EDN2

Summary

EDN2 (endothelin 2, HGNC:3177) is a protein-coding gene on chromosome 1p34.2, encoding Endothelin-2 (P20800). Endothelins are endothelium-derived vasoconstrictor peptides.

This gene encodes a member of the endothelin protein family of secretory vasoconstrictive peptides. The preproprotein is processed to a short mature form which functions as a ligand for the endothelin receptors that initiate intracellular signaling events. This gene product is involved in a wide range of biological processes, such as hypertension and ovulation. Altered expression of this gene is implicated in tumorigenesis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1907 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 30 total
• MANE Select transcript: NM_001956

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3177
Approved symbol	EDN2
Name	endothelin 2
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	ET2
Ensembl gene	ENSG00000127129
Ensembl biotype	protein_coding
OMIM	131241
Entrez	1907

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000372587, ENST00000460255, ENST00000467046, ENST00000467872, ENST00000490783, ENST00000877256, ENST00000877257, ENST00000877258, ENST00000877259

RefSeq mRNA: 2 — MANE Select: NM_001956 NM_001302269, NM_001956

CCDS: CCDS462

Canonical transcript exons

ENST00000372587 — 5 exons

Exon	Start	End
ENSE00000870139	41484047	41484203
ENSE00001458158	41478775	41479502
ENSE00001827727	41484538	41484683
ENSE00003490806	41482466	41482588
ENSE00003547805	41481095	41481193

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 95.16.

FANTOM5 (CAGE): breadth broad, TPM avg 1.2625 / max 113.9820, expressed in 303 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11954	1.2625	303

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	95.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.87	gold quality
buccal mucosa cell	CL:0002336	81.41	gold quality
small intestine Peyer’s patch	UBERON:0003454	79.65	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	79.33	gold quality
skin of abdomen	UBERON:0001416	78.54	gold quality
esophagus mucosa	UBERON:0002469	77.61	gold quality
vagina	UBERON:0000996	77.55	gold quality
endometrium epithelium	UBERON:0004811	76.95	gold quality
small intestine	UBERON:0002108	76.48	gold quality
mucosa of transverse colon	UBERON:0004991	76.03	gold quality
hair follicle	UBERON:0002073	75.89	silver quality
skin of leg	UBERON:0001511	75.55	gold quality
metanephros cortex	UBERON:0010533	73.90	gold quality
zone of skin	UBERON:0000014	73.32	gold quality
right uterine tube	UBERON:0001302	71.70	gold quality
esophagus squamous epithelium	UBERON:0006920	69.97	silver quality
pancreatic ductal cell	CL:0002079	69.92	silver quality
epithelium of esophagus	UBERON:0001976	69.80	silver quality
cervix squamous epithelium	UBERON:0006922	69.80	gold quality
minor salivary gland	UBERON:0001830	69.76	gold quality
frontal pole	UBERON:0002795	69.76	gold quality
trachea	UBERON:0003126	69.70	gold quality
paraflocculus	UBERON:0005351	69.47	gold quality
middle frontal gyrus	UBERON:0002702	69.21	gold quality
mouth mucosa	UBERON:0003729	68.99	gold quality
esophagus	UBERON:0001043	68.21	gold quality
duodenum	UBERON:0002114	68.05	gold quality
rectum	UBERON:0001052	66.38	gold quality
saliva-secreting gland	UBERON:0001044	66.36	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

34 targeting EDN2, 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-5692A	100.00	74.40	6850
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-5584-3P	99.23	68.79	1351
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-6804-5P	98.39	65.77	1084
HSA-MIR-1304-3P	98.29	66.44	1207
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-6772-3P	97.04	65.89	784
HSA-MIR-4448	97.04	66.22	752
HSA-MIR-3194-5P	96.80	64.90	1027

Literature-anchored findings (GeneRIF, showing 13)

