FZD8_HUMAN
ID FZD8_HUMAN Reviewed; 694 AA.
AC Q9H461;
DT 05-DEC-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2001, sequence version 1.
DT 03-AUG-2022, entry version 183.
DE RecName: Full=Frizzled-8;
DE Short=Fz-8;
DE Short=hFz8;
DE Flags: Precursor;
GN Name=FZD8;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11295046; DOI=10.3892/ijo.18.5.991;
RA Saitoh T., Hirai M., Katoh M.;
RT "Molecular cloning and characterization of human Frizzled-8 gene on
RT chromosome 10p11.2.";
RL Int. J. Oncol. 18:991-996(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [3]
RP INTERACTION WITH LRP5 AND LRP6 IN THE WNT-FZD-LRP5-LRP6 COMPLEX, AND
RP FUNCTION.
RX PubMed=11448771; DOI=10.1016/s0960-9822(01)00290-1;
RA Semenov M.V., Tamai K., Brott B.K., Kuhl M., Sokol S., He X.;
RT "Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6.";
RL Curr. Biol. 11:951-961(2001).
RN [4]
RP INTERACTION WITH GOPC.
RX PubMed=16882988; DOI=10.1110/ps.062087506;
RA Li X., Zhang J., Cao Z., Wu J., Shi Y.;
RT "Solution structure of GOPC PDZ domain and its interaction with the C-
RT terminal motif of neuroligin.";
RL Protein Sci. 15:2149-2158(2006).
RN [5]
RP UBIQUITINATION BY ZNRF3.
RX PubMed=22575959; DOI=10.1038/nature11019;
RA Hao H.X., Xie Y., Zhang Y., Charlat O., Oster E., Avello M., Lei H.,
RA Mickanin C., Liu D., Ruffner H., Mao X., Ma Q., Zamponi R., Bouwmeester T.,
RA Finan P.M., Kirschner M.W., Porter J.A., Serluca F.C., Cong F.;
RT "ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner.";
RL Nature 485:195-200(2012).
RN [6]
RP INTERACTION WITH GPC3.
RX PubMed=24496449; DOI=10.1242/jcs.140871;
RA Capurro M., Martin T., Shi W., Filmus J.;
RT "Glypican-3 binds to Frizzled and plays a direct role in the stimulation of
RT canonical Wnt signaling.";
RL J. Cell Sci. 127:1565-1575(2014).
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. The beta-catenin canonical signaling pathway leads to the
CC activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear
CC accumulation of beta-catenin and activation of Wnt target genes. A
CC second signaling pathway involving PKC and calcium fluxes has been seen
CC for some family members, but it is not yet clear if it represents a
CC distinct pathway or if it can be integrated in the canonical pathway,
CC as PKC seems to be required for Wnt-mediated inactivation of GSK-3
CC kinase. Both pathways seem to involve interactions with G-proteins. May
CC be involved in transduction and intercellular transmission of polarity
CC information during tissue morphogenesis and/or in differentiated
CC tissues. Coreceptor along with RYK of Wnt proteins, such as WNT1.
CC {ECO:0000269|PubMed:11448771}.
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. Interacts with GPOC, RSPO1 and RSPO3 (By
CC similarity). Interacts with glypican GPC3 (PubMed:24496449).
CC {ECO:0000250, ECO:0000269|PubMed:24496449}.
CC -!- INTERACTION:
CC Q9H461; P56704: WNT3A; NbExp=2; IntAct=EBI-6254212, EBI-6173037;
CC Q9H461; P98086: C1qa; Xeno; NbExp=3; IntAct=EBI-6254212, EBI-299840;
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein. Golgi
CC apparatus {ECO:0000250}. Cell membrane {ECO:0000250}; Multi-pass
CC membrane protein {ECO:0000250}. Note=Colocalizes with GOPC at the Golgi
CC apparatus. {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Most abundant in fetal kidney, followed by brain
CC and lung. In adult tissues, expressed in kidney, heart, pancreas and
CC skeletal muscle.
CC -!- DOMAIN: The PDZ-binding motif mediates interaction with GOPC.
CC {ECO:0000250}.
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:0000269|PubMed:22575959}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor Fz/Smo family.
CC {ECO:0000305}.
