FZD4_MOUSE
ID FZD4_MOUSE Reviewed; 537 AA.
AC Q61088;
DT 05-DEC-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 182.
DE RecName: Full=Frizzled-4;
DE Short=Fz-4;
DE Short=mFz4;
DE AltName: CD_antigen=CD344;
DE Flags: Precursor;
GN Name=Fzd4;
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].
RX PubMed=8626800; DOI=10.1074/jbc.271.8.4468;
RA Wang Y., Macke J.P., Abella B.S., Andreasson K., Worley P., Gilbert D.J.,
RA Copeland N.G., Jenkins N.A., Nathans J.;
RT "A large family of putative transmembrane receptors homologous to the
RT product of the Drosophila tissue polarity gene frizzled.";
RL J. Biol. Chem. 271:4468-4476(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP WNT-MEDIATED PKC ACTIVATION.
RX PubMed=10395542; DOI=10.1016/s0960-9822(99)80310-8;
RA Sheldahl L.C., Park M., Malbon C.C., Moon R.T.;
RT "Protein kinase C is differentially stimulated by Wnt and Frizzled homologs
RT in a G-protein-dependent manner.";
RL Curr. Biol. 9:695-698(1999).
RN [4]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=10097073; DOI=10.1073/pnas.96.7.3546;
RA Hsieh J.C., Rattner A., Smallwood P.M., Nathans J.;
RT "Biochemical characterization of Wnt-frizzled interactions using a soluble,
RT biologically active vertebrate Wnt protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:3546-3551(1999).
RN [5]
RP INTERACTION WITH NDP, AND DISRUPTION PHENOTYPE.
RX PubMed=15035989; DOI=10.1016/s0092-8674(04)00216-8;
RA Xu Q., Wang Y., Dabdoub A., Smallwood P.M., Williams J., Woods C.,
RA Kelley M.W., Jiang L., Tasman W., Zhang K., Nathans J.;
RT "Vascular development in the retina and inner ear: control by Norrin and
RT Frizzled-4, a high-affinity ligand-receptor pair.";
RL Cell 116:883-895(2004).
RN [6]
RP INTERACTION WITH MAGI3.
RX PubMed=15195140; DOI=10.1038/sj.onc.1207817;
RA Yao R., Natsume Y., Noda T.;
RT "MAGI-3 is involved in the regulation of the JNK signaling pathway as a
RT scaffold protein for frizzled and Ltap.";
RL Oncogene 23:6023-6030(2004).
RN [7]
RP FUNCTION, AND IDENTIFICATION IN A COMPLEX WITH NDP AND TSPAN12.
RX PubMed=19837033; DOI=10.1016/j.cell.2009.07.048;
RA Junge H.J., Yang S., Burton J.B., Paes K., Shu X., French D.M., Costa M.,
RA Rice D.S., Ye W.;
RT "TSPAN12 regulates retinal vascular development by promoting Norrin-but not
RT Wnt-induced FZD4/beta-catenin signaling.";
RL Cell 139:299-311(2009).
RN [8]
RP INTERACTION WITH TSKU.
RX PubMed=21856951; DOI=10.1073/pnas.1100513108;
RA Ohta K., Ito A., Kuriyama S., Lupo G., Kosaka M., Ohnuma S., Nakagawa S.,
RA Tanaka H.;
RT "Tsukushi functions as a Wnt signaling inhibitor by competing with Wnt2b
RT for binding to transmembrane protein Frizzled4.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:14962-14967(2011).
CC -!- FUNCTION: Receptor for Wnt proteins (PubMed:10097073). Most frizzled
CC receptors are coupled to the beta-catenin (CTNNB1) canonical signaling
CC pathway, which leads to the activation of disheveled proteins,
CC inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin
CC (CTNNB1) and activation of Wnt target genes (PubMed:19837033). Plays a
CC critical role in retinal vascularization by acting as a receptor for
CC Wnt proteins and norrin (NDP) (PubMed:19837033). In retina, it can be
CC activated by Wnt protein-binding and also by Wnt-independent signaling
CC via binding of norrin (NDP), promoting in both cases beta-catenin
CC (CTNNB1) accumulation and stimulation of LEF/TCF-mediated
CC transcriptional programs (PubMed:19837033). A second signaling pathway
CC involving PKC and calcium fluxes has been seen for some family members,
CC but it is not yet clear if it represents a distinct pathway or if it
CC can be integrated in the canonical pathway, as PKC seems to be required
CC for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to
CC involve interactions with G-proteins. May be involved in transduction
CC and intercellular transmission of polarity information during tissue
CC morphogenesis and/or in differentiated tissues. Activation by Wnt5A
CC stimulates PKC activity via a G-protein-dependent mechanism.
