SFRP4_HUMAN
ID SFRP4_HUMAN Reviewed; 346 AA.
AC Q6FHJ7; B4DYC1; O14877; Q05BG7; Q1ZYW2; Q4G124; Q6FHM0; Q6PD64;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 15-MAR-2005, sequence version 2.
DT 03-AUG-2022, entry version 165.
DE RecName: Full=Secreted frizzled-related protein 4;
DE Short=sFRP-4;
DE AltName: Full=Frizzled protein, human endometrium;
DE Short=FrpHE;
DE Flags: Precursor;
GN Name=SFRP4; Synonyms=FRPHE;
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=Endometrium;
RX PubMed=10211996;
RA Abu-Jawdeh G.M., Comella N., Brown L.F., Tognazzi K., Kocher O.;
RT "Differential expression of frpHE: a novel human stromal protein of the
RT secreted frizzled gene family, during the endometrial cycle and
RT malignancy.";
RL Lab. Invest. 79:439-447(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND POSSIBLE FUNCTION AS A PHOSPHATURIC AGENT.
RC TISSUE=Mesenchymal tumor;
RX PubMed=12952927; DOI=10.1172/jci200318563;
RA Berndt T., Craig T.A., Bowe A.E., Vassiliadis J., Reczek D., Finnegan R.,
RA Jan De Beur S.M., Schiavi S.C., Kumar R.;
RT "Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic
RT agent.";
RL J. Clin. Invest. 112:785-794(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT THR-320.
RC TISSUE=Ovary;
RA Drake J.M., Zeps N., Dharmarajan A.;
RT "Open reading frame of the human secreted frizzled related protein 4.";
RL Submitted (FEB-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS THR-320 AND LYS-340.
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT THR-320.
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D.,
RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S.,
RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R.,
RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N.,
RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E.,
RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R.,
RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T.,
RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W.,
RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A.,
RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X.,
RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E.,
RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J.,
RA Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS THR-320 AND LYS-340.
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 [9]
RP TISSUE SPECIFICITY.
RX PubMed=10728394; DOI=10.1016/s0008-6363(99)00376-4;
RA Schumann H., Holtz J., Zerkowski H.R., Hatzfeld M.;
RT "Expression of secreted frizzled related proteins 3 and 4 in human
RT ventricular myocardium correlates with apoptosis related gene expression.";
RL Cardiovasc. Res. 45:720-728(2000).
RN [10]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=19480240;
RA Drake J., Shearwood A.M., White J., Friis R., Zeps N., Charles A.,
RA Dharmarajan A.;
RT "Expression of secreted frizzled-related protein 4 (SFRP4) in primary
RT serous ovarian tumours.";
RL Eur. J. Gynaecol. Oncol. 30:133-141(2009).
RN [11]
RP INVOLVEMENT IN PYL.
RX PubMed=27355534; DOI=10.1056/nejmoa1509342;
RA Simsek Kiper P.O., Saito H., Gori F., Unger S., Hesse E., Yamana K.,
RA Kiviranta R., Solban N., Liu J., Brommage R., Boduroglu K., Bonafe L.,
RA Campos-Xavier B., Dikoglu E., Eastell R., Gossiel F., Harshman K.,
RA Nishimura G., Girisha K.M., Stevenson B.J., Takita H., Rivolta C.,
RA Superti-Furga A., Baron R.;
RT "Cortical-Bone Fragility--Insights from sFRP4 Deficiency in Pyle's
RT Disease.";
RL N. Engl. J. Med. 374:2553-2562(2016).
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 (By similarity). SFRP4 plays a role in bone morphogenesis.
CC May also act as a regulator of adult uterine morphology and function.
CC May also increase apoptosis during ovulation possibly through
CC modulation of FZ1/FZ4/WNT4 signaling (By similarity). Has phosphaturic
CC effects by specifically inhibiting sodium-dependent phosphate uptake
CC (PubMed:12952927). {ECO:0000250|UniProtKB:Q9JLS4,
CC ECO:0000250|UniProtKB:Q9Z1N6, ECO:0000269|PubMed:12952927}.
CC -!- INTERACTION:
CC Q6FHJ7; Q13520: AQP6; NbExp=3; IntAct=EBI-2854879, EBI-13059134;
CC Q6FHJ7; Q8NBQ5: HSD17B11; NbExp=3; IntAct=EBI-2854879, EBI-1052304;
CC Q6FHJ7; Q8WXH2: JPH3; NbExp=3; IntAct=EBI-2854879, EBI-1055254;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:19480240}.
CC Note=Cytoplasmic in ovarian tumor cells.
CC -!- TISSUE SPECIFICITY: Expressed in mesenchymal cells. Highly expressed in
CC the stroma of proliferative endometrium. Expressed in cardiomyocytes.
CC Shows moderate to strong expression in ovarian tumors with expression
CC increasing as the tumor stage increases. In ovarian tumors, expression
CC levels are inversely correlated with expression of CTNNB1 (at protein
CC level). {ECO:0000269|PubMed:10728394, ECO:0000269|PubMed:19480240}.
CC -!- INDUCTION: Increased levels in failing myocardium. Up-regulated in
CC several tumor types including ostomalacia-associated tumors and
CC endometrial and breast carcinomas.
CC -!- DOMAIN: The FZ domain is involved in binding with Wnt ligands.
CC {ECO:0000250}.
CC -!- DISEASE: Pyle disease (PYL) [MIM:265900]: A disorder characterized by
CC cortical-bone thinning, limb deformity, bone fragility and fractures.
CC {ECO:0000269|PubMed:27355534}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the secreted frizzled-related protein (sFRP)
CC family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAG63683.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/SFRP4ID42277ch7p14.html";
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DR EMBL; AF026692; AAC04617.1; -; mRNA.