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DR EMBL; AB043703; BAB41064.1; -; mRNA.
DR EMBL; AL121749; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS7192.1; -.
DR RefSeq; NP_114072.1; NM_031866.2.
DR PDB; 5UN5; X-ray; 2.99 A; A/B=28-150.
DR PDB; 5UN6; X-ray; 3.20 A; A/B/C/D=28-150.
DR PDB; 6NDZ; X-ray; 2.26 A; A/C/E=32-150.
DR PDBsum; 5UN5; -.
DR PDBsum; 5UN6; -.
DR PDBsum; 6NDZ; -.
DR AlphaFoldDB; Q9H461; -.
DR SMR; Q9H461; -.
DR BioGRID; 113921; 18.
DR IntAct; Q9H461; 6.
DR STRING; 9606.ENSP00000363826; -.
DR ChEMBL; CHEMBL3559689; -.
DR GuidetoPHARMACOLOGY; 236; -.
DR GlyGen; Q9H461; 3 sites.
DR iPTMnet; Q9H461; -.
DR PhosphoSitePlus; Q9H461; -.
DR BioMuta; FZD8; -.
DR DMDM; 17433053; -.
DR jPOST; Q9H461; -.
DR MassIVE; Q9H461; -.
DR PaxDb; Q9H461; -.
DR PeptideAtlas; Q9H461; -.
DR PRIDE; Q9H461; -.
DR ProteomicsDB; 80787; -.
DR ABCD; Q9H461; 39 sequenced antibodies.
DR Antibodypedia; 13314; 337 antibodies from 40 providers.
DR DNASU; 8325; -.
DR Ensembl; ENST00000374694.3; ENSP00000363826.1; ENSG00000177283.8.
DR GeneID; 8325; -.
DR KEGG; hsa:8325; -.
DR MANE-Select; ENST00000374694.3; ENSP00000363826.1; NM_031866.3; NP_114072.1.
DR UCSC; uc001iyz.2; human.
DR CTD; 8325; -.
DR DisGeNET; 8325; -.
DR GeneCards; FZD8; -.
DR HGNC; HGNC:4046; FZD8.
DR HPA; ENSG00000177283; Tissue enhanced (choroid).
DR MIM; 606146; gene.
DR neXtProt; NX_Q9H461; -.
DR OpenTargets; ENSG00000177283; -.
DR PharmGKB; PA28463; -.
DR VEuPathDB; HostDB:ENSG00000177283; -.
DR eggNOG; KOG3577; Eukaryota.
DR GeneTree; ENSGT00940000161191; -.
DR HOGENOM; CLU_007873_2_0_1; -.
DR InParanoid; Q9H461; -.
DR OMA; MECYLLG; -.
DR OrthoDB; 509772at2759; -.
DR PhylomeDB; Q9H461; -.
DR TreeFam; TF317907; -.
DR PathwayCommons; Q9H461; -.
DR Reactome; R-HSA-373080; Class B/2 (Secretin family receptors).
DR Reactome; R-HSA-4608870; Asymmetric localization of PCP proteins.
DR Reactome; R-HSA-4641263; Regulation of FZD by ubiquitination.
DR Reactome; R-HSA-5340588; Signaling by RNF43 mutants.
DR SignaLink; Q9H461; -.
DR SIGNOR; Q9H461; -.
DR BioGRID-ORCS; 8325; 13 hits in 1062 CRISPR screens.
DR GeneWiki; FZD8; -.
DR GenomeRNAi; 8325; -.
DR Pharos; Q9H461; Tbio.
DR PRO; PR:Q9H461; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; Q9H461; protein.
DR Bgee; ENSG00000177283; Expressed in ventricular zone and 169 other tissues.
DR Genevisible; Q9H461; HS.
DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:1990851; C:Wnt-Frizzled-LRP5/6 complex; IEA:Ensembl.
DR GO; GO:0004930; F:G protein-coupled receptor activity; IEA:UniProtKB-KW.
DR GO; GO:0030165; F:PDZ domain binding; IPI:BHF-UCL.
DR GO; GO:0005102; F:signaling receptor binding; IEA:Ensembl.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:0042813; F:Wnt receptor activity; IDA:WormBase.
DR GO; GO:0017147; F:Wnt-protein binding; IBA:GO_Central.
