FZD6_MOUSE
ID FZD6_MOUSE Reviewed; 709 AA.
AC Q61089;
DT 05-DEC-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=Frizzled-6;
DE Short=Fz-6;
DE Short=mFz6;
DE Flags: Precursor;
GN Name=Fzd6;
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 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 [3]
RP 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 [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-656, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP DISRUPTION PHENOTYPE.
RX PubMed=21665003; DOI=10.1016/j.ajhg.2011.05.013;
RA Frojmark A.S., Schuster J., Sobol M., Entesarian M., Kilander M.B.,
RA Gabrikova D., Nawaz S., Baig S.M., Schulte G., Klar J., Dahl N.;
RT "Mutations in Frizzled 6 cause isolated autosomal-recessive nail
RT dysplasia.";
RL Am. J. Hum. Genet. 88:852-860(2011).
RN [6]
RP FUNCTION, DISRUPTION PHENOTYPE, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=16495441; DOI=10.1523/jneurosci.4698-05.2005;
RA Wang Y., Guo N., Nathans J.;
RT "The role of Frizzled3 and Frizzled6 in neural tube closure and in the
RT planar polarity of inner-ear sensory hair cells.";
RL J. Neurosci. 26:2147-2156(2006).
RN [7]
RP INTERACTION WITH LMBR1L, AND SUBCELLULAR LOCATION.
RX PubMed=31073040; DOI=10.1126/science.aau0812;
RA Choi J.H., Zhong X., McAlpine W., Liao T.C., Zhang D., Fang B., Russell J.,
RA Ludwig S., Nair-Gill E., Zhang Z., Wang K.W., Misawa T., Zhan X., Choi M.,
RA Wang T., Li X., Tang M., Sun Q., Yu L., Murray A.R., Moresco E.M.Y.,
RA Beutler B.;
RT "LMBR1L regulates lymphopoiesis through Wnt/beta-catenin signaling.";
RL Science 364:0-0(2019).
CC -!- FUNCTION: Receptor for Wnt proteins. Most of frizzled receptors are
CC coupled to the beta-catenin canonical signaling pathway, which leads to
CC the activation of disheveled proteins, inhibition of GSK-3 kinase,
CC nuclear accumulation of beta-catenin and activation of Wnt target
CC genes. A second signaling pathway involving PKC and calcium fluxes has
CC been seen for some family members, but it is not yet clear if it
CC 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. Activation by Wnt5A stimulates PKC
CC activity via a G-protein-dependent mechanism. Involved in transduction
CC and intercellular transmission of polarity information during tissue
CC morphogenesis and/or in differentiated tissues (By similarity).
CC Together with FZD3, is involved in the neural tube closure and plays a
CC role in the regulation of the establishment of planar cell polarity
CC (PCP), particularly in the orientation of asymmetric bundles of
CC stereocilia on the apical faces of a subset of auditory and vestibular
CC sensory cells located in the inner ear. {ECO:0000250,
CC ECO:0000269|PubMed:16495441}.
CC -!- SUBUNIT: Interacts with LMBR1L. {ECO:0000269|PubMed:31073040}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000269|PubMed:10097073}; Multi-
CC pass membrane protein {ECO:0000255}. Cell membrane
CC {ECO:0000269|PubMed:10097073}; Multi-pass membrane protein
CC {ECO:0000255}. Cell surface {ECO:0000269|PubMed:16495441}. Apical cell
CC membrane {ECO:0000269|PubMed:16495441}; Multi-pass membrane protein
CC {ECO:0000255}. Cytoplasmic vesicle membrane
CC {ECO:0000269|PubMed:16495441}; Multi-pass membrane protein
CC {ECO:0000255}. Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:31073040}; Multi-pass membrane protein
CC {ECO:0000255}. Note=Colocalizes with FZD3 at the apical face of cells
CC (PubMed:16495441). Localizes to the endoplasmic reticulum membrane in
CC the presence of LMBR1L (PubMed:31073040). {ECO:0000269|PubMed:16495441,
CC ECO:0000269|PubMed:31073040}.
