ID   FZD8_MOUSE              Reviewed;         685 AA.
AC   Q61091; A2RTK9;
DT   05-DEC-2001, integrated into UniProtKB/Swiss-Prot.
DT   27-JUL-2011, sequence version 2.
DT   04-NOV-2026, entry version 205.
DE   RecName: Full=Frizzled-8;
DE            Short=Fz-8;
DE            Short=mFz8;
DE   Flags: Precursor;
GN   Name=Fzd8;
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 [GENOMIC DNA].
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 GENOMIC DNA].
RA   Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain;
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   [4]
RP   FUNCTION IN BETA-CATENIN SIGNALING.
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   [5]
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   [6]
RP   INTERACTION WITH GOPC, SUBCELLULAR LOCATION, AND MUTAGENESIS OF VAL-685.
RX   PubMed=11520064; DOI=10.1006/bbrc.2001.5430;
RA   Yao R., Maeda T., Takada S., Noda T.;
RT   "Identification of a PDZ domain containing Golgi protein, GOPC, as an
RT   interaction partner of frizzled.";
RL   Biochem. Biophys. Res. Commun. 286:771-778(2001).
RN   [7]
RP   FUNCTION.
RX   PubMed=15454084; DOI=10.1016/j.cell.2004.09.019;
RA   Lu W., Yamamoto V., Ortega B., Baltimore D.;
RT   "Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite
RT   outgrowth.";
RL   Cell 119:97-108(2004).
RN   [8]
RP   INTERACTION WITH RSPO1 AND RSPO3, AND FUNCTION.
RX   PubMed=16543246; DOI=10.1074/jbc.m508324200;
RA   Nam J.-S., Turcotte T.J., Smith P.F., Choi S., Yoon J.K.;
RT   "Mouse cristin/R-spondin family proteins are novel ligands for the Frizzled
RT   8 and LRP6 receptors and activate beta-catenin-dependent gene expression.";
RL   J. Biol. Chem. 281:13247-13257(2006).
RN   [9]
RP   X-RAY CRYSTALLOGRAPHY, AND DISULFIDE BONDS.
RX   PubMed=11452312; DOI=10.1038/35083601;
RA   Dann C.E., Hsieh J.-C., Rattner A., Sharma D., Nathans J., Leahy D.J.;
RT   "Insights into Wnt binding and signalling from the structures of two
RT   Frizzled cysteine-rich domains.";
RL   Nature 412:86-90(2001).
RN   [10]
RP   X-RAY CRYSTALLOGRAPHY IN COMPLEX WITH XENOPUS WNT8.
RX   PubMed=22653731; DOI=10.1126/science.1222879;
RA   Janda C.Y., Waghray D., Levin A.M., Thomas C., Garcia K.C.;
RT   "Structural basis of Wnt recognition by Frizzled.";
RL   Science 337:59-64(2012).
CC   -!- FUNCTION: Receptor for Wnt proteins. Component of the Wnt-Fzd-LRP5-LRP6
CC       complex that triggers beta-catenin signaling through inducing
CC       aggregation of receptor-ligand complexes into ribosome-sized
CC       signalosomes (By similarity). The beta-catenin canonical signaling
CC       pathway leads to the activation of disheveled proteins, inhibition of
CC       GSK-3 kinase, nuclear accumulation of beta-catenin and activation of
CC       Wnt target genes. A second signaling pathway involving PKC and calcium
CC       fluxes has been seen for some family members, but it is not yet clear
CC       if it represents a distinct pathway or if it can be integrated in the
CC       canonical pathway, as PKC seems to be required for Wnt-mediated
CC       inactivation of GSK-3 kinase. Both pathways seem to involve
CC       interactions with G proteins. May be involved in transduction and
CC       intercellular transmission of polarity information during tissue
CC       morphogenesis and/or in differentiated tissues. Coreceptor along with
CC       RYK of Wnt proteins, such as WNT1. {ECO:0000250,
CC       ECO:0000269|PubMed:10097073, ECO:0000269|PubMed:10395542,
CC       ECO:0000269|PubMed:15454084, ECO:0000269|PubMed:16543246}.
CC   -!- SUBUNIT: Component of a Wnt-signaling complex that contains a WNT
CC       protein, a FZD protein and LRP5 or LRP6. Interacts directly with LRP5
CC       or LRP6; the interaction is promoted by Wnt-binding and signaling and
CC       inhibited by DKK1 (By similarity). Interacts (via the PDZ-binding
CC       motif) with GPOC (via its PDZ domain). Interacts with RSPO1 and RSPO3.