DR GO; GO:0001525; P:angiogenesis; IEA:Ensembl.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IDA:WormBase.
DR GO; GO:0030182; P:neuron differentiation; ISS:UniProtKB.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IEA:Ensembl.
DR GO; GO:0033077; P:T cell differentiation in thymus; IEA:Ensembl.
DR CDD; cd07461; CRD_FZ8; 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; IPR041776; FZ8_CRD.
DR InterPro; IPR017981; GPCR_2-like.
DR PANTHER; PTHR11309; PTHR11309; 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 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..694
FT /note="Frizzled-8"
FT /id="PRO_0000013000"
FT TOPO_DOM 28..275
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 276..296
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 297..312
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 313..333
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 334..396
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 397..417
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 418..439
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 440..460
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 461..483
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 484..504
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 505..532
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 533..553
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 554..584
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 585..605
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 606..694
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 /evidence="ECO:0000250"
FT REGION 147..152
FT /note="Wnt-binding"
FT /evidence="ECO:0000250"
FT REGION 155..226
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 648..668
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 608..613
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 692..694
FT /note="PDZ-binding"
FT COMPBIAS 162..179
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 71..78
FT /ligand="hexadecanoate"
FT /ligand_id="ChEBI:CHEBI:7896"
FT /evidence="ECO:0000250"
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 475
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 35..96
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT DISULFID 43..89
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT DISULFID 80..118
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT DISULFID 107..148
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT DISULFID 111..135
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT STRAND 35..37
FT /evidence="ECO:0007829|PDB:5UN6"
FT HELIX 41..43
FT /evidence="ECO:0007829|PDB:6NDZ"
FT STRAND 50..54
FT /evidence="ECO:0007829|PDB:5UN6"
FT HELIX 62..70
FT /evidence="ECO:0007829|PDB:6NDZ"
FT HELIX 73..78
FT /evidence="ECO:0007829|PDB:6NDZ"
FT HELIX 84..92
FT /evidence="ECO:0007829|PDB:6NDZ"
FT HELIX 108..124
FT /evidence="ECO:0007829|PDB:6NDZ"
FT HELIX 131..133
FT /evidence="ECO:0007829|PDB:6NDZ"
FT STRAND 135..138
FT /evidence="ECO:0007829|PDB:6NDZ"
FT STRAND 144..146
FT /evidence="ECO:0007829|PDB:6NDZ"
SQ SEQUENCE 694 AA; 73300 MW; E740CBFDA2A233EF CRC64;
MEWGYLLEVT SLLAALALLQ RSSGAAAASA KELACQEITV PLCKGIGYNY TYMPNQFNHD
TQDEAGLEVH QFWPLVEIQC SPDLKFFLCS MYTPICLEDY KKPLPPCRSV CERAKAGCAP
LMRQYGFAWP DRMRCDRLPE QGNPDTLCMD YNRTDLTTAA PSPPRRLPPP PPGEQPPSGS
GHGRPPGARP PHRGGGRGGG GGDAAAPPAR GGGGGGKARP PGGGAAPCEP GCQCRAPMVS
VSSERHPLYN RVKTGQIANC ALPCHNPFFS QDERAFTVFW IGLWSVLCFV STFATVSTFL
IDMERFKYPE RPIIFLSACY LFVSVGYLVR LVAGHEKVAC SGGAPGAGGA GGAGGAAAGA
GAAGAGAGGP GGRGEYEELG AVEQHVRYET TGPALCTVVF LLVYFFGMAS SIWWVILSLT
WFLAAGMKWG NEAIAGYSQY FHLAAWLVPS VKSIAVLALS SVDGDPVAGI CYVGNQSLDN
LRGFVLAPLV IYLFIGTMFL LAGFVSLFRI RSVIKQQDGP TKTHKLEKLM IRLGLFTVLY
TVPAAVVVAC LFYEQHNRPR WEATHNCPCL RDLQPDQARR PDYAVFMLKY FMCLVVGITS
GVWVWSGKTL ESWRSLCTRC CWASKGAAVG GGAGATAAGG GGGPGGGGGG GPGGGGGPGG
GGGSLYSDVS TGLTWRSGTA SSVSYPKQMP LSQV