CC -!- TISSUE SPECIFICITY: Expressed in both hair cells and supporting cells
CC in the utricle, saccule, cristae and the organ of Corti in the inner
CC ear (at protein level). {ECO:0000269|PubMed:16495441}.
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: Half of the males without the gene, but not
CC females, display abnormal claw morphology or absent claws compared to
CC wild-type; at the age of 2 to 3 months, the claws disappear or become
CC rudimentary on the hind limbs (PubMed:21665003). FZD3 and FZD6 double
CC knockout embryos have a curled tail, exhibit defects in neural tube and
CC eyelids closure, in the orientation of hair bundles on inner-ear
CC sensory cells and die at birth (PubMed:16495441).
CC {ECO:0000269|PubMed:16495441, ECO:0000269|PubMed:21665003}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor Fz/Smo family.
CC {ECO:0000305}.
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DR EMBL; U43319; AAC52431.1; -; mRNA.
DR CCDS; CCDS27441.1; -.
DR RefSeq; NP_001155966.1; NM_001162494.1.
DR RefSeq; NP_032082.3; NM_008056.3.
DR RefSeq; XP_017171919.1; XM_017316430.1.
DR AlphaFoldDB; Q61089; -.
DR SMR; Q61089; -.
DR BioGRID; 199779; 2.
DR IntAct; Q61089; 1.
DR STRING; 10090.ENSMUSP00000022906; -.
DR GlyGen; Q61089; 3 sites.
DR iPTMnet; Q61089; -.
DR PhosphoSitePlus; Q61089; -.
DR MaxQB; Q61089; -.
DR PaxDb; Q61089; -.
DR PRIDE; Q61089; -.
DR ProteomicsDB; 272927; -.
DR Antibodypedia; 2906; 350 antibodies from 37 providers.
DR DNASU; 14368; -.
DR Ensembl; ENSMUST00000022906; ENSMUSP00000022906; ENSMUSG00000022297.
DR Ensembl; ENSMUST00000179165; ENSMUSP00000136328; ENSMUSG00000022297.
DR GeneID; 14368; -.
DR KEGG; mmu:14368; -.
DR UCSC; uc007vny.2; mouse.
DR CTD; 8323; -.
DR MGI; MGI:108474; Fzd6.
DR VEuPathDB; HostDB:ENSMUSG00000022297; -.
DR eggNOG; KOG3577; Eukaryota.
DR GeneTree; ENSGT00940000158485; -.
DR HOGENOM; CLU_007873_4_0_1; -.
DR InParanoid; Q61089; -.
DR OMA; HAVAWGM; -.
DR OrthoDB; 330751at2759; -.
DR PhylomeDB; Q61089; -.
DR TreeFam; TF317907; -.
DR Reactome; R-MMU-4086398; Ca2+ pathway.
DR Reactome; R-MMU-4086400; PCP/CE pathway.
DR Reactome; R-MMU-4641263; Regulation of FZD by ubiquitination.
DR BioGRID-ORCS; 14368; 2 hits in 72 CRISPR screens.
DR ChiTaRS; Fzd6; mouse.
DR PRO; PR:Q61089; -.
DR Proteomes; UP000000589; Chromosome 15.
DR RNAct; Q61089; protein.
DR Bgee; ENSMUSG00000022297; Expressed in lip and 141 other tissues.
DR ExpressionAtlas; Q61089; baseline and differential.
DR Genevisible; Q61089; MM.
DR GO; GO:0045177; C:apical part of cell; IDA:MGI.
DR GO; GO:0016324; C:apical plasma membrane; IDA:MGI.
DR GO; GO:0016327; C:apicolateral plasma membrane; IDA:MGI.
DR GO; GO:0009986; C:cell surface; IEA:UniProtKB-SubCell.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0004930; F:G protein-coupled receptor activity; IEA:UniProtKB-KW.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR GO; GO:0042813; F:Wnt receptor activity; ISO:MGI.
DR GO; GO:0017147; F:Wnt-protein binding; IPI:BHF-UCL.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IBA:GO_Central.
DR GO; GO:0033278; P:cell proliferation in midbrain; IGI:MGI.