CC {ECO:0000250|UniProtKB:Q9ULV1, ECO:0000269|PubMed:10097073,
CC ECO:0000269|PubMed:19837033}.
CC -!- SUBUNIT: Interacts with MAGI3 and NDP (PubMed:15035989,
CC PubMed:15195140). Component of a complex, at least composed of TSPAN12,
CC FZD4 and norrin (NDP) (PubMed:19837033). Interacts (via FZ domain) with
CC TSKU; TSKU competes with WNT2B for binding to FZD4, inhibiting Wnt
CC signaling and repressing peripheral eye development (PubMed:21856951).
CC Interacts with glypican GPC3 (By similarity).
CC {ECO:0000250|UniProtKB:Q9ULV1, ECO:0000269|PubMed:15035989,
CC ECO:0000269|PubMed:15195140, ECO:0000269|PubMed:19837033,
CC ECO:0000269|PubMed:21856951}.
CC -!- INTERACTION:
CC Q61088; P0CG48: UBC; Xeno; NbExp=3; IntAct=EBI-7987880, EBI-3390054;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10097073};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Expressed in chondrocytes.
CC -!- DOMAIN: Lys-Thr-X-X-X-Trp motif interacts with the PDZ domain of Dvl
CC (Disheveled) family members and is involved in the activation of the
CC Wnt/beta-catenin signaling pathway. {ECO:0000250}.
CC -!- DOMAIN: The FZ domain is involved in binding with Wnt ligands.
CC {ECO:0000250}.
CC -!- PTM: Ubiquitinated by ZNRF3, leading to its degradation by the
CC proteasome. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Defects in retinal vascularization.
CC {ECO:0000269|PubMed:15035989}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor Fz/Smo family.
CC {ECO:0000305}.
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DR EMBL; U43317; AAC52430.1; -; mRNA.
DR EMBL; BC015256; AAH15256.1; -; mRNA.
DR CCDS; CCDS21441.1; -.
DR RefSeq; NP_032081.3; NM_008055.4.
DR AlphaFoldDB; Q61088; -.
DR SMR; Q61088; -.
DR BioGRID; 199777; 3.
DR CORUM; Q61088; -.
DR DIP; DIP-41623N; -.
DR IntAct; Q61088; 9.
DR MINT; Q61088; -.
DR STRING; 10090.ENSMUSP00000049852; -.
DR GuidetoPHARMACOLOGY; 232; -.
DR GlyGen; Q61088; 2 sites.
DR PhosphoSitePlus; Q61088; -.
DR MaxQB; Q61088; -.
DR PaxDb; Q61088; -.
DR PRIDE; Q61088; -.
DR ProteomicsDB; 273400; -.
DR Antibodypedia; 17696; 543 antibodies from 39 providers.
DR DNASU; 14366; -.
DR Ensembl; ENSMUST00000058755; ENSMUSP00000049852; ENSMUSG00000049791.
DR GeneID; 14366; -.
DR KEGG; mmu:14366; -.
DR UCSC; uc009ifx.2; mouse.
DR CTD; 8322; -.
DR MGI; MGI:108520; Fzd4.
DR VEuPathDB; HostDB:ENSMUSG00000049791; -.
DR eggNOG; KOG3577; Eukaryota.
DR GeneTree; ENSGT00940000157141; -.
DR HOGENOM; CLU_007873_2_1_1; -.
DR InParanoid; Q61088; -.
DR OMA; HWGEFRA; -.
DR OrthoDB; 509772at2759; -.
DR PhylomeDB; Q61088; -.
