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 24-JAN-2024, entry version 190. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 GlyCosmos; Q61088; 2 sites, No reported glycans. DR GlyGen; Q61088; 2 sites. DR PhosphoSitePlus; Q61088; -. DR MaxQB; Q61088; -. DR PaxDb; 10090-ENSMUSP00000049852; -. DR ProteomicsDB; 273400; -. DR Antibodypedia; 17696; 583 antibodies from 40 providers. DR DNASU; 14366; -. DR Ensembl; ENSMUST00000058755.5; ENSMUSP00000049852.4; ENSMUSG00000049791.5. DR GeneID; 14366; -. DR KEGG; mmu:14366; -. DR UCSC; uc009ifx.2; mouse. DR AGR; MGI:108520; -. 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; 5483535at2759; -. 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 77 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 263 other cell types or tissues. DR ExpressionAtlas; Q61088; baseline and differential. 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:0098978; C:glutamatergic synapse; IDA:SynGO. 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:0001525; P:angiogenesis; IMP:MGI. 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:0008283; P:cell population proliferation; IMP:MGI. 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:0045446; P:endothelial cell differentiation; IMP:MGI. DR GO; GO:0060856; P:establishment of blood-brain barrier; IMP:MGI. 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:0010812; P:negative regulation of cell-substrate adhesion; IMP:BHF-UCL. DR GO; GO:0035567; P:non-canonical Wnt signaling pathway; IBA:GO_Central. 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:0050775; P:positive regulation of dendrite morphogenesis; ISO:MGI. DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; IDA:BHF-UCL. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:BHF-UCL. DR GO; GO:0150012; P:positive regulation of neuron projection arborization; IGI:ARUK-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:0001666; P:response to hypoxia; IMP:MGI. DR GO; GO:0061298; P:retina vasculature development in camera-type eye; 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; cd15038; 7tmF_FZD4; 1. DR CDD; cd07448; CRD_FZ4; 1. DR Gene3D; 1.10.2000.10; Frizzled cysteine-rich domain; 1. DR Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1. DR InterPro; IPR015526; Frizzled/SFRP. DR InterPro; IPR000539; Frizzled/Smoothened_7TM. DR InterPro; IPR020067; Frizzled_dom. DR InterPro; IPR036790; Frizzled_dom_sf. DR InterPro; IPR041765; FZ4_CRD. DR InterPro; IPR026551; FZD4_7TM. DR InterPro; IPR017981; GPCR_2-like_7TM. DR PANTHER; PTHR11309; FRIZZLED; 1. DR PANTHER; PTHR11309:SF23; FRIZZLED-4; 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; Frizzled cysteine-rich domain; 1. DR PROSITE; PS50038; FZ; 1. DR PROSITE; PS50261; G_PROTEIN_RECEP_F2_4; 1. DR Genevisible; Q61088; MM. 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 //