 signaling pathway	2
signaling receptor activator activity	2
cellular anatomical structure	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
antral ovarian follicle growth	1
ovulation cycle process	1
fused antrum stage	1
developmental growth	1
developmental process involved in reproduction	1
cell maturation	1
oocyte development	1
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
meiotic cell cycle	1
meiotic nuclear division	1
ERBB signaling pathway	1
cell communication	1
signaling	1
positive regulation of cellular process	1
negative regulation of cellular process	1
DNA-templated transcription	1
mRNA metabolic process	1
developmental process	1
anatomical structure development	1
anatomical structure morphogenesis	1
animal organ development	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
epidermal cell differentiation	1
skin development	1
multicellular organismal reproductive process	1
positive regulation of cytokine production	1
interleukin-6 production	1

Protein interactions and networks

STRING

1469 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EREG	EGFR	P00533	996
EREG	AREG	P15514	995
EREG	ERBB4	Q15303	994
EREG	ERBB3	P21860	952
EREG	HBEGF	Q99075	928
EREG	EGF	P01133	893
EREG	TGFA	P01135	871
EREG	LHCGR	P22888	767
EREG	ANGPTL4	Q9BY76	761
EREG	BTC	P35070	716
EREG	MMP1	P03956	682
EREG	EPGN	Q6UW88	678
EREG	NRG2	O14511	630
EREG	ERBB2	P04626	617
EREG	MMP2	P08253	608

IntAct

22 interactions, top by confidence:

A	B	Type	Score
EGFR	EREG	psi-mi:“MI:0407”(direct interaction)	0.620
EREG	EGFR	psi-mi:“MI:0407”(direct interaction)	0.620
MS4A13	EREG	psi-mi:“MI:0915”(physical association)	0.560
EREG	MS4A13	psi-mi:“MI:0915”(physical association)	0.560
EREG	NINJ2	psi-mi:“MI:0915”(physical association)	0.560
EREG	OLFM4	psi-mi:“MI:0915”(physical association)	0.560
EREG	CXCL9	psi-mi:“MI:0915”(physical association)	0.560
EREG	RAB4A	psi-mi:“MI:0914”(association)	0.530
EGF	EREG	psi-mi:“MI:0915”(physical association)	0.400
NRG1	EREG	psi-mi:“MI:0915”(physical association)	0.400
CFTR	EREG	psi-mi:“MI:0915”(physical association)	0.370
EREG	LGALS1	psi-mi:“MI:0914”(association)	0.350
JAZF1	TNPO2	psi-mi:“MI:0914”(association)	0.350
NINJ2	EREG	psi-mi:“MI:0915”(physical association)	0.000
OLFM4	EREG	psi-mi:“MI:0915”(physical association)	0.000
CXCL9	EREG	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): RAB4A (Affinity Capture-MS), TMX4 (Affinity Capture-MS), LGALS1 (Affinity Capture-MS), RAB4A (Affinity Capture-MS), TMX4 (Affinity Capture-MS), LGALS1 (Affinity Capture-MS), EREG (Two-hybrid), CXCL9 (Two-hybrid), NINJ2 (Two-hybrid), MS4A13 (Two-hybrid), RAB4A (Affinity Capture-MS), TMX4 (Affinity Capture-MS), ERBB4 (Affinity Capture-Luminescence), EGFR (Affinity Capture-Luminescence), EREG (Proximity Label-MS)

ESM2 similar proteins: D5K8A9, E7FEC4, O14944, O70534, O75129, O76095, O77049, O88823, O88824, O95727, P04441, P22934, P25118, P30931, P35070, P43303, P80370, Q02092, Q05928, Q09163, Q13145, Q149L7, Q3SXY7, Q5BVD1, Q60943, Q61521, Q6P9G4, Q7T2L7, Q80Z10, Q80ZD7, Q80ZD8, Q8BGE4, Q8C351, Q8C5C9, Q8HYZ0, Q8IYV9, Q8JZL1, Q8NFM7, Q8WWG1, Q90375

Diamond homologs: A0A7H0DMZ6, O14944, O57166, P01132, P01136, P0DOP9, P0DOQ0, P0DSL4, P20494, P56974, Q00968, Q17QD6, Q5EG71, Q61521, Q6RZT5, Q776B5, Q86607, Q8V307, Q924X1, Q9J524, Q9JFH4, Q9QYM9, Q9UIK5, Q9Z0L5, P07522, P0DQX9, Q05928, Q06175, Q6PFE7, Q8IYR6, Q9QYV1, Q9W7C5, Q6UW88, A0A6G9KJM3, P01134, P01135, P15514, P24338, P31955, P35070

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
EREG	up-regulates	ERBB3	binding
EREG	up-regulates	ERBB4	binding
EREG	up-regulates	EGFR	binding
ADAM17	“up-regulates activity”	EREG	cleavage
EREG	up-regulates	“ErbB receptor family”	binding

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

842 predictions. Top by Δscore:

