ID   SFRP3_HUMAN             Reviewed;         325 AA.
AC   Q92765; O00181; Q99686;
DT   01-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-2001, sequence version 2.
DT   27-MAR-2024, entry version 199.
DE   RecName: Full=Secreted frizzled-related protein 3;
DE            Short=sFRP-3;
DE   AltName: Full=Frezzled;
DE   AltName: Full=Fritz;
DE   AltName: Full=Frizzled-related protein 1;
DE   AltName: Full=FrzB-1;
DE   Flags: Precursor;
GN   Name=FRZB; Synonyms=FIZ, FRE, FRP, FRZB1, SFRP3;
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].
RC   TISSUE=Placenta;
RX   PubMed=8824257; DOI=10.1074/jbc.271.42.26131;
RA   Hoang B., Moos M. Jr., Vukicevic S., Luyten F.P.;
RT   "Primary structure and tissue distribution of FRZB, a novel protein related
RT   to Drosophila frizzled, suggest a role in skeletal morphogenesis.";
RL   J. Biol. Chem. 271:26131-26137(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=9178261; DOI=10.1016/s0925-4773(97)00035-x;
RA   Mayr T., Deutsch U., Kuehl M., Drexler H.C.A., Lottspeich F., Deutzmann R.,
RA   Wedlich D., Risau W.;
RT   "Fritz: a secreted frizzled-related protein that inhibits Wnt activity.";
RL   Mech. Dev. 63:109-125(1997).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Embryo;
RX   PubMed=9118218; DOI=10.1016/s0092-8674(00)81921-2;
RA   Leyns L., Bouwmeester T., Kim S.-H., Piccolo S., de Robertis E.M.;
RT   "Frzb-1 is a secreted antagonist of Wnt signaling expressed in the Spemann
RT   organizer.";
RL   Cell 88:747-756(1997).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Pancreas, and Spleen;
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   [6]
RP   PROTEIN SEQUENCE OF 33-47.
RX   PubMed=15340161; DOI=10.1110/ps.04682504;
RA   Zhang Z., Henzel W.J.;
RT   "Signal peptide prediction based on analysis of experimentally verified
RT   cleavage sites.";
RL   Protein Sci. 13:2819-2824(2004).
RN   [7]
RP   INTERACTION WITH MYOC.
RX   PubMed=19188438; DOI=10.1128/mcb.01274-08;
RA   Kwon H.S., Lee H.S., Ji Y., Rubin J.S., Tomarev S.I.;
RT   "Myocilin is a modulator of Wnt signaling.";
RL   Mol. Cell. Biol. 29:2139-2154(2009).
RN   [8]
RP   INVOLVEMENT IN OS1, VARIANT OS1 GLY-324, AND VARIANT TRP-200.
RX   PubMed=15210948; DOI=10.1073/pnas.0403456101;
RA   Loughlin J., Dowling B., Chapman K., Marcelline L., Mustafa Z., Southam L.,
RA   Ferreira A., Ciesielski C., Carson D.A., Corr M.;
RT   "Functional variants within the secreted frizzled-related protein 3 gene
RT   are associated with hip osteoarthritis in females.";
RL   Proc. Natl. Acad. Sci. U.S.A. 101:9757-9762(2004).
CC   -!- FUNCTION: Soluble frizzled-related proteins (sFRPS) function as
CC       modulators of Wnt signaling through direct interaction with Wnts. They
CC       have a role in regulating cell growth and differentiation in specific
CC       cell types. SFRP3/FRZB appears to be involved in limb skeletogenesis.
CC       Antagonist of Wnt8 signaling. Regulates chondrocyte maturation and long
CC       bone development.
CC   -!- SUBUNIT: Interacts with MYOC. {ECO:0000269|PubMed:19188438}.
CC   -!- INTERACTION:
CC       Q92765; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-2822789, EBI-3867333;
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}.
CC   -!- TISSUE SPECIFICITY: Expressed primarily in the cartilaginous cores of
CC       the long bone during embryonic and fetal development and in the
CC       appendicular skeleton (6-13 weeks). At 13 weeks of gestation,
CC       transcripts were present in early chondroblasts of the tarsal bones of
CC       the foot, the carpal bones of the hands and the epiphysis of long
CC       bones. Highly expressed in placenta and heart, followed by brain,
CC       skeletal muscle, kidney and pancreas. Weakly expressed in lung and
CC       liver.
CC   -!- DOMAIN: The FZ domain is involved in binding with Wnt ligands.
CC       {ECO:0000250}.
CC   -!- DISEASE: Osteoarthritis 1 (OS1) [MIM:165720]: A degenerative disease of
CC       the joints characterized by degradation of the hyaline articular
CC       cartilage and remodeling of the subchondral bone with sclerosis.
CC       Clinical symptoms include pain and joint stiffness often leading to
CC       significant disability and joint replacement.
