P56705 (WNT4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Protein Wnt-4

Gene names

Name:	WNT4
ORF Names:	UNQ426/PRO864

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	351 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	Ligand for members of the frizzled family of seven transmembrane receptors. Probable developmental protein. May be a signaling molecule which affects the development of discrete regions of tissues. Is likely to signal over only few cell diameters By similarity. Overexpression may be associated with abnormal proliferation in human breast tissue.
Subunit structure	Interacts with PORCN By similarity.
Subcellular location	Secreted › extracellular space › extracellular matrix.
Involvement in disease	Defects in WNT4 are a cause of Rokitansky-Kuster-Hauser syndrome (RKH syndrome) [MIM:277000]; also called Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH syndrome or MRKH anomaly). RKH syndrome is characterized by utero-vaginal atresia in otherwise phenotypically normal female with a normal 46,XX karyotype. Anomalies of the genital tract range from upper vaginal atresia to total Muellerian agenesis with urinary tract abnormalities. It has an incidence of approximately 1 in 5'000 newborn girls. Defects in WNT4 are the cause of female sex reversal with dysgenesis of kidneys, adrenals, and lungs (SERKAL) [MIM:611812]; also known as SERKAL syndrome. Ref.12 Defects in WNT4 are the cause of Muellerian aplasia (MULLAPL) [MIM:158330].
Sequence similarities	Belongs to the Wnt family.

Ontologies

Keywords
Biological process	Wnt signaling pathway
Cellular component	Extracellular matrix Secreted
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Signal
Molecular function	Developmental protein
PTM	Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	adrenal gland development Inferred from expression pattern. Source: UniProtKB androgen biosynthetic process Inferred from direct assay Ref.11. Source: UniProtKB anterior/posterior pattern specification Inferred from Biological aspect of Ancestor. Source: RefGenome axis specification Inferred from Biological aspect of Ancestor. Source: RefGenome branching involved in ureteric bud morphogenesis Inferred from Biological aspect of Ancestor. Source: RefGenome canonical Wnt receptor signaling pathway Inferred from direct assay Ref.10. Source: UniProtKB cellular response to transforming growth factor beta stimulus Inferred from expression pattern. Source: UniProtKB dermatome development Inferred from direct assay. Source: BHF-UCL endoderm development Inferred from Biological aspect of Ancestor. Source: RefGenome epithelial to mesenchymal transition Inferred from expression pattern. Source: UniProtKB establishment of protein localization in plasma membrane Inferred from direct assay. Source: UniProtKB female gonad development Inferred from sequence or structural similarity. Source: UniProtKB female sex determination Inferred from mutant phenotype Ref.2. Source: UniProtKB liver development Inferred from expression pattern. Source: UniProtKB male gonad development Inferred from mutant phenotype Ref.2. Source: UniProtKB mesonephric tubule development Inferred from Biological aspect of Ancestor. Source: RefGenome metanephric mesenchymal cell differentiation Non-traceable author statement. Source: UniProtKB negative regulation of canonical Wnt receptor signaling pathway Inferred from direct assay. Source: UniProtKB negative regulation of fibroblast growth factor receptor signaling pathway Inferred from Biological aspect of Ancestor. Source: RefGenome negative regulation of male gonad development Inferred from mutant phenotype Ref.2. Source: UniProtKB negative regulation of testicular blood vessel morphogenesis Inferred from mutant phenotype. Source: UniProtKB negative regulation of testosterone biosynthetic process Inferred from mutant phenotype. Source: UniProtKB negative regulation