Variant	Effect	Δscore
4:74365374:GG:G	donor_gain	1.0000
4:74365375:GG:G	donor_gain	1.0000
4:74365376:G:GA	donor_loss	1.0000
4:74365376:G:GG	donor_gain	1.0000
4:74365377:T:A	donor_loss	1.0000
4:74381012:A:AG	acceptor_gain	1.0000
4:74381013:G:GA	acceptor_gain	1.0000
4:74381013:GTTCA:G	acceptor_gain	1.0000
4:74381133:TGCAG:T	donor_loss	1.0000
4:74381134:GCAGG:G	donor_loss	1.0000
4:74381135:CAGG:C	donor_loss	1.0000
4:74381136:AGG:A	donor_loss	1.0000
4:74381138:G:GC	donor_loss	1.0000
4:74381139:T:G	donor_loss	1.0000
4:74382633:A:AG	acceptor_gain	1.0000
4:74382634:T:G	acceptor_gain	1.0000
4:74382640:TTCAG:T	acceptor_loss	1.0000
4:74382641:TCAGG:T	acceptor_loss	1.0000
4:74382643:A:AT	acceptor_loss	1.0000
4:74382644:GGT:G	acceptor_gain	1.0000
4:74382791:GATG:G	donor_gain	1.0000
4:74382795:G:C	donor_loss	1.0000
4:74382795:G:GG	donor_gain	1.0000
4:74382796:T:A	donor_loss	1.0000
4:74384834:GGA:G	donor_gain	1.0000
4:74384835:G:T	donor_gain	1.0000
4:74365371:CCTGG:C	donor_gain	0.9900
4:74372497:C:T	donor_gain	0.9900
4:74381011:CA:C	acceptor_loss	0.9900
4:74381012:AGT:A	acceptor_loss	0.9900

AlphaMissense

1097 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:74382673:T:A	C103S	0.997
4:74382674:G:C	C103S	0.997
4:74381085:T:A	C76S	0.996
4:74381086:G:C	C76S	0.996
4:74381100:T:A	C81S	0.996
4:74381101:G:C	C81S	0.996
4:74382664:G:T	G100C	0.996
4:74382646:T:A	C94S	0.995
4:74382647:G:C	C94S	0.995
4:74381087:T:G	C76W	0.994
4:74381095:G:T	G79V	0.994
4:74381100:T:C	C81R	0.994
4:74382673:T:C	C103R	0.994
4:74382674:G:A	C103Y	0.994
4:74382674:G:T	C103F	0.994
4:74381095:G:A	G79E	0.993
4:74381133:T:A	C92S	0.993
4:74381134:G:C	C92S	0.993
4:74382675:T:G	C103W	0.993
4:74381085:T:C	C76R	0.992
4:74381102:C:G	C81W	0.992
4:74381135:C:G	C92W	0.992
4:74382665:G:T	G100V	0.992
4:74381061:T:A	C68S	0.991
4:74381062:G:C	C68S	0.991
4:74381086:G:A	C76Y	0.991
4:74381134:G:A	C92Y	0.991
4:74382646:T:C	C94R	0.990
4:74381061:T:C	C68R	0.988
4:74381085:T:G	C76G	0.988

dbSNP variants (sampled 300 via entrez): RS1000176130 (4:74380420 T>C,G), RS1000219567 (4:74374658 G>A), RS1000362457 (4:74385217 C>T), RS1000367802 (4:74363748 C>G,T), RS10004189 (4:74370626 T>A,G), RS1000447508 (4:74369000 T>C), RS1000632822 (4:74380575 G>A), RS1000841861 (4:74380006 A>G), RS1000991430 (4:74365119 G>C,T), RS1000997664 (4:74374104 T>C), RS1001096444 (4:74386526 G>C), RS1001146433 (4:74369196 C>A,T), RS1001189225 (4:74370547 C>A,T), RS1001510837 (4:74375381 C>G,T), RS10015759 (4:74372162 G>A)

Disease associations

OMIM: gene MIM:602061 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000281_12	Attention deficit hyperactivity disorder	8.000000e-06
GCST001585_33	Breast size	5.000000e-08
GCST001639_32	Metabolite levels	6.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4662939 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items; also 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
EREG EXPRESSION	Panitumumab	Colorectal Cancer	Sensitivity/Response	CIViC B	EID1021
EREG EXPRESSION	Cetuximab	Colorectal Cancer	Sensitivity/Response	CIViC B	EID789

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1017733	EREG		0.00	0
rs7687621	EREG		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects reaction, increases expression, decreases methylation	10
Tetrachlorodibenzodioxin	increases activity, affects expression, affects cotreatment, decreases reaction, increases expression (+2 more)	9
Particulate Matter	increases abundance, increases expression, increases secretion	6
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	5
Air Pollutants	increases expression, affects cotreatment, decreases expression, increases abundance	4
Tobacco Smoke Pollution	increases expression	4
Arsenic	affects expression, decreases expression, increases abundance, affects cotreatment	3
Estradiol	decreases expression, increases expression, affects cotreatment	3
Colforsin	increases expression	3
Smoke	increases expression, decreases expression, increases abundance	3
Cyclosporine	increases expression	3
Aflatoxin B1	affects expression, increases expression	3
bisphenol A	decreases expression, increases methylation	2
nimesulide	decreases reaction, increases expression	2
monomethylarsonous acid	decreases expression, increases methylation	2
Troglitazone	increases expression	2
Atrazine	affects cotreatment, decreases reaction, increases expression	2
Silicon Dioxide	increases expression	2
Valproic Acid	decreases expression, increases expression	2
Asbestos, Crocidolite	increases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	increases expression	1
methyleugenol	increases expression	1
triphenyl phosphate	increases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
propionaldehyde	increases expression	1
lead acetate	increases expression	1
pirprofen	increases expression	1
sodium arsenate	decreases expression, increases abundance	1
2-methyl-4-isothiazolin-3-one	increases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1W7	Abcam A-549 EREG KO	Cancer cell line	Male
CVCL_D2AK	Abcam HCT 116 EREG KO	Cancer cell line	Male
CVCL_D7PL	Ubigene A-549 EREG KO	Cancer cell line	Male
CVCL_E1EE	Ubigene U-87 MG EREG KO	Cancer cell line	Male

Clinical trials (associated diseases)

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