CC       Interacts with glypican GPC3 (By similarity). {ECO:0000250,
CC       ECO:0000250|UniProtKB:Q9H461, ECO:0000269|PubMed:11520064,
CC       ECO:0000269|PubMed:16543246, ECO:0000269|PubMed:22653731}.
CC   -!- INTERACTION:
CC       Q61091; Q8BH60: Gopc; NbExp=3; IntAct=EBI-6171689, EBI-296357;
CC       Q61091; P47879: Igfbp4; NbExp=3; IntAct=EBI-6171689, EBI-15706768;
CC       Q61091; P27467: Wnt3a; NbExp=7; IntAct=EBI-6171689, EBI-2899665;
CC       Q61091; O75581: LRP6; Xeno; NbExp=4; IntAct=EBI-6171689, EBI-910915;
CC       Q61091; P56703: WNT3; Xeno; NbExp=2; IntAct=EBI-6171689, EBI-3644922;
CC       Q61091; P28026: wnt8; Xeno; NbExp=3; IntAct=EBI-6171689, EBI-6257743;
CC   -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein. Golgi
CC       apparatus. Cell membrane; Multi-pass membrane protein. Note=Colocalizes
CC       with GOPC at the Golgi apparatus.
CC   -!- TISSUE SPECIFICITY: Expressed in chondrocytes.
CC   -!- DOMAIN: Lys-Thr-Xaa-Xaa-Xaa-Trp motif interacts with the PDZ domain of
CC       Dvl (Disheveled) family members and is involved in the activation of
CC       the Wnt/beta-catenin signaling pathway. {ECO:0000250}.
CC   -!- DOMAIN: The FZ domain is involved in binding with Wnt ligands.
CC   -!- PTM: Ubiquitinated by ZNRF3, leading to its degradation by the
CC       proteasome. {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the G protein-coupled receptor Fz/Smo family.
CC       {ECO:0000305}.
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DR   EMBL; U43321; AAC52433.1; -; Genomic_DNA.
DR   EMBL; CH466592; EDL23012.1; -; Genomic_DNA.
DR   EMBL; BC132543; AAI32544.1; -; mRNA.
DR   EMBL; BC138062; AAI38063.1; -; mRNA.
DR   CCDS; CCDS29048.1; -.
DR   RefSeq; NP_032084.2; NM_008058.2.
DR   PDB; 1IJY; X-ray; 1.35 A; A/B=28-155.
DR   PDB; 4F0A; X-ray; 3.25 A; A=28-150.
DR   PDB; 6AHY; X-ray; 2.80 A; A/C/E=28-159.
DR   PDB; 6TFB; X-ray; 1.68 A; A/B=28-151.
DR   PDB; 6TFM; X-ray; 2.34 A; A/B/C/D=28-151.
DR   PDB; 8CTG; EM; 3.80 A; A=28-150.
DR   AlphaFoldDB; Q61091; -.
DR   EMDB; EMD-26989; -.
DR   SMR; Q61091; -.
DR   BioGRID; 199781; 4.
DR   CORUM; Q61091; -.
DR   DIP; DIP-41258N; -.
DR   FunCoup; Q61091; 509.
DR   IntAct; Q61091; 13.
DR   STRING; 10090.ENSMUSP00000039660; -.
DR   BindingDB; Q61091; -.
DR   ChEMBL; CHEMBL4523332; -.
DR   DrugCentral; Q61091; -.
DR   GlyCosmos; Q61091; 3 sites, No reported glycans.
DR   GlyGen; Q61091; 3 sites.
DR   iPTMnet; Q61091; -.
DR   PhosphoSitePlus; Q61091; -.
DR   PaxDb; 10090-ENSMUSP00000039660; -.
DR   ProteomicsDB; 271621; -.
DR   Antibodypedia; 13314; 378 antibodies from 45 providers.
DR   DNASU; 14370; -.
DR   Ensembl; ENSMUST00000041080.7; ENSMUSP00000039660.6; ENSMUSG00000036904.7.
DR   GeneID; 14370; -.
DR   KEGG; mmu:14370; -.
DR   UCSC; uc008eag.2; mouse.
DR   AGR; MGI:108460; -.
