WNT4_MOUSE
ID WNT4_MOUSE Reviewed; 351 AA.
AC P22724;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1991, sequence version 1.
DT 03-AUG-2022, entry version 182.
DE RecName: Full=Protein Wnt-4;
DE Flags: Precursor;
GN Name=Wnt4; Synonyms=Wnt-4;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RX PubMed=2279700; DOI=10.1101/gad.4.12b.2319;
RA Gavin B.J., McMahon J.A., McMahon A.P.;
RT "Expression of multiple novel Wnt-1/int-1-related genes during fetal and
RT adult mouse development.";
RL Genes Dev. 4:2319-2332(1990).
RN [2]
RP FUNCTION, DISRUPTION PHENOTYPE, AND DEVELOPMENTAL STAGE.
RX PubMed=7990960; DOI=10.1038/372679a0;
RA Stark K., Vainio S., Vassileva G., McMahon A.P.;
RT "Epithelial transformation of metanephric mesenchyme in the developing
RT kidney regulated by Wnt-4.";
RL Nature 372:679-683(1994).
RN [3]
RP FUNCTION, DISRUPTION PHENOTYPE, AND DEVELOPMENTAL STAGE.
RX PubMed=9989404; DOI=10.1038/17068;
RA Vainio S., Heikkilae M., Kispert A., Chin N., McMahon A.P.;
RT "Female development in mammals is regulated by Wnt-4 signalling.";
RL Nature 397:405-409(1999).
RN [4]
RP INTERACTION WITH PORCN.
RX PubMed=10866835; DOI=10.1046/j.1432-1033.2000.01478.x;
RA Tanaka K., Okabayashi H., Asashima M., Perrimon N., Kadowaki T.;
RT "The evolutionarily conserved porcupine gene family is involved in the
RT processing of the Wnt family.";
RL Eur. J. Biochem. 267:4300-4311(2000).
RN [5]
RP FUNCTION.
RX PubMed=16054034; DOI=10.1016/j.devcel.2005.05.016;
RA Carroll T.J., Park J.S., Hayashi S., Majumdar A., McMahon A.P.;
RT "Wnt9b plays a central role in the regulation of mesenchymal to epithelial
RT transitions underlying organogenesis of the mammalian urogenital system.";
RL Dev. Cell 9:283-292(2005).
RN [6]
RP FUNCTION.
RX PubMed=17537789; DOI=10.1242/dev.006155;
RA Park J.S., Valerius M.T., McMahon A.P.;
RT "Wnt/beta-catenin signaling regulates nephron induction during mouse kidney
RT development.";
RL Development 134:2533-2539(2007).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=19830824; DOI=10.1002/dvg.20566;
RA Shan J., Jokela T., Peltoketo H., Vainio S.;
RT "Generation of an allele to inactivate Wnt4 gene function conditionally in
RT the mouse.";
RL Genesis 47:782-788(2009).
RN [8]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=26321050; DOI=10.1016/j.ydbio.2015.08.017;
RA Caprioli A., Villasenor A., Wylie L.A., Braitsch C., Marty-Santos L.,
RA Barry D., Karner C.M., Fu S., Meadows S.M., Carroll T.J., Cleaver O.;
RT "Wnt4 is essential to normal mammalian lung development.";
RL Dev. Biol. 406:222-234(2015).
CC -!- FUNCTION: Ligand for members of the frizzled family of seven
CC transmembrane receptors (Probable). Plays an important role in the
CC embryonic development of the urogenital tract and the lung
CC (PubMed:7990960, PubMed:9989404, PubMed:16054034, PubMed:17537789,
CC PubMed:19830824, PubMed:26321050). Required for normal mesenchyme to
CC epithelium transition during embryonic kidney development
CC (PubMed:7990960, PubMed:16054034, PubMed:17537789, PubMed:19830824).
