P14138 (EDN3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Endothelin-3
Short name=ET-3

Alternative name(s):
Preproendothelin-3
Short name=PPET3

Gene names

Name:

EDN3

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	238 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Endothelins are endothelium-derived vasoconstrictor peptides.
Subcellular location	Secreted.
Tissue specificity	Expressed in trophoblasts and placental stem villi vessels, but not in cultured placental smooth muscle cells. Ref.9
Involvement in disease	Defects in EDN3 are the cause of Hirschsprung disease type 4 (HSCR4) [MIM:613712]; also known as aganglionic megacolon (MGC). A genetic disorder of neural crest development characterized by the absence of intramural ganglion cells in the hindgut; often resulting in intestinal obstruction. Ref.14 Defects in EDN3 are a cause of congenital central hypoventilation syndrome (CCHS) [MIM:209880]; also known as congenital failure of autonomic control or Ondine curse. CCHS is a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. Ref.13 Defects in EDN3 are a cause of Waardenburg syndrome type 4 (WS4B) [MIM:613265]; also known as Waardenburg-Shah syndrome. WS4B is characterized by the association of Waardenburg features (depigmentation and deafness) and the absence of enteric ganglia in the distal part of the intestine (Hirschsprung disease). Ref.12 Ref.15 Ref.16
Sequence similarities	Belongs to the endothelin/sarafotoxin family.
Sequence caution	The sequence AAR16083.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
Cellular component	Secreted
Coding sequence diversity	Alternative splicing
Disease	Deafness Disease mutation Hirschsprung disease Waardenburg syndrome
Domain	Signal
Molecular function	Vasoactive Vasoconstrictor
PTM	Cleavage on pair of basic residues Disulfide bond
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	cell surface receptor linked signaling pathway Inferred from direct assay. Source: BHF-UCL inositol phosphate-mediated signaling Inferred from direct assay. Source: BHF-UCL neutrophil chemotaxis Inferred from direct assay. Source: BHF-UCL peptide hormone secretion Inferred from direct assay. Source: BHF-UCL positive regulation of MAP kinase activity Inferred from direct assay. Source: BHF-UCL positive regulation of heart rate Inferred from direct assay. Source: BHF-UCL positive regulation of hormone secretion Inferred from direct assay. Source: BHF-UCL positive regulation of leukocyte chemotaxis Inferred from direct assay. Source: BHF-UCL positive regulation of mitosis Inferred from direct assay. Source: BHF-UCL regulation of systemic arterial blood pressure by endothelin Inferred from direct assay. Source: BHF-UCL regulation of vasoconstriction Inferred from electronic annotation. Source: InterPro vein smooth muscle contraction Inferred from direct assay. Source: BHF-UCL
Cellular component	extracellular space Inferred from direct assay. Source: BHF-UCL soluble fraction Traceable author statement. Source: ProtInc
Molecular function	endothelin B receptor binding Inferred from physical interaction. Source: BHF-UCL hormone activity Inferred from direct assay. Source: BHF-UCL
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform Long (identifier: P14138-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform Short (identifier: P14138-2)

The sequence of this isoform differs from the canonical sequence as follows:
     181-196: SNSRTAEKTDKEEEGK → RQ

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 16	16	Potential
	Propeptide	17 – 94	78			PRO_0000008111
	Peptide	97 – 117	21	Endothelin-3		PRO_0000008112
	Propeptide	118 – 238	121			PRO_0000008113
Regions
	Region	159 – 173	15	Endothelin-like
Sites
	Site	117 – 118	2	Cleavage; by KEL
Amino acid modifications
	Disulfide bond	97 ↔ 111
	Disulfide bond	99 ↔ 107
Natural variations
	Alternative sequence	181 – 196	16	SNSRT…EEEGK → RQ in isoform Short.		VSP_001445
	Natural variant	17	1	A → T in HSCR4. Ref.4 Ref.14 Corresponds to variant rs11570255 [ dbSNP | Ensembl ].		VAR_009078
	Natural variant	127	1	Y → C in WS4B. Ref.16		VAR_015238
	Natural variant	159	1	C → F in WS4B. Ref.12		VAR_002353
	Natural variant	224	1	A → T in HSCR4. Ref.14 Corresponds to variant rs11570351 [ dbSNP | Ensembl ].		VAR_009079