CC       {ECO:0000269|PubMed:15210948}. Note=Disease susceptibility is
CC       associated with variants affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the secreted frizzled-related protein (sFRP)
CC       family. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="https://atlasgeneticsoncology.org/gene/44457/FRZB";
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DR   EMBL; U24163; AAC50736.1; -; mRNA.
DR   EMBL; U91903; AAB51298.1; -; mRNA.
DR   EMBL; U68057; AAC51217.1; -; mRNA.
DR   EMBL; BT019883; AAV38686.1; -; mRNA.
DR   EMBL; BC027855; AAH27855.1; -; mRNA.
DR   CCDS; CCDS2286.1; -.
DR   RefSeq; NP_001454.2; NM_001463.3.
DR   AlphaFoldDB; Q92765; -.
DR   SMR; Q92765; -.
DR   BioGRID; 108765; 11.
DR   IntAct; Q92765; 11.
DR   MINT; Q92765; -.
DR   STRING; 9606.ENSP00000295113; -.
DR   GlyConnect; 1725; 3 N-Linked glycans (1 site).
DR   GlyCosmos; Q92765; 1 site, 2 glycans.
DR   GlyGen; Q92765; 2 sites, 2 N-linked glycans (1 site), 1 O-linked glycan (1 site).
DR   iPTMnet; Q92765; -.
DR   PhosphoSitePlus; Q92765; -.
DR   BioMuta; FRZB; -.
DR   DMDM; 14194748; -.
DR   jPOST; Q92765; -.
DR   MassIVE; Q92765; -.
DR   PaxDb; 9606-ENSP00000295113; -.
DR   PeptideAtlas; Q92765; -.
DR   ProteomicsDB; 75449; -.
DR   Antibodypedia; 3981; 379 antibodies from 30 providers.
DR   DNASU; 2487; -.
DR   Ensembl; ENST00000295113.5; ENSP00000295113.4; ENSG00000162998.5.
DR   GeneID; 2487; -.
DR   KEGG; hsa:2487; -.
DR   MANE-Select; ENST00000295113.5; ENSP00000295113.4; NM_001463.4; NP_001454.2.
DR   UCSC; uc002upa.4; human.
DR   AGR; HGNC:3959; -.
DR   CTD; 2487; -.
DR   DisGeNET; 2487; -.
DR   GeneCards; FRZB; -.
DR   HGNC; HGNC:3959; FRZB.
DR   HPA; ENSG00000162998; Group enriched (choroid plexus, lymphoid tissue, retina, tongue).
DR   MIM; 165720; phenotype.
DR   MIM; 605083; gene.
DR   neXtProt; NX_Q92765; -.
DR   OpenTargets; ENSG00000162998; -.
DR   PharmGKB; PA28377; -.
DR   VEuPathDB; HostDB:ENSG00000162998; -.
DR   eggNOG; KOG3577; Eukaryota.
DR   GeneTree; ENSGT00940000160494; -.
DR   HOGENOM; CLU_058446_1_0_1; -.
DR   InParanoid; Q92765; -.
DR   OMA; IRYRHAW; -.
DR   OrthoDB; 2919179at2759; -.
DR   PhylomeDB; Q92765; -.
DR   PathwayCommons; Q92765; -.
DR   SignaLink; Q92765; -.
DR   SIGNOR; Q92765; -.
DR   BioGRID-ORCS; 2487; 7 hits in 1149 CRISPR screens.
DR   ChiTaRS; FRZB; human.
DR   GenomeRNAi; 2487; -.
DR   Pharos; Q92765; Tbio.
DR   PRO; PR:Q92765; -.
DR   Proteomes; UP000005640; Chromosome 2.
DR   RNAct; Q92765; Protein.
DR   Bgee; ENSG00000162998; Expressed in pigmented layer of retina and 188 other cell types or tissues.
DR   ExpressionAtlas; Q92765; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005615; C:extracellular space; HDA:BHF-UCL.
DR   GO; GO:0016020; C:membrane; TAS:ProtInc.
DR   GO; GO:0017147; F:Wnt-protein binding; ISS:UniProtKB.
DR   GO; GO:0060070; P:canonical Wnt signaling pathway; IBA:GO_Central.
DR   GO; GO:0090103; P:cochlea morphogenesis; IEA:Ensembl.
DR   GO; GO:0060029; P:convergent extension involved in organogenesis; IEA:Ensembl.
DR   GO; GO:0002064; P:epithelial cell development; IEA:Ensembl.
DR   GO; GO:0070365; P:hepatocyte differentiation; IEA:Ensembl.
DR   GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:UniProtKB.
DR   GO; GO:0061037; P:negative regulation of cartilage development; IEA:Ensembl.
DR   GO; GO:0010721; P:negative regulation of cell development; IEA:Ensembl.
DR   GO; GO:0030308; P:negative regulation of cell growth; IDA:UniProtKB.
DR   GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:UniProtKB.