DR GO; GO:0035880; P:embryonic nail plate morphogenesis; IMP:MGI.
DR GO; GO:0048105; P:establishment of body hair planar orientation; IGI:MGI.
DR GO; GO:0001736; P:establishment of planar polarity; IGI:MGI.
DR GO; GO:0001942; P:hair follicle development; IMP:MGI.
DR GO; GO:0042472; P:inner ear morphogenesis; IGI:MGI.
DR GO; GO:0030901; P:midbrain development; IGI:MGI.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; ISO:MGI.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; ISO:MGI.
DR GO; GO:0001843; P:neural tube closure; IGI:MGI.
DR GO; GO:0035567; P:non-canonical Wnt signaling pathway; ISO:MGI.
DR GO; GO:0030168; P:platelet activation; IMP:MGI.
DR GO; GO:0060071; P:Wnt signaling pathway, planar cell polarity pathway; IDA:MGI.
DR CDD; cd07450; CRD_FZ6; 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; IPR041770; FZ6_CRD.
DR InterPro; IPR026543; FZD6.
DR InterPro; IPR017981; GPCR_2-like.
DR PANTHER; PTHR11309; PTHR11309; 1.
DR PANTHER; PTHR11309:SF75; PTHR11309:SF75; 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; Cytoplasmic vesicle; Developmental protein; Disulfide bond;
KW Endoplasmic reticulum; G-protein coupled receptor; Glycoprotein; Membrane;
KW Neurogenesis; Phosphoprotein; Receptor; Reference proteome; Signal;
KW Transducer; Transmembrane; Transmembrane helix; Ubl conjugation;
KW Wnt signaling pathway.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..709
FT /note="Frizzled-6"
FT /id="PRO_0000012995"
FT TOPO_DOM 19..201
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 202..222
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 223..233
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 234..254
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 255..284
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 285..305
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 306..324
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 325..345
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 346..370
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 371..391
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 392..416
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 417..437
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 438..473
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 474..494
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 495..709
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 19..132
FT /note="FZ"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT REGION 583..709
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 498..503
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 COMPBIAS 594..611
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 663..694
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 656
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT CARBOHYD 38
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 256
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 352
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 24..85
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT DISULFID 32..78
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT DISULFID 69..106
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT DISULFID 95..129
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT DISULFID 99..123
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
SQ SEQUENCE 709 AA; 79082 MW; 01374A9EC9122484 CRC64;
MERSPFLLAC ILLPLVRGHS LFTCEPITVP RCMKMTYNMT FFPNLMGHYD QGIAAVEMGH
FLHLANLECS PNIEMFLCQA FIPTCTEQIH VVLPCRKLCE KIVSDCKKLM DTFGIRWPEE
LECNRLPHCD DTVPVTSHPH TELSGPQKKS DQVPRDIGFW CPKHLRTSGD QGYRFLGIEQ
CAPPCPNMYF KSDELDFAKS FIGIVSIFCL CATLFTFLTF LIDVRRFRYP ERPIIYYSVC
YSIVSLMYFV GFLLGNSTAC NKADEKLELG DTVVLGSKNK ACSVVFMFLY FFTMAGTVWW
VILTITWFLA AGRKWSCEAI EQKAVWFHAV AWGAPGFLTV MLLAMNKVEG DNISGVCFVG
LYDLDASRYF VLLPLCLCVF VGLSLLLAGI ISLNHVRQVI QHDGRNQEKL KKFMIRIGVF
SGLYLVPLVT LLGCYVYELV NRITWEMTWF SDHCHQYRIP CPYQANPKAR PELALFMIKY
LMTLIVGISA VFWVGSKKTC TEWAGFFKRN RKRDPISESR RVLQESCEFF LKHNSKVKHK
KKHGAPGPHR LKVISKSMGT STGATTNHGT SAMAIADHDY LGQETSTEVH TSPEASVKEG
RADRANTPSA KDRDCGESAG PSSKLSGNRN GRESRAGGLK ERSNGSEGAP SEGRVSPKSS
VPETGLIDCS TSQAASSPEP TSLKGSTSLP VHSASRARKE QGAGSHSDA