CC Required for the formation of early epithelial renal vesicles during
CC kidney development (PubMed:16054034). Required for normal formation of
CC the Mullerian duct in females, and normal levels of oocytes in the
CC ovaries (PubMed:9989404, PubMed:19830824). Required for normal down-
CC regulation of 3 beta-hydroxysteroid dehydrogenase in the ovary
CC (PubMed:9989404). Required for normal lung development and for normal
CC patterning of trachael cartilage rings (PubMed:26321050).
CC {ECO:0000269|PubMed:16054034, ECO:0000269|PubMed:17537789,
CC ECO:0000269|PubMed:19830824, ECO:0000269|PubMed:26321050,
CC ECO:0000269|PubMed:7990960, ECO:0000269|PubMed:9989404, ECO:0000305}.
CC -!- SUBUNIT: Interacts with PORCN (PubMed:10866835). Interacts with PKD1
CC (By similarity). {ECO:0000250|UniProtKB:P56705,
CC ECO:0000269|PubMed:10866835}.
CC -!- INTERACTION:
CC P22724; O35082: Kl; NbExp=2; IntAct=EBI-1570945, EBI-1570828;
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular
CC matrix.
CC -!- TISSUE SPECIFICITY: In adults in lung and brain.
CC {ECO:0000269|PubMed:2279700}.
CC -!- DEVELOPMENTAL STAGE: Detected along the length of the mesonephros at
CC 9.5 to 10.5 dpc. At 11.0 dpc, detected in the mesenchyme of the gonads
CC in both sexes and in mesonephros. At 11.5 dpc, sex-specific
CC differentiation of the gonads begins, and Wnt4 is down-regulated in
CC male gonads, but not in female gonads. Detected in mesenchyme cells
CC underlying the newly formed Mullerian duct in females, but not in the
CC Wolffian duct in males (PubMed:9989404). During kidney development,
CC detected at 11.5 dpc in condensed mesenchymal cells on both sides of
CC the stalk of the ureter. Detected on pretubular aggregates upon
CC initiation of ureteric bud branching at 12.5 dpc. Detected on primitive
CC tubular aggregates at 13.5 dpc. Detected on comma-shaped and S-shaped
CC bodies by 14.5 dpc, and is restricted to kidney cortex by 16.5 dpc
CC (PubMed:7990960). {ECO:0000269|PubMed:7990960,
CC ECO:0000269|PubMed:9989404}.
CC -!- PTM: Palmitoleoylation is required for efficient binding to frizzled
CC receptors. Depalmitoleoylation leads to Wnt signaling pathway
CC inhibition. {ECO:0000250|UniProtKB:P27467,
CC ECO:0000250|UniProtKB:P56704}.
CC -!- DISRUPTION PHENOTYPE: Mutant embryos show normal early stages of kidney
CC development, but later stages of kidney development are disrupted
CC (PubMed:7990960, PubMed:19830824). Mutant embryos develop to term, but
CC the pups die within 24 hours after birth, probably due to the absence
CC of functional kidneys (PubMed:7990960). Reproductive organs in newborn
CC males appear normal (PubMed:9989404). External genitalia from newborn
CC females appear normal, but they lack a Mullerian duct and their gonads
CC and sex ducts appear masculinized (PubMed:9989404, PubMed:19830824).
CC Their ovaries contain less than 10% of the normal number of oocytes,
CC and these are in the process of degenerating (PubMed:9989404). Mutant
CC embryos display altered patterning of tracheal cartilage rings. By 13.5
CC dpc the size of their lungs is significantly reduced, and at 17.5 dpc
CC the left lung lobe is on average 35% smaller than for wild-type
CC (PubMed:26321050). {ECO:0000269|PubMed:19830824,
CC ECO:0000269|PubMed:26321050, ECO:0000269|PubMed:7990960,
CC ECO:0000269|PubMed:9989404}.
CC -!- SIMILARITY: Belongs to the Wnt family. {ECO:0000305}.
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DR EMBL; M89797; AAA40566.1; -; mRNA.
DR CCDS; CCDS18815.1; -.
DR PIR; C36470; C36470.