DR TreeFam; TF317907; -.
DR Reactome; R-MMU-4086398; Ca2+ pathway.
DR Reactome; R-MMU-4608870; Asymmetric localization of PCP proteins.
DR Reactome; R-MMU-4641263; Regulation of FZD by ubiquitination.
DR Reactome; R-MMU-5099900; WNT5A-dependent internalization of FZD4.
DR Reactome; R-MMU-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR Reactome; R-MMU-8856828; Clathrin-mediated endocytosis.
DR BioGRID-ORCS; 14366; 6 hits in 72 CRISPR screens.
DR ChiTaRS; Fzd4; mouse.
DR PRO; PR:Q61088; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; Q61088; protein.
DR Bgee; ENSMUSG00000049791; Expressed in pigmented layer of retina and 261 other tissues.
DR ExpressionAtlas; Q61088; baseline and differential.
DR Genevisible; Q61088; MM.
DR GO; GO:0009986; C:cell surface; ISO:MGI.
DR GO; GO:0005911; C:cell-cell junction; IDA:MGI.
DR GO; GO:0030425; C:dendrite; IMP:ARUK-UCL.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL.
DR GO; GO:0045202; C:synapse; IDA:SynGO.
DR GO; GO:0001540; F:amyloid-beta binding; ISO:MGI.
DR GO; GO:0019955; F:cytokine binding; IPI:BHF-UCL.
DR GO; GO:0004896; F:cytokine receptor activity; ISO:MGI.
DR GO; GO:0004930; F:G protein-coupled receptor activity; IEA:UniProtKB-KW.
DR GO; GO:0030165; F:PDZ domain binding; ISO:MGI.
DR GO; GO:0046982; F:protein heterodimerization activity; ISO:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0038023; F:signaling receptor activity; IGI:ARUK-UCL.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR GO; GO:0042813; F:Wnt receptor activity; IPI:MGI.
DR GO; GO:0017147; F:Wnt-protein binding; IPI:AgBase.
DR GO; GO:0001568; P:blood vessel development; IMP:MGI.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IGI:ParkinsonsUK-UCL.
DR GO; GO:1990830; P:cellular response to leukemia inhibitory factor; IEP:MGI.
DR GO; GO:0061301; P:cerebellum vasculature morphogenesis; IMP:BHF-UCL.
DR GO; GO:0035426; P:extracellular matrix-cell signaling; IDA:BHF-UCL.
DR GO; GO:0031987; P:locomotion involved in locomotory behavior; IMP:MGI.
DR GO; GO:0001553; P:luteinization; IMP:MGI.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IBA:GO_Central.
DR GO; GO:0010812; P:negative regulation of cell-substrate adhesion; IMP:BHF-UCL.
DR GO; GO:0110135; P:Norrin signaling pathway; IDA:BHF-UCL.
DR GO; GO:0030335; P:positive regulation of cell migration; ISO:MGI.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; IDA:BHF-UCL.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IGI:MGI.
DR GO; GO:0150012; P:positive regulation of neuron projection arborization; IGI:ARUK-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:BHF-UCL.
DR GO; GO:0042701; P:progesterone secretion; IMP:MGI.
DR GO; GO:0030947; P:regulation of vascular endothelial growth factor receptor signaling pathway; IMP:MGI.
DR GO; GO:0061299; P:retina vasculature morphogenesis in camera-type eye; IMP:MGI.
DR GO; GO:0061304; P:retinal blood vessel morphogenesis; IMP:BHF-UCL.
DR GO; GO:0007605; P:sensory perception of sound; IMP:MGI.
DR GO; GO:0034446; P:substrate adhesion-dependent cell spreading; IMP:MGI.
DR GO; GO:0001570; P:vasculogenesis; IMP:MGI.
DR GO; GO:0016055; P:Wnt signaling pathway; IGI:ARUK-UCL.
DR GO; GO:0007223; P:Wnt signaling pathway, calcium modulating pathway; ISO:MGI.
DR CDD; cd07448; CRD_FZ4; 1.
DR Gene3D; 1.10.2000.10; -; 1.
DR InterPro; IPR015526; Frizzled/SFRP.