DR   CTD; 8325; -.
DR   MGI; MGI:108460; Fzd8.
DR   VEuPathDB; HostDB:ENSMUSG00000036904; -.
DR   eggNOG; KOG3577; Eukaryota.
DR   GeneTree; ENSGT00940000161191; -.
DR   HOGENOM; CLU_007873_2_0_1; -.
DR   InParanoid; Q61091; -.
DR   OMA; AAGRXEA; -.
DR   OrthoDB; 10053709at2759; -.
DR   PhylomeDB; Q61091; -.
DR   Reactome; R-MMU-4608870; Asymmetric localization of PCP proteins.
DR   Reactome; R-MMU-4641263; Regulation of FZD by ubiquitination.
DR   BioGRID-ORCS; 14370; 1 hit in 78 CRISPR screens.
DR   EvolutionaryTrace; Q61091; -.
DR   PRO; PR:Q61091; -.
DR   Proteomes; UP000000589; Chromosome 18.
DR   RNAct; Q61091; protein.
DR   Bgee; ENSMUSG00000036904; Expressed in ventricular zone and 223 other cell types or tissues.
DR   GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR   GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR   GO; GO:0098992; C:neuronal dense core vesicle; IDA:SynGO.
DR   GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL.
DR   GO; GO:1990851; C:Wnt-Frizzled-LRP5/6 complex; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0030165; F:PDZ domain binding; IPI:BHF-UCL.
DR   GO; GO:0005102; F:signaling receptor binding; IPI:BHF-UCL.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:GO_Central.
DR   GO; GO:0042813; F:Wnt receptor activity; IPI:MGI.
DR   GO; GO:0017147; F:Wnt-protein binding; IPI:ParkinsonsUK-UCL.
DR   GO; GO:0001525; P:angiogenesis; IDA:MGI.
DR   GO; GO:0060070; P:canonical Wnt signaling pathway; IDA:MGI.
DR   GO; GO:0035567; P:non-canonical Wnt signaling pathway; IBA:GO_Central.
DR   GO; GO:0043507; P:positive regulation of JUN kinase activity; IDA:MGI.
DR   GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:MGI.
DR   GO; GO:0033077; P:T cell differentiation in thymus; IMP:MGI.
DR   GO; GO:0016055; P:Wnt signaling pathway; IDA:ParkinsonsUK-UCL.
DR   CDD; cd15250; 7tmF_FZD8; 1.
DR   CDD; cd07461; CRD_FZ8; 1.
DR   FunFam; 1.20.1070.10:FF:000262; Frizzled 2; 1.
DR   FunFam; 1.10.2000.10:FF:000004; Frizzled class receptor 8a; 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; IPR041776; FZ8_CRD.
DR   InterPro; IPR017981; GPCR_2-like_7TM.
DR   PANTHER; PTHR11309; FRIZZLED; 1.
DR   PANTHER; PTHR11309:SF90; FRIZZLED-8; 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.
PE   1: Evidence at protein level;
KW   3D-structure; Cell membrane; Developmental protein; Disulfide bond;
KW   G protein-coupled receptor; Glycoprotein; Golgi apparatus; Membrane;
KW   Receptor; Reference proteome; Signal; Transducer; Transmembrane;
KW   Transmembrane helix; Ubl conjugation; Wnt signaling pathway.