DR RefSeq; NP_033549.1; NM_009523.2.
DR AlphaFoldDB; P22724; -.
DR SMR; P22724; -.
DR BioGRID; 204576; 4.
DR IntAct; P22724; 3.
DR MINT; P22724; -.
DR STRING; 10090.ENSMUSP00000036580; -.
DR GlyGen; P22724; 2 sites.
DR PhosphoSitePlus; P22724; -.
DR PaxDb; P22724; -.
DR PRIDE; P22724; -.
DR ProteomicsDB; 299794; -.
DR Antibodypedia; 2555; 498 antibodies from 36 providers.
DR DNASU; 22417; -.
DR Ensembl; ENSMUST00000045747; ENSMUSP00000036580; ENSMUSG00000036856.
DR GeneID; 22417; -.
DR KEGG; mmu:22417; -.
DR UCSC; uc008viv.2; mouse.
DR CTD; 54361; -.
DR MGI; MGI:98957; Wnt4.
DR VEuPathDB; HostDB:ENSMUSG00000036856; -.
DR eggNOG; KOG3913; Eukaryota.
DR GeneTree; ENSGT00940000159654; -.
DR HOGENOM; CLU_033039_1_0_1; -.
DR InParanoid; P22724; -.
DR OMA; CWRAMPP; -.
DR OrthoDB; 745245at2759; -.
DR PhylomeDB; P22724; -.
DR TreeFam; TF105310; -.
DR Reactome; R-MMU-3238698; WNT ligand biogenesis and trafficking.
DR Reactome; R-MMU-4086400; PCP/CE pathway.
DR BioGRID-ORCS; 22417; 3 hits in 72 CRISPR screens.
DR PRO; PR:P22724; -.
DR Proteomes; UP000000589; Chromosome 4.
DR RNAct; P22724; protein.
DR Bgee; ENSMUSG00000036856; Expressed in inner medulla of kidney and 266 other tissues.
DR ExpressionAtlas; P22724; baseline and differential.
DR Genevisible; P22724; MM.
DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0031012; C:extracellular matrix; IDA:MGI.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI.
DR GO; GO:0005125; F:cytokine activity; IBA:GO_Central.
DR GO; GO:0005109; F:frizzled binding; IPI:BHF-UCL.
DR GO; GO:0048018; F:receptor ligand activity; ISO:MGI.
DR GO; GO:0005102; F:signaling receptor binding; TAS:MGI.
DR GO; GO:0003714; F:transcription corepressor activity; IDA:UniProtKB.
DR GO; GO:0030325; P:adrenal gland development; IEA:Ensembl.
DR GO; GO:0048856; P:anatomical structure development; IGI:MGI.
DR GO; GO:0097190; P:apoptotic signaling pathway; IGI:MGI.
DR GO; GO:0001658; P:branching involved in ureteric bud morphogenesis; IMP:MGI.
DR GO; GO:0048754; P:branching morphogenesis of an epithelial tube; IGI:MGI.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IDA:BHF-UCL.
DR GO; GO:0030154; P:cell differentiation; IMP:MGI.
DR GO; GO:0045165; P:cell fate commitment; IMP:MGI.
DR GO; GO:0007267; P:cell-cell signaling; TAS:MGI.
DR GO; GO:0009267; P:cellular response to starvation; IEP:MGI.
DR GO; GO:0071560; P:cellular response to transforming growth factor beta stimulus; IEA:Ensembl.
DR GO; GO:0001838; P:embryonic epithelial tube formation; IDA:MGI.
DR GO; GO:0001837; P:epithelial to mesenchymal transition; IEA:Ensembl.
DR GO; GO:0008585; P:female gonad development; IMP:MGI.
DR GO; GO:0030237; P:female sex determination; ISS:UniProtKB.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; IGI:MGI.
DR GO; GO:0007276; P:gamete generation; IGI:MGI.
DR GO; GO:0042445; P:hormone metabolic process; IMP:MGI.