of transcription, DNA-dependent Inferred from mutant phenotype. Source: UniProtKB oocyte development Inferred from Biological aspect of Ancestor. Source: RefGenome paramesonephric duct development Inferred from mutant phenotype Ref.13. Source: UniProtKB positive regulation of aldosterone biosynthetic process Inferred from direct assay. Source: UniProtKB positive regulation of bone mineralization Inferred from direct assay. Source: BHF-UCL positive regulation of canonical Wnt receptor signaling pathway Inferred from direct assay Ref.11Ref.13. Source: UniProtKB positive regulation of collagen biosynthetic process Inferred from direct assay. Source: BHF-UCL positive regulation of cortisol biosynthetic process Inferred from direct assay. Source: UniProtKB positive regulation of osteoblast differentiation Inferred from direct assay. Source: BHF-UCL positive regulation of transcription, DNA-dependent Inferred from direct assay Ref.11Ref.13. Source: UniProtKB protein palmitoylation Inferred from direct assay Ref.10. Source: UniProtKB renal vesicle formation Inferred from Biological aspect of Ancestor. Source: RefGenome smooth muscle cell differentiation Inferred from Biological aspect of Ancestor. Source: RefGenome somatotropin secreting cell differentiation Inferred from Biological aspect of Ancestor. Source: RefGenome tertiary branching involved in mammary gland duct morphogenesis Inferred from Biological aspect of Ancestor. Source: RefGenome thyroid-stimulating hormone-secreting cell differentiation Inferred from Biological aspect of Ancestor. Source: RefGenome
Cellular component	Golgi apparatus Inferred from Biological aspect of Ancestor. Source: RefGenome cell surface Inferred from sequence or structural similarity. Source: UniProtKB extracellular space Inferred from direct assay Ref.11. Source: UniProtKB plasma membrane Inferred from Biological aspect of Ancestor. Source: RefGenome proteinaceous extracellular matrix Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	extracellular matrix structural constituent Non-traceable author statement. Source: UniProtKB transcription corepressor activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 22	22	Potential
	Chain	23 – 351	329	Protein Wnt-4		PRO_0000041421
Amino acid modifications
	Glycosylation	88	1	N-linked (GlcNAc...) Potential
	Glycosylation	297	1	N-linked (GlcNAc...) Potential
Natural variations
	Natural variant	12	1	L → P in RKH syndrome; unable to suppress steroidogenesis in an ovarian adenocarcinoma cell line resulting in increased androgen production. Ref.13		VAR_043497
	Natural variant	83	1	R → C in RKH syndrome; with androgen excess, normal kidney size and location; unable to suppress expression of steroidogenic enzymes in ovarian; impairs protein secretion. Ref.11		VAR_043498
	Natural variant	114	1	A → V in SERKAL; reduced transcript levels. Ref.12		VAR_043499
	Natural variant	216	1	E → G in RKH syndrome; unable to suppress expression of steroidogenic enzymes in ovarian and adrenal cell lines. Ref.10		VAR_034703
	Natural variant	277	1	P → L. Corresponds to variant rs34228276 [ dbSNP | Ensembl ].		VAR_052955
Experimental info
	Sequence conflict	106	1	T → I in AAG38658. Ref.1
	Sequence conflict	111	1	F → L in AAG38658. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P56705 [UniParc]. Last modified May 10, 2002. Version 4. Checksum: 465D08755C992DA8	FASTA	351	39,052
	10 20 30 40 50 60 MSPRSCLRSL RLLVFAVFSA AASNWLYLAK LSSVGSISEE ETCEKLKGLI QRQVQMCKRN 70 80 90 100 110 120 LEVMDSVRRG AQLAIEECQY QFRNRRWNCS TLDSLPVFGK VVTQGTREAA FVYAISSAGV 130 140 150 160 170 180 AFAVTRACSS GELEKCGCDR TVHGVSPQGF QWSGCSDNIA YGVAFSQSFV DVRERSKGAS 190 200 210 220 230 240 SSRALMNLHN NEAGRKAILT HMRVECKCHG VSGSCEVKTC WRAVPPFRQV GHALKEKFDG 250 260 270 280 290 300 ATEVEPRRVG SSRALVPRNA QFKPHTDEDL VYLEPSPDFC EQDMRSGVLG TRGRTCNKTS 310 320 330 340 350 KAIDGCELLC CGRGFHTAQV ELAERCSCKF HWCCFVKCRQ CQRLVELHTC R