Sequences

	Sequence		Length	Mass (Da)
	Isoform Long [UniParc]. Last modified January 1, 1990. Version 1. Checksum: 7D7E90BC7DE37273	FASTA	238	25,454
	10 20 30 40 50 60 MEPGLWLLFG LTVTSAAGFV PCSQSGDAGR RGVSQAPTAA RSEGDCEETV AGPGEETVAG 70 80 90 100 110 120 PGEGTVAPTA LQGPSPGSPG QEQAAEGAPE HHRSRRCTCF TYKDKECVYY CHLDIIWINT 130 140 150 160 170 180 PEQTVPYGLS NYRGSFRGKR SAGPLPGNLQ LSHRPHLRCA CVGRYDKACL HFCTQTLDVS 190 200 210 220 230 SNSRTAEKTD KEEEGKVEVK DQQSKQALDL HHPKLMPGSG LALAPSTCPR CLFQEGAP
	Isoform Short [UniParc]. Checksum: 9A2295791A408FF3	FASTA	224	23,948
	10 20 30 40 50 60 MEPGLWLLFG LTVTSAAGFV PCSQSGDAGR RGVSQAPTAA RSEGDCEETV AGPGEETVAG 70 80 90 100 110 120 PGEGTVAPTA LQGPSPGSPG QEQAAEGAPE HHRSRRCTCF TYKDKECVYY CHLDIIWINT 130 140 150 160 170 180 PEQTVPYGLS NYRGSFRGKR SAGPLPGNLQ LSHRPHLRCA CVGRYDKACL HFCTQTLDVS 190 200 210 220 RQVEVKDQQS KQALDLHHPK LMPGSGLALA PSTCPRCLFQ EGAP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"cDNA cloning and chromosomal assignment of the gene encoding endothelin 3." Bloch K.D., Eddy R.L., Shows T.B., Quertermous T. J. Biol. Chem. 264:18156-18161(1989) [PubMed: 2509452] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"One of the endothelin gene family, endothelin 3 gene, is expressed in the placenta." Onda H., Ohkubo S., Ogi K., Kosaka T., Kimura C., Matsumoto H., Suzuki N., Fujino M. FEBS Lett. 261:327-330(1990) [PubMed: 2178974] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT). Tissue: Placenta.
[3]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG).
[4]	NIEHS SNPs program Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT THR-17.
[5]	"The DNA sequence and comparative analysis of human chromosome 20." Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J. Nature 414:865-871(2001) [PubMed: 11780052] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG). Tissue: Muscle.
[8]	"Proteolytic processing of big endothelin-3 by the kell blood group protein." Lee S., Lin M., Mele A., Cao Y., Farmar J., Russo D., Redman C. Blood 94:1440-1450(1999) [PubMed: 10438732] [Abstract] Cited for: PARTIAL PROTEIN SEQUENCE, CLEAVAGE BY KELL, MASS SPECTROMETRY.
[9]	"Endothelin-1 and ETA receptor expression in vascular smooth muscle cells from human placenta: a new ETA receptor messenger ribonucleic acid is generated by alternative splicing of exon 3." Bourgeois C., Robert B., Rebourcet R., Mondon F., Mignot T.-M., Duc-Goiran P., Ferre F. J. Clin. Endocrinol. Metab. 82:3116-3123(1997) [PubMed: 9284755] [Abstract] Cited for: TISSUE SPECIFICITY.
[10]	"Solution structure of endothelin-3 determined using NMR spectroscopy." Mills R.G., O'Donoghue S.I., Smith R., King G.F. Biochemistry 31:5640-5645(1992) [PubMed: 1610811] [Abstract] Cited for: STRUCTURE BY NMR OF ET-3.
[11]	"Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype." Hofstra R.M.W., Osinga J., Buys C.H.C.M. Eur. J. Hum. Genet. 5:180-185(1997) [PubMed: 9359036] [Abstract] Cited for: REVIEW ON VARIANTS.
[12]	"A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome)." Hofstra R.M.W., Tan-Sindhunata G., Wu Y., Kamsteeg E.-J., Stulp R.P., van Ravenswaaij-Arts C., Majoor-Krakauer D., Angrist M., Chakravarti A., Meijers C., Buys C.H.C.M. Nat. Genet. 12:445-447(1996) [PubMed: 8630503] [Abstract] Cited for: VARIANT WS4B PHE-159.
[13]	"Endothelin-3 frameshift mutation in congenital central hypoventilation syndrome." Bolk S., Angrist M., Xie J., Yanagisawa M., Silvestri J.M., Weese-Mayer D.E., Chakravarti A. Nat. Genet. 13:395-396(1996) [PubMed: 8696331] [Abstract] Cited for: INVOLVEMENT IN CCHS.
[14]	"Endothelin-3 gene mutations in isolated and syndromic Hirschsprung disease." Bidaud C., Salomon R., Van Camp G., Pelet A., Attie T., Eng C., Bonduelle M., Amiel J., Nihoul-Fekete C., Willems P.J., Munnich A., Lyonnet S. Eur. J. Hum. Genet. 5:247-251(1997) [PubMed: 9359047] [Abstract] Cited for: VARIANTS HSCR4 THR-17 AND THR-224.
[15]	"A heterozygous endothelin 3 mutation in Waardenburg-Hirschsprung disease: is there a dosage effect of EDN3/EDNRB gene mutations on neurocristopathy phenotypes?" Pingault V., Bondurand N., Lemort N., Sancandi M., Ceccherini I., Hugot J.P., Jouk P.S., Goossens M. J. Med. Genet. 38:205-209(2001) [PubMed: 11303518] [Abstract] Cited for: INVOLVEMENT IN WS4B.
[16]	"SOX10 mutations in chronic intestinal pseudo-obstruction suggest a complex physiopathological mechanism." Pingault V., Girard M., Bondurand N., Dorkins H., Van Maldergem L., Mowat D., Shimotake T., Verma I., Baumann C., Goossens M. Hum. Genet. 111:198-206(2002) [PubMed: 12189494] [Abstract] Cited for: VARIANT WS4B CYS-127.
+	Additional computationally mapped references.