DR GO; GO:0033080; P:immature T cell proliferation in thymus; IMP:MGI.
DR GO; GO:0060993; P:kidney morphogenesis; IGI:MGI.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0008584; P:male gonad development; IMP:MGI.
DR GO; GO:0140013; P:meiotic nuclear division; IGI:MGI.
DR GO; GO:0060231; P:mesenchymal to epithelial transition; IMP:MGI.
DR GO; GO:0072164; P:mesonephric tubule development; IGI:MGI.
DR GO; GO:0001823; P:mesonephros development; IMP:UniProtKB.
DR GO; GO:0072162; P:metanephric mesenchymal cell differentiation; NAS:UniProtKB.
DR GO; GO:0072210; P:metanephric nephron development; IMP:MGI.
DR GO; GO:0072273; P:metanephric nephron morphogenesis; IMP:MGI.
DR GO; GO:0072174; P:metanephric tubule formation; IMP:MGI.
DR GO; GO:0001656; P:metanephros development; IMP:MGI.
DR GO; GO:2000180; P:negative regulation of androgen biosynthetic process; ISS:UniProtKB.
DR GO; GO:2001234; P:negative regulation of apoptotic signaling pathway; IGI:MGI.
DR GO; GO:0045596; P:negative regulation of cell differentiation; IMP:MGI.
DR GO; GO:0030336; P:negative regulation of cell migration; IGI:BHF-UCL.
DR GO; GO:0040037; P:negative regulation of fibroblast growth factor receptor signaling pathway; IGI:MGI.
DR GO; GO:0010629; P:negative regulation of gene expression; IMP:MGI.
DR GO; GO:2000019; P:negative regulation of male gonad development; ISS:UniProtKB.
DR GO; GO:0010894; P:negative regulation of steroid biosynthetic process; ISS:UniProtKB.
DR GO; GO:0061369; P:negative regulation of testicular blood vessel morphogenesis; ISO:MGI.
DR GO; GO:2000225; P:negative regulation of testosterone biosynthetic process; IMP:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0061045; P:negative regulation of wound healing; IGI:BHF-UCL.
DR GO; GO:0072006; P:nephron development; IMP:MGI.
DR GO; GO:0030182; P:neuron differentiation; IBA:GO_Central.
DR GO; GO:0035567; P:non-canonical Wnt signaling pathway; IDA:MGI.
DR GO; GO:0038030; P:non-canonical Wnt signaling pathway via MAPK cascade; ISO:MGI.
DR GO; GO:0048599; P:oocyte development; IMP:MGI.
DR GO; GO:0061205; P:paramesonephric duct development; IMP:UniProtKB.
DR GO; GO:1904238; P:pericyte cell differentiation; IDA:MGI.
DR GO; GO:0032349; P:positive regulation of aldosterone biosynthetic process; ISS:UniProtKB.
DR GO; GO:0030501; P:positive regulation of bone mineralization; ISS:UniProtKB.
DR GO; GO:0032967; P:positive regulation of collagen biosynthetic process; ISS:UniProtKB.
DR GO; GO:2000066; P:positive regulation of cortisol biosynthetic process; ISS:UniProtKB.
DR GO; GO:0061184; P:positive regulation of dermatome development; ISS:UniProtKB.
DR GO; GO:0051894; P:positive regulation of focal adhesion assembly; IGI:BHF-UCL.
DR GO; GO:0043547; P:positive regulation of GTPase activity; IGI:BHF-UCL.
DR GO; GO:0045836; P:positive regulation of meiotic nuclear division; IGI:MGI.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; ISS:UniProtKB.
DR GO; GO:0051496; P:positive regulation of stress fiber assembly; IGI:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0022407; P:regulation of cell-cell adhesion; IMP:MGI.
DR GO; GO:0072033; P:renal vesicle formation; IMP:MGI.
DR GO; GO:0072034; P:renal vesicle induction; IDA:MGI.
DR GO; GO:0060008; P:Sertoli cell differentiation; IMP:MGI.