• Endothelin-2 is a macrophage chemoattractant. ET-2 expression by tumors may modulate the behavior of macrophages such that activated cells accumulate in areas of hypoxia. (PMID:12207323)
• Endothelin-2 is a hypoxia-induced autocrine survival factor for breast tumor cells (PMID:12516960)
• The EDN2 A985 allele, which is considered to be protective in cardiovascular disease, may be a risk factor for atrial fibrillation in patients with hypertrophic cardiomyopathy. (PMID:18037749)
• EDN3, in contrast to EDN1 and EDN2, may act as natural tumour suppressor in the human mammary gland (PMID:19527488)
• although endothelin 2 does not appear to be an independent prognostic marker, there is evidence of a putative role in clear cell renal cell carcinoma progression (PMID:22047647)
• In granulosa lutein cells from women with polycystic ovary syndrome, endothelin-2 mRNA was reduced as compared with normally ovulating women (PMID:22727793)
• Studies revealed hypermethylation of EDN2 and EDN3 genes in human primary colon cancers and in a panel of human colon cancer cell lines. Epigenetic inactivation of ET-2 and ET-3 occurs frequently in both rat and human colon cancers. (PMID:22865632)
• plasma levels of big ET-2, and big ET-3 are markedly increased in patients with end stage renal disease on hemodialysis (PMID:22921304)
• Endothelin 2 and endothelin receptor type B may be a regenerative pathway for central nervous system myelination and remyelination. (PMID:23518706)
• Overexpression of Edn2 in the mouse retina causes an excess of tip cells and inhibits vascular growth. Overexpression of Edn2 in the brain and skin had no effect, but vascular development was inhibited in midgestation mouse embryos. (PMID:24043815)
• EDN2 expression in left internal mammary arteries depends on tissue harvesting technique. (PMID:24647318)
• Reduced Endothelin-2 and Hypoxic Signaling Pathways in Granulosa-Lutein Cells of PCOS Women. (PMID:34360981)
• The loss of endothelin-2 exhibits an anticancer effect in A549 human lung adenocarcinoma cell line. (PMID:35679618)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	edn2	ENSDARG00000070578
mus_musculus	Edn2	ENSMUSG00000028635
rattus_norvegicus	Edn2	ENSRNOG00000009390

Paralogs (2): EDN1 (ENSG00000078401), EDN3 (ENSG00000124205)

Protein

Protein identifiers

Endothelin-2 — P20800 (reviewed: P20800)

Alternative names: Preproendothelin-2

All UniProt accessions (1): P20800

UniProt curated annotations — full annotation on UniProt →

Function. Endothelins are endothelium-derived vasoconstrictor peptides.

Subcellular location. Secreted.

Tissue specificity. Expressed in lung, but not in placental stem villi vessels or cultured placental villi smooth muscle cells.

Similarity. Belongs to the endothelin/sarafotoxin family.

RefSeq proteins (2): NP_001289198, NP_001947* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001928	Endothln-like_toxin	Domain
IPR019764	Endothelin_toxin_CS	Conserved_site
IPR020475	Endothelin	Family

Pfam: PF00322

UniProt features (12 total): propeptide 2, sequence variant 2, region of interest 2, disulfide bond 2, signal peptide 1, peptide 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20800-F1	64.58	0.07

Functional residue map

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

Catalytic / active sites (1): 69–70 (cleavage; by kel)

Disulfide bonds (2): 49–63, 51–59

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 259 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, MODULE_92, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_MYELOID_LEUKOCYTE_MIGRATION, HARRIS_HYPOXIA, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOBP_RESPONSE_TO_PEPTIDE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GOBP_GROWTH, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CONTRACTION

GO Biological Process (31): angiogenesis (GO:0001525), temperature homeostasis (GO:0001659), positive regulation of leukocyte chemotaxis (GO:0002690), hormonal regulation of the force of heart contraction (GO:0003058), positive regulation of the force of heart contraction by chemical signal (GO:0003099), regulation of systemic arterial blood pressure by endothelin (GO:0003100), intracellular calcium ion homeostasis (GO:0006874), cell surface receptor signaling pathway (GO:0007166), positive regulation of cell population proliferation (GO:0008284), cell tip growth (GO:0009932), positive regulation of heart rate (GO:0010460), artery smooth muscle contraction (GO:0014824), vein smooth muscle contraction (GO:0014826), cytokine-mediated signaling pathway (GO:0019221), regulation of vasoconstriction (GO:0019229), neutrophil chemotaxis (GO:0030593), positive regulation of prostaglandin biosynthetic process (GO:0031394), macrophage activation (GO:0042116), vasoconstriction (GO:0042310), endothelial cell migration (GO:0043542), positive regulation of smooth muscle contraction (GO:0045987), macrophage chemotaxis (GO:0048246), lung alveolus development (GO:0048286), axon extension (GO:0048675), positive regulation of calcium-mediated signaling (GO:0050850), endothelin receptor signaling pathway (GO:0086100), energy homeostasis (GO:0097009), vasculature development (GO:0001944), smooth muscle contraction (GO:0006939), neuron projection development (GO:0031175), blood vessel diameter maintenance (GO:0097746)