DR   GO; GO:0070367; P:negative regulation of hepatocyte differentiation; IEA:Ensembl.
DR   GO; GO:0030178; P:negative regulation of Wnt signaling pathway; IDA:UniProtKB.
DR   GO; GO:0014033; P:neural crest cell differentiation; IEA:Ensembl.
DR   GO; GO:0035567; P:non-canonical Wnt signaling pathway; IBA:GO_Central.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IGI:MGI.
DR   GO; GO:0045600; P:positive regulation of fat cell differentiation; IDA:MGI.
DR   GO; GO:0001501; P:skeletal system development; TAS:ProtInc.
DR   GO; GO:0061053; P:somite development; IEA:Ensembl.
DR   CDD; cd07441; CRD_SFRP3; 1.
DR   CDD; cd03581; NTR_Sfrp3_like; 1.
DR   Gene3D; 2.40.50.120; -; 1.
DR   Gene3D; 1.10.2000.10; Frizzled cysteine-rich domain; 1.
DR   InterPro; IPR015526; Frizzled/SFRP.
DR   InterPro; IPR020067; Frizzled_dom.
DR   InterPro; IPR036790; Frizzled_dom_sf.
DR   InterPro; IPR001134; Netrin_domain.
DR   InterPro; IPR018933; Netrin_module_non-TIMP.
DR   InterPro; IPR035813; NTR_Sfrp3.
DR   InterPro; IPR041759; SFRP3_CRD.
DR   InterPro; IPR008993; TIMP-like_OB-fold.
DR   PANTHER; PTHR11309; FRIZZLED; 1.
DR   PANTHER; PTHR11309:SF97; SECRETED FRIZZLED-RELATED PROTEIN 3; 1.
DR   Pfam; PF01392; Fz; 1.
DR   Pfam; PF01759; NTR; 1.
DR   SMART; SM00643; C345C; 1.
DR   SMART; SM00063; FRI; 1.
DR   SUPFAM; SSF63501; Frizzled cysteine-rich domain; 1.
DR   SUPFAM; SSF50242; TIMP-like; 1.
DR   PROSITE; PS50038; FZ; 1.
DR   PROSITE; PS50189; NTR; 1.
DR   Genevisible; Q92765; HS.
PE   1: Evidence at protein level;
KW   Developmental protein; Differentiation; Direct protein sequencing;
KW   Disease variant; Disulfide bond; Glycoprotein; Reference proteome;
KW   Secreted; Signal; Wnt signaling pathway.
FT   SIGNAL          1..32
FT                   /evidence="ECO:0000269|PubMed:15340161"
FT   CHAIN           33..325
FT                   /note="Secreted frizzled-related protein 3"
FT                   /id="PRO_0000032546"
FT   DOMAIN          33..150
FT                   /note="FZ"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT   DOMAIN          178..298
FT                   /note="NTR"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT   REGION          297..325
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        298..325
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   CARBOHYD        49
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        35..96
FT                   /evidence="ECO:0000250"
FT   DISULFID        43..89
FT                   /evidence="ECO:0000250"
FT   DISULFID        80..119
FT                   /evidence="ECO:0000250"
FT   DISULFID        108..147
FT                   /evidence="ECO:0000250"
FT   DISULFID        112..136
FT                   /evidence="ECO:0000250"
FT   VARIANT         200
FT                   /note="R -> W (in dbSNP:rs288326)"
FT                   /evidence="ECO:0000269|PubMed:15210948"
FT                   /id="VAR_021411"
FT   VARIANT         324
FT                   /note="R -> G (in OS1; associated with disease
FT                   susceptibility; has diminished ability to antagonize Wnt
FT                   signaling, in vitro; dbSNP:rs7775)"
FT                   /evidence="ECO:0000269|PubMed:15210948"
FT                   /id="VAR_014862"
FT   CONFLICT        63
FT                   /note="A -> D (in Ref. 2; AAB51298)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        106
FT                   /note="K -> N (in Ref. 1; AAC50736)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   325 AA;  36254 MW;  8337C51BBA9A4B07 CRC64;
     MVCGSPGGML LLRAGLLALA ALCLLRVPGA RAAACEPVRI PLCKSLPWNM TKMPNHLHHS
     TQANAILAIE QFEGLLGTHC SPDLLFFLCA MYAPICTIDF QHEPIKPCKS VCERARQGCE
     PILIKYRHSW PENLACEELP VYDRGVCISP EAIVTADGAD FPMDSSNGNC RGASSERCKC
     KPIRATQKTY FRNNYNYVIR AKVKEIKTKC HDVTAVVEVK EILKSSLVNI PRDTVNLYTS
     SGCLCPPLNV NEEYIIMGYE DEERSRLLLV EGSIAEKWKD RLGKKVKRWD MKLRHLGLSK
     SDSSNSDSTQ SQKSGRNSNP RQARN
//