DR GO; GO:0007548; P:sex differentiation; IMP:MGI.
DR GO; GO:0007165; P:signal transduction; TAS:MGI.
DR GO; GO:0051145; P:smooth muscle cell differentiation; IDA:MGI.
DR GO; GO:0060126; P:somatotropin secreting cell differentiation; IMP:MGI.
DR GO; GO:0033077; P:T cell differentiation in thymus; IDA:MGI.
DR GO; GO:0060748; P:tertiary branching involved in mammary gland duct morphogenesis; IMP:MGI.
DR GO; GO:0060129; P:thyroid-stimulating hormone-secreting cell differentiation; IMP:MGI.
DR GO; GO:0035239; P:tube morphogenesis; IMP:MGI.
DR Gene3D; 3.30.2460.20; -; 1.
DR InterPro; IPR005817; Wnt.
DR InterPro; IPR009142; Wnt4.
DR InterPro; IPR043158; Wnt_C.
DR InterPro; IPR018161; Wnt_CS.
DR PANTHER; PTHR12027; PTHR12027; 1.
DR Pfam; PF00110; wnt; 1.
DR PRINTS; PR01844; WNT4PROTEIN.
DR PRINTS; PR01349; WNTPROTEIN.
DR SMART; SM00097; WNT1; 1.
DR PROSITE; PS00246; WNT1; 1.
PE 1: Evidence at protein level;
KW Developmental protein; Disulfide bond; Extracellular matrix; Glycoprotein;
KW Lipoprotein; Reference proteome; Secreted; Signal; Wnt signaling pathway.
FT SIGNAL 1..22
FT /evidence="ECO:0000255"
FT CHAIN 23..351
FT /note="Protein Wnt-4"
FT /id="PRO_0000041422"
FT LIPID 212
FT /note="O-palmitoleoyl serine; by PORCN"
FT /evidence="ECO:0000250|UniProtKB:P56704"
FT CARBOHYD 88
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 297
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 78..89
FT /evidence="ECO:0000250|UniProtKB:P28026"
FT DISULFID 128..136
FT /evidence="ECO:0000250|UniProtKB:P28026"
FT DISULFID 138..155
FT /evidence="ECO:0000250|UniProtKB:P28026"
FT DISULFID 206..220
FT /evidence="ECO:0000250|UniProtKB:P28026"
FT DISULFID 208..215
FT /evidence="ECO:0000250|UniProtKB:P28026"
FT DISULFID 280..311
FT /evidence="ECO:0000250|UniProtKB:P28026"
FT DISULFID 296..306
FT /evidence="ECO:0000250|UniProtKB:P28026"
FT DISULFID 310..350
FT /evidence="ECO:0000250|UniProtKB:P28026"
FT DISULFID 326..341
FT /evidence="ECO:0000250|UniProtKB:P28026"
FT DISULFID 328..338
FT /evidence="ECO:0000250|UniProtKB:P28026"
FT DISULFID 333..334
FT /evidence="ECO:0000250|UniProtKB:P28026"
SQ SEQUENCE 351 AA; 39050 MW; 7E1C5C739BE939D9 CRC64;
MSPRSCLRSL RLLVFAVFSA AASNWLYLAK LSSVGSISEE ETCEKLKGLI QRQVQMCKRN
LEVMDSVRRG AQLAIEECQY QFRNRRWNCS TLDSLPVFGK VVTQGTREAA FVYAISSAGV
AFAVTRACSS GELEKCGCDR TVHGVSPQGF QWSGCSDNIA YGVAFSQSFV DVRERSKGAS
SSRALMNLHN NEAGRKAILT HMRVECKCHG VSGSCEVKTC WRAVPPFRQV GHALKEKFDG
ATEVEPRRVG SSRALVPRNA QFKPHTDEDL VYLEPSPDFC EQDIRSGVLG TRGRTCNKTS
KAIDGCELLC CGRGFHTAQV ELAERCGCRF HWCCFVKCRQ CQRLVEMHTC R