GO Molecular Function (2): hormone activity (GO:0005179), endothelin B receptor binding (GO:0031708)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of the force of heart contraction by chemical signal	2
positive regulation of heart contraction	2
vascular associated smooth muscle contraction	2
blood vessel diameter maintenance	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
multicellular organismal-level homeostasis	1
positive regulation of leukocyte migration	1
regulation of leukocyte chemotaxis	1
leukocyte chemotaxis	1
positive regulation of chemotaxis	1
regulation of systemic arterial blood pressure by hormone	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
signal transduction	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
unidimensional cell growth	1
regulation of heart rate	1
tonic smooth muscle contraction	1
phasic smooth muscle contraction	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
vasoconstriction	1
regulation of blood circulation	1
granulocyte chemotaxis	1
neutrophil migration	1
prostaglandin biosynthetic process	1
regulation of prostaglandin biosynthetic process	1
positive regulation of unsaturated fatty acid biosynthetic process	1
myeloid leukocyte activation	1
cell migration	1
receptor ligand activity	1
bombesin receptor binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

748 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EDN2	EDNRA	P25101	999
EDN2	EDNRB	P24530	998
EDN2	ECE1	P42892	847
EDN2	ECE2	P0DPD6	821
EDN2	EEF1AKMT4-ECE2	P0DPD8	749
EDN2	AGT	P01019	587
EDN2	KEL	P23276	560
EDN2	MCHR1	Q99705	497
EDN2	STOML3	Q8TAV4	497
EDN2	EDN1	P05305	496
EDN2	LCN2	P30150	453
EDN2	KITLG	P21583	444
EDN2	CCR3	P51677	443
EDN2	TRPV1	Q8NER1	439
EDN2	AGTR1	P30556	433

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A1B0GVZ6, A0A1W2PR82, A5A752, A5PKC7, A6NDZ8, A6NE82, A6NJ08, A6NJI1, A6QP24, A8MTW9, A8MXV6, A8MYA2, O94850, O95196, O95873, P0C7X2, P13207, P14138, P19998, P20800, P22389, P23943, P29560, P48299, P50617, Q08648, Q3UN58, Q5NRP8, Q5NRQ0, Q5U2P6, Q5VZ46, Q6MG51, Q6P1B3, Q6PDA7, Q71M36, Q765Z4, Q765Z5, Q80TS7, Q867A9, Q867D0

Diamond homologs: A5A752, P05305, P09558, P12064, P13206, P13207, P13211, P14138, P17322, P19998, P20800, P22387, P22388, P22389, P23943, P29560, P48299, P80163, P97740, Q5NRP8, Q5NRP9, Q5NRQ0, Q5NRQ1, Q765Z4, Q765Z5, Q867A9, Q867D0, Q8MJW9, Q9BG76, P0DJK0, Q28469, P0DJK1, P13208, Q28470, Q09GK2, Q6RY98

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	25
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

725 predictions. Top by Δscore:

Variant	Effect	Δscore
1:41484045:A:AC	donor_gain	1.0000
1:41484046:C:CC	donor_gain	1.0000
1:41484046:CT:C	donor_gain	1.0000
1:41484202:CC:C	acceptor_gain	1.0000
1:41484203:CC:C	acceptor_gain	1.0000
1:41482585:CTGT:C	acceptor_gain	0.9900
1:41482589:C:CC	acceptor_gain	0.9900
1:41482614:G:GC	acceptor_gain	0.9900
1:41482617:G:C	acceptor_gain	0.9900
1:41482617:G:GC	acceptor_gain	0.9900
1:41482619:G:C	acceptor_gain	0.9900
1:41482619:G:GC	acceptor_gain	0.9900
1:41482624:G:C	acceptor_gain	0.9900
1:41482624:G:GC	acceptor_gain	0.9900
1:41484043:TCA:T	donor_loss	0.9900
1:41484044:CA:C	donor_loss	0.9900
1:41484045:ACT:A	donor_gain	0.9900
1:41484046:C:CG	donor_loss	0.9900
1:41484046:CTC:C	donor_gain	0.9900
1:41484049:A:AC	donor_gain	0.9900
1:41484199:CTTCC:C	acceptor_gain	0.9900
1:41484200:TTCC:T	acceptor_gain	0.9900
1:41484201:TCC:T	acceptor_gain	0.9900
1:41484202:CCC:C	acceptor_gain	0.9900
1:41484204:C:CC	acceptor_gain	0.9900
1:41484204:CTG:C	acceptor_loss	0.9900
1:41484205:T:A	acceptor_loss	0.9900
1:41484208:A:C	acceptor_gain	0.9900
1:41484211:C:CT	acceptor_gain	0.9900
1:41484213:C:CT	acceptor_gain	0.9900