Web resources

GeneReviews

NIEHS-SNPs

Cross-references

Sequence databases
EMBL GenBank DDBJ	J05081 mRNA. Translation: AAA52405.1. X52001 mRNA. Translation: CAA36252.1. BT007085 mRNA. Translation: AAP35748.1. AY444503 Genomic DNA. Translation: AAR16083.1. Sequence problems. AL035250 Genomic DNA. Translation: CAB65996.1. AL035250 Genomic DNA. Translation: CAB65998.1. CH471077 Genomic DNA. Translation: EAW75434.1. CH471077 Genomic DNA. Translation: EAW75437.1. BC008876 mRNA. Translation: AAH08876.1.
IPI	IPI00025365. IPI00220210.
PIR	A34378.
RefSeq	NP_000105.1. NM_000114.2. NP_996915.1. NM_207032.1. NP_996916.1. NM_207033.1. NP_996917.1. NM_207034.1.
UniGene	Hs.1408.
3D structure databases
ProteinModelPortal	P14138.
ModBase	Search...
Protein-protein interaction databases
STRING	P14138.
Polymorphism databases
DMDM	119618.
Proteomic databases
PRIDE	P14138.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000337938; ENSP00000337128; ENSG00000124205. ENST00000371028; ENSP00000360067; ENSG00000124205.
GeneID	1908.
KEGG	hsa:1908.
UCSC	uc002yap.1. human. uc002yas.1. human.
Organism-specific databases
CTD	1908.
GeneCards	GC20P057875.
H-InvDB	HIX0015962.
HGNC	HGNC:3178. EDN3.
MIM	131242. gene. 209880. phenotype. 613265. phenotype. 613712. phenotype.
neXtProt	NX_P14138.
Orphanet	388. Hirschsprung disease. 661. Ondine syndrome. 897. Waardenburg-Shah syndrome.
PharmGKB	PA27616.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG16247.
HOGENOM	HBG126091.
HOVERGEN	HBG051442.
InParanoid	P14138.
OMA	QDSACLH.
OrthoDB	EOG4Z62PG.
PhylomeDB	P14138.
Enzyme and pathway databases
Pathway_Interaction_DB	endothelinpathway. Endothelins.
Reactome	REACT_111102. Signal Transduction.
Gene expression databases
ArrayExpress	P14138.
Bgee	P14138.
CleanEx	HS_EDN3.
Genevestigator	P14138.
GermOnline	ENSG00000124205. Homo sapiens.
Family and domain databases
InterPro	IPR020475. Bibrotoxin/Sarafotoxin-D. IPR019764. Endothelin_toxin_CS. IPR001928. Endothln-like_toxin. [Graphical view]
KO	K05227.
Pfam	PF00322. Endothelin. 1 hit. [Graphical view]
PRINTS	PR00365. ENDOTHELIN.
SMART	SM00272. END. 2 hits. [Graphical view]
PROSITE	PS00270. ENDOTHELIN. 2 hits. [Graphical view]
ProtoNet	Search...
Other
NextBio	7765.
PMAP-CutDB	P14138.
SOURCE	Search...

Entry information

Entry name

EDN3_HUMAN

Accession

Primary (citable) accession number: P14138
Secondary accession number(s): E1P5I5, Q03229

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 1, 1990
Last sequence update:	January 1, 1990
Last modified:	January 25, 2012
This is version 129 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.