FT   SIGNAL          1..27
FT                   /evidence="ECO:0000255"
FT   CHAIN           28..685
FT                   /note="Frizzled-8"
FT                   /id="PRO_0000013001"
FT   TOPO_DOM        28..272
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        273..293
FT                   /note="Helical; Name=1"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        294..309
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        310..330
FT                   /note="Helical; Name=2"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        331..394
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        395..415
FT                   /note="Helical; Name=3"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        416..437
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        438..458
FT                   /note="Helical; Name=4"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        459..481
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        482..502
FT                   /note="Helical; Name=5"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        503..530
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        531..551
FT                   /note="Helical; Name=6"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        552..582
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        583..603
FT                   /note="Helical; Name=7"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        604..685
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          30..151
FT                   /note="FZ"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT   REGION          95..100
FT                   /note="Wnt-binding"
FT   REGION          147..152
FT                   /note="Wnt-binding"
FT   REGION          155..223
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          631..656
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           606..611
FT                   /note="Lys-Thr-Xaa-Xaa-Xaa-Trp motif, mediates interaction
FT                   with the PDZ domain of Dvl family members"
FT                   /evidence="ECO:0000250"
FT   MOTIF           683..685
FT                   /note="PDZ-binding"
FT   COMPBIAS        161..176
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        177..187
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        200..223
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        631..655
FT                   /note="Gly residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         71..78
FT                   /ligand="hexadecanoate"
FT                   /ligand_id="ChEBI:CHEBI:7896"
FT   CARBOHYD        49
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        152
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        473
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        35..96
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00090,
FT                   ECO:0000269|PubMed:11452312"
FT   DISULFID        43..89
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00090,
FT                   ECO:0000269|PubMed:11452312"
FT   DISULFID        80..118
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00090,
FT                   ECO:0000269|PubMed:11452312"
FT   DISULFID        107..148
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00090,
FT                   ECO:0000269|PubMed:11452312"
FT   DISULFID        111..135
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00090,
FT                   ECO:0000269|PubMed:11452312"
FT   MUTAGEN         685
FT                   /note="V->A: Reduces interaction with GOPC."
FT                   /evidence="ECO:0000269|PubMed:11520064"
FT   CONFLICT        347
FT                   /note="A -> R (in Ref. 1; AAC52433)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        363
FT                   /note="A -> R (in Ref. 1; AAC52433)"
FT                   /evidence="ECO:0000305"
FT   HELIX           41..43
FT                   /evidence="ECO:0007829|PDB:1IJY"
FT   STRAND          49..51
FT                   /evidence="ECO:0007829|PDB:4F0A"
FT   HELIX           62..69
FT                   /evidence="ECO:0007829|PDB:1IJY"
FT   HELIX           70..72
FT                   /evidence="ECO:0007829|PDB:1IJY"
FT   HELIX           73..78
FT                   /evidence="ECO:0007829|PDB:1IJY"
FT   HELIX           84..92
FT                   /evidence="ECO:0007829|PDB:1IJY"
FT   HELIX           108..124
FT                   /evidence="ECO:0007829|PDB:1IJY"
FT   HELIX           127..130
FT                   /evidence="ECO:0007829|PDB:6AHY"
FT   HELIX           131..133
FT                   /evidence="ECO:0007829|PDB:1IJY"
FT   HELIX           135..137
FT                   /evidence="ECO:0007829|PDB:1IJY"
FT   STRAND          144..146
FT                   /evidence="ECO:0007829|PDB:4F0A"
FT   STRAND          149..151
FT                   /evidence="ECO:0007829|PDB:6TFB"
SQ   SEQUENCE   685 AA;  73045 MW;  9DB95F068BC45CD8 CRC64;
     MEWGYLLEVT SLLAALAVLQ RSSGAAAASA KELACQEITV PLCKGIGYNY TYMPNQFNHD
     TQDEAGLEVH QFWPLVEIQC SPDLKFFLCS MYTPICLEDY KKPLPPCRSV CERAKAGCAP
     LMRQYGFAWP DRMRCDRLPE QGNPDTLCMD YNRTDLTTAA PSPPRRLPPP PPPGEQPPSG
     SGHSRPPGAR PPHRGGSSRG SGDAAAAPPS RGGKARPPGG GAAPCEPGCQ CRAPMVSVSS
     ERHPLYNRVK TGQIANCALP CHNPFFSQDE RAFTVFWIGL WSVLCFVSTF ATVSTFLIDM
     ERFKYPERPI IFLSACYLFV SVGYLVRLVA GHEKVACSGG APGAGGAGGA GGAAAAGAGA
     AGAGASSPGA RGEYEELGAV EQHVRYETTG PALCTVVFLL VYFFGMASSI WWVILSLTWF
     LAAGMKWGNE AIAGYSQYFH LAAWLVPSVK SIAVLALSSV DGDPVAGICY VGNQSLDNLR
     GFVLAPLVIY LFIGTMFLLA GFVSLFRIRS VIKQQGGPTK THKLEKLMIR LGLFTVLYTV
     PAAVVVACLF YEQHNRPRWE ATHNCPCLRD LQPDQARRPD YAVFMLKYFM CLVVGITSGV
     WVWSGKTLES WRALCTRCCW ASKGAAVGAG AGGSGPGGSG PGPGGGGGHG GGGGSLYSDV
     STGLTWRSGT ASSVSYPKQM PLSQV
//