AlphaMissense

1133 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:41484061:C:A	W69C	0.997
1:41484061:C:G	W69C	0.997
1:41484082:G:C	F62L	0.995
1:41484082:G:T	F62L	0.995
1:41484084:A:G	F62L	0.995
1:41484080:C:G	C63S	0.994
1:41484081:A:T	C63S	0.994
1:41484080:C:T	C63Y	0.993
1:41484083:A:C	F62C	0.992
1:41484092:C:G	C59S	0.991
1:41484093:A:T	C59S	0.991
1:41484078:G:C	H64D	0.990
1:41484080:C:A	C63F	0.987
1:41482483:G:C	F109L	0.986
1:41482483:G:T	F109L	0.986
1:41482485:A:G	F109L	0.986
1:41484079:G:C	C63W	0.986
1:41484122:C:G	C49S	0.985
1:41484123:A:T	C49S	0.985
1:41484081:A:G	C63R	0.984
1:41484116:C:G	C51S	0.984
1:41484116:C:T	C51Y	0.984
1:41484117:A:T	C51S	0.984
1:41482484:A:C	F109C	0.980
1:41484086:T:C	Y61C	0.980
1:41484092:C:T	C59Y	0.980
1:41484068:A:G	I67T	0.979
1:41484076:G:C	H64Q	0.979
1:41484076:G:T	H64Q	0.979
1:41484093:A:G	C59R	0.979

dbSNP variants (sampled 300 via entrez): RS1000431197 (1:41484320 G>A), RS1000500995 (1:41482259 A>T), RS1000934191 (1:41480277 C>T), RS1001343865 (1:41482963 G>C), RS1001602905 (1:41484640 G>T), RS1001724505 (1:41479403 A>G), RS1002521126 (1:41480394 C>A), RS1002949321 (1:41486075 G>T), RS1002999657 (1:41485761 G>A), RS1003070180 (1:41485417 G>A,T), RS1003976968 (1:41481543 T>TA), RS1004407433 (1:41483678 C>T), RS1004524652 (1:41479839 C>G), RS1004634881 (1:41485439 C>T), RS1005380419 (1:41484689 C>T)

Disease associations

OMIM: gene MIM:131241 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003542_104	Night sleep phenotypes	9.000000e-07
GCST004750_95	Squamous cell lung carcinoma	2.000000e-06
GCST008755_3	Phenylephrine infusion rate during anesthesia	6.000000e-07
GCST009391_889	Metabolite levels	2.000000e-06
GCST010320_124	PR interval	3.000000e-13
GCST010321_173	PR interval	2.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010440	triacylglycerol 58:6 measurement
EFO:0004462	PR interval

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects expression, affects cotreatment, decreases expression, increases expression	4
sodium arsenite	decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases expression	3
Ethinyl Estradiol	affects expression, decreases expression	3
Cadmium Chloride	decreases expression, increases expression	3
Resveratrol	affects cotreatment, decreases expression, increases expression	2
Genistein	decreases expression	2
aristolochic acid I	increases expression	1
tungsten carbide	affects binding, increases expression	1
propionaldehyde	increases expression	1
bisphenol A	affects expression	1
lead acetate	decreases expression	1
afimoxifene	affects reaction, increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	increases expression	1
nickel chloride	increases expression	1
cupric chloride	decreases expression	1
hydroquinone	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
pentanal	increases expression	1
cobalt oxide	increases expression	1
tamibarotene	increases expression	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases phosphorylation	1
tricetin	decreases expression	1
abrine	increases expression	1
Acetaminophen	decreases expression	1
Gemcitabine	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Aldehydes	increases expression	1
Arsenic	increases expression	1

Clinical trials (associated diseases)

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