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning and characterization of six novel human WNT genes." Testa T.T., Mossakowska D.E., Carter P.S., Hu E., Zhu Y., Kelsell D.P., Murdock P.R., Herrity N.C., Lewis C.J., Cross D.A., Culbert A.A., Reith A.D., Barnes M.R. Submitted (AUG-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Up-regulation of wnt-4 signaling and dosage-sensitive sex reversal in humans." Jordan B.K., Mohammed M., Ching S.T., Delot E., Chen X.N., Dewing P., Swain A., Rao P.N., Elejalde B.R., Vilain E. Am. J. Hum. Genet. 68:1102-1109(2001) [PubMed: 11283799] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment." Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E. , Heldens S., Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M. Genome Res. 13:2265-2270(2003) [PubMed: 12975309] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]	"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 (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed: 16710414] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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]. Tissue: Placenta.
[7]	"Differential expression of human Wnt genes 2, 3, 4, and 7B in human breast cell lines and normal and disease states of human breast tissue." Huguet E.L., McMahon J.A., McMahon A.P., Bicknell R., Harris A.L. Cancer Res. 54:2615-2621(1994) [PubMed: 8168088] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 210-329. Tissue: Mammary gland.
[8]	Peltoketo H., Heikkila M., Vainio S. Submitted (JAN-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-26.
[9]	"Expression of Wnt-4 can be regulated by the Wilms' tumor suppressor gene, WT1." Sim U.E., Smith A., Szilagi E., Ioannou P., Lindsay M.H., Little M.H. Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-26.
[10]	"A WNT4 mutation associated with Muellerian-duct regression and virilization in a 46,XX woman." Biason-Lauber A., Konrad D., Navratil F., Schoenle E.J. N. Engl. J. Med. 351:792-798(2004) [PubMed: 15317892] [Abstract] Cited for: VARIANT RKH SYNDROME GLY-216, CHARACTERIZATION OF VARIANT RKH SYNDROME GLY-216.
[11]	"WNT4 deficiency-a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report." Biason-Lauber A., De Filippo G., Konrad D., Scarano G., Nazzaro A., Schoenle E.J. Hum. Reprod. 22:224-229(2007) [PubMed: 16959810] [Abstract] Cited for: VARIANT RKH SYNDROME CYS-83, CHARACTERIZATION OF VARIANT RKH SYNDROME CYS-83.
[12]	"SERKAL syndrome: an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4." Mandel H., Shemer R., Borochowitz Z.U., Okopnik M., Knopf C., Indelman M., Drugan A., Tiosano D., Gershoni-Baruch R., Choder M., Sprecher E. Am. J. Hum. Genet. 82:39-47(2008) [PubMed: 18179883] [Abstract] Cited for: VARIANT SERKAL VAL-114, CHARACTERIZATION OF VARIANT SERKAL VAL-114.
[13]	"Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and Muellerian duct abnormalities: a French collaborative study." Philibert P., Biason-Lauber A., Rouzier R., Pienkowski C., Paris F., Konrad D., Schoenle E., Sultan C. J. Clin. Endocrinol. Metab. 93:895-900(2008) [PubMed: 18182450] [Abstract] Cited for: VARIANT RKH SYNDROME PRO-12, CHARACTERIZATION OF VARIANT RKH SYNDROME PRO-12.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	AY009398 mRNA. Translation: AAG38658.1. AF316543 mRNA. Translation: AAK51699.1. AY358947 mRNA. Translation: AAQ89306.1. BT020125 mRNA. Translation: AAV38928.1. AL445253, AL031281 Genomic DNA. Translation: CAI22251.1. AL031281, AL445253 Genomic DNA. Translation: CAI19848.1. BC057781 mRNA. Translation: AAH57781.1. AF335591 Genomic DNA. Translation: AAK25765.1. AY033057 Genomic DNA. Translation: AAK50427.1.
IPI	IPI00011028.
RefSeq	NP_110388.2. NM_030761.4.
UniGene	Hs.25766.
3D structure databases
ProteinModelPortal	P56705.
ModBase	Search...
Protein-protein interaction databases
IntAct	P56705. 1 interaction.
STRING	P56705.
PTM databases
PhosphoSite	P56705.
Polymorphism databases
DMDM	20532425.
Proteomic databases
PRIDE	P56705.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000290167; ENSP00000290167; ENSG00000162552.
GeneID	54361.
KEGG	hsa:54361.
UCSC	uc001bfs.2. human.
Organism-specific databases
CTD	54361.
GeneCards	GC01M022443.
H-InvDB	HIX0028503.
HGNC	HGNC:12783. WNT4.
HPA	HPA011397.
MIM	158330. phenotype. 277000. phenotype. 603490. gene. 611812. phenotype.
neXtProt	NX_P56705.
Orphanet	247768. Atypical Mayer-Rokitansky-Kuester-Hauser syndrome. 139466. SERKAL syndrome.
PharmGKB	PA37384.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG18158.
HOGENOM	HBG446188.
HOVERGEN	HBG001595.
InParanoid	P56705.
OMA	VERCSCK.
OrthoDB	EOG49P9ZP.
PhylomeDB	P56705.
Enzyme and pathway databases
Pathway_Interaction_DB	wnt_calcium_pathway. Noncanonical Wnt signaling pathway. wnt_signaling_pathway. Wnt signaling.
Reactome	REACT_111102. Signal Transduction.
Gene expression databases
ArrayExpress	P56705.
Bgee	P56705.
CleanEx	HS_WNT4.
Genevestigator	P56705.
GermOnline	ENSG00000162552. Homo sapiens.
Family and domain databases
InterPro	IPR005817. Wnt. IPR009142. Wnt4. IPR018161. Wnt_grthfactor_CS. [Graphical view]
KO	K00408.
PANTHER	PTHR12027. Wnt. 1 hit. PTHR12027:SF19. Wnt4. 1 hit.
Pfam	PF00110. wnt. 1 hit. [Graphical view]
PRINTS	PR01844. WNT4PROTEIN. PR01349. WNTPROTEIN.
SMART	SM00097. WNT1. 1 hit. [Graphical view]
PROSITE	PS00246. WNT1. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	56599.
SOURCE	Search...

Entry information

Entry name

WNT4_HUMAN

Accession

Primary (citable) accession number: P56705
Secondary accession number(s): Q5TZQ0 , Q96T81, Q9BXF5, Q9H1J8, Q9UJM2

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	May 10, 2002
Last modified:	January 25, 2012
This is version 110 of the entry and version 4 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.