DR InterPro; IPR000539; Frizzled/Smoothened_TM.
DR InterPro; IPR020067; Frizzled_dom.
DR InterPro; IPR036790; Frizzled_dom_sf.
DR InterPro; IPR041765; FZ4_CRD.
DR InterPro; IPR026551; FZD4.
DR InterPro; IPR017981; GPCR_2-like.
DR PANTHER; PTHR11309; PTHR11309; 1.
DR PANTHER; PTHR11309:SF23; PTHR11309:SF23; 1.
DR Pfam; PF01534; Frizzled; 1.
DR Pfam; PF01392; Fz; 1.
DR PRINTS; PR00489; FRIZZLED.
DR SMART; SM00063; FRI; 1.
DR SMART; SM01330; Frizzled; 1.
DR SUPFAM; SSF63501; SSF63501; 1.
DR PROSITE; PS50038; FZ; 1.
DR PROSITE; PS50261; G_PROTEIN_RECEP_F2_4; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Developmental protein; Disulfide bond;
KW G-protein coupled receptor; Glycoprotein; Membrane; Receptor;
KW Reference proteome; Signal; Transducer; Transmembrane; Transmembrane helix;
KW Ubl conjugation; Wnt signaling pathway.
FT SIGNAL 1..36
FT /evidence="ECO:0000255"
FT CHAIN 37..537
FT /note="Frizzled-4"
FT /id="PRO_0000012986"
FT TOPO_DOM 37..212
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT TRANSMEM 213..243
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT TOPO_DOM 244..249
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT TRANSMEM 250..275
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT TOPO_DOM 276..299
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT TRANSMEM 300..333
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT TOPO_DOM 334..336
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT TRANSMEM 337..365
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT TOPO_DOM 366..383
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT TRANSMEM 384..410
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT TOPO_DOM 411..431
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT TRANSMEM 432..460
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT TOPO_DOM 461..473
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT TRANSMEM 474..495
FT /note="Helical; Name=7"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT TOPO_DOM 496..537
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 40..161
FT /note="FZ"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT MOTIF 499..504
FT /note="Lys-Thr-X-X-X-Trp motif, mediates interaction with
FT the PDZ domain of Dvl family members"
FT /evidence="ECO:0000250"
FT MOTIF 535..537
FT /note="PDZ-binding"
FT CARBOHYD 59
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 144
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 45..106
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT DISULFID 53..99
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT DISULFID 90..128
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT DISULFID 117..158
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT DISULFID 121..145
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT DISULFID 181..200
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT DISULFID 204..282
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT DISULFID 302..377
FT /evidence="ECO:0000250|UniProtKB:Q9ULV1"
FT CONFLICT 27
FT /note="F -> L (in Ref. 2; AAH15256)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 537 AA; 60143 MW; 6641996E6960BCD8 CRC64;
MAWPGTGPSS RGAPGGVGLR LGLLLQFLLL LRPTLGFGDE EERRCDPIRI AMCQNLGYNV
TKMPNLVGHE LQTDAELQLT TFTPLIQYGC SSQLQFFLCS VYVPMCTEKI NIPIGPCGGM
CLSVKRRCEP VLREFGFAWP DTLNCSKFPP QNDHNHMCME GPGDEEVPLP HKTPIQPGEE
CHSVGSNSDQ YIWVKRSLNC VLKCGYDAGL YSRSAKEFTD IWMAVWASLC FISTTFTVLT
FLIDSSRFSY PERPIIFLSM CYNIYSIAYI VRLTVGRERI SCDFEEAAEP VLIQEGLKNT
GCAIIFLLMY FFGMASSIWW VILTLTWFLA AGLKWGHEAI EMHSSYFHIA AWAIPAVKTI
VILIMRLVDA DELTGLCYVG NQNLDALTGF VVAPLFTYLV IGTLFIAAGL VALFKIRSNL
QKDGTKTDKL ERLMVKIGVF SVLYTVPATC VIACYFYEIS NWALFRYSAD DSNMAVEMLK
IFMSLLVGIT SGMWIWSAKT LHTWQKCSNR LVNSGKVKRE KRGNGWVKPG KGNETVV