DR EMBL; DQ420628; ABD83351.1; -; mRNA.
DR EMBL; AK302357; BAG63683.1; ALT_INIT; mRNA.
DR EMBL; CR541731; CAG46532.1; -; mRNA.
DR EMBL; CR541755; CAG46555.1; -; mRNA.
DR EMBL; BT019679; AAV38485.1; -; mRNA.
DR EMBL; CH236951; EAL23981.1; -; Genomic_DNA.
DR EMBL; BC047684; AAH47684.1; -; mRNA.
DR EMBL; BC058911; AAH58911.1; -; mRNA.
DR CCDS; CCDS5453.1; -.
DR RefSeq; NP_003005.2; NM_003014.3.
DR AlphaFoldDB; Q6FHJ7; -.
DR SMR; Q6FHJ7; -.
DR BioGRID; 112322; 45.
DR IntAct; Q6FHJ7; 34.
DR MINT; Q6FHJ7; -.
DR STRING; 9606.ENSP00000410715; -.
DR DrugBank; DB00606; Cyclothiazide.
DR DrugBank; DB00790; Perindopril.
DR GlyConnect; 1726; 9 N-Linked glycans (1 site).
DR GlyGen; Q6FHJ7; 5 sites, 8 N-linked glycans (1 site).
DR iPTMnet; Q6FHJ7; -.
DR PhosphoSitePlus; Q6FHJ7; -.
DR BioMuta; SFRP4; -.
DR DMDM; 61216780; -.
DR EPD; Q6FHJ7; -.
DR jPOST; Q6FHJ7; -.
DR MassIVE; Q6FHJ7; -.
DR PaxDb; Q6FHJ7; -.
DR PeptideAtlas; Q6FHJ7; -.
DR PRIDE; Q6FHJ7; -.
DR ProteomicsDB; 66293; -.
DR Antibodypedia; 1568; 391 antibodies from 40 providers.
DR DNASU; 6424; -.
DR Ensembl; ENST00000436072.7; ENSP00000410715.2; ENSG00000106483.12.
DR GeneID; 6424; -.
DR KEGG; hsa:6424; -.
DR MANE-Select; ENST00000436072.7; ENSP00000410715.2; NM_003014.4; NP_003005.2.
DR UCSC; uc003tfo.5; human.
DR CTD; 6424; -.
DR DisGeNET; 6424; -.
DR GeneCards; SFRP4; -.
DR HGNC; HGNC:10778; SFRP4.
DR HPA; ENSG00000106483; Group enriched (cervix, endometrium, fallopian tube).
DR MalaCards; SFRP4; -.
DR MIM; 265900; phenotype.
DR MIM; 606570; gene.
DR neXtProt; NX_Q6FHJ7; -.
DR OpenTargets; ENSG00000106483; -.
DR Orphanet; 3005; Pyle disease.
DR PharmGKB; PA35694; -.
DR VEuPathDB; HostDB:ENSG00000106483; -.
DR eggNOG; KOG3577; Eukaryota.
DR GeneTree; ENSGT00940000160766; -.
DR HOGENOM; CLU_058446_0_0_1; -.
DR InParanoid; Q6FHJ7; -.
DR OMA; YAPICAL; -.
DR OrthoDB; 1339129at2759; -.
DR PhylomeDB; Q6FHJ7; -.
DR PathwayCommons; Q6FHJ7; -.
DR SignaLink; Q6FHJ7; -.
DR BioGRID-ORCS; 6424; 8 hits in 1074 CRISPR screens.
DR ChiTaRS; SFRP4; human.
DR GeneWiki; SFRP4; -.
DR GenomeRNAi; 6424; -.
DR Pharos; Q6FHJ7; Tbio.
DR PRO; PR:Q6FHJ7; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; Q6FHJ7; protein.
DR Bgee; ENSG00000106483; Expressed in right uterine tube and 150 other tissues.
DR ExpressionAtlas; Q6FHJ7; baseline and differential.
DR Genevisible; Q6FHJ7; HS.
DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0017147; F:Wnt-protein binding; IDA:MGI.
DR GO; GO:0060349; P:bone morphogenesis; IMP:UniProtKB.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IBA:GO_Central.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:BHF-UCL.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:BHF-UCL.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; IDA:BHF-UCL.
DR GO; GO:2000051; P:negative regulation of non-canonical Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:2000119; P:negative regulation of sodium-dependent phosphate transport; IDA:BHF-UCL.
DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; NAS:ParkinsonsUK-UCL.
DR GO; GO:0055062; P:phosphate ion homeostasis; IDA:BHF-UCL.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:BHF-UCL.
DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IGI:MGI.
DR GO; GO:0045606; P:positive regulation of epidermal cell differentiation; IDA:BHF-UCL.
DR GO; GO:0010628; P:positive regulation of gene expression; IDA:BHF-UCL.
DR GO; GO:1902174; P:positive regulation of keratinocyte apoptotic process; IDA:BHF-UCL.
DR GO; GO:0002092; P:positive regulation of receptor internalization; IDA:BHF-UCL.
DR GO; GO:0030510; P:regulation of BMP signaling pathway; ISS:UniProtKB.
DR GO; GO:0009725; P:response to hormone; NAS:BHF-UCL.
DR Gene3D; 1.10.2000.10; -; 1.
DR Gene3D; 2.40.50.120; -; 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; IPR026560; SFRP4.
DR InterPro; IPR008993; TIMP-like_OB-fold.
DR PANTHER; PTHR11309; PTHR11309; 1.
DR PANTHER; PTHR11309:SF7; PTHR11309:SF7; 1.
DR Pfam; PF01392; Fz; 1.
DR Pfam; PF01759; NTR; 1.
DR SMART; SM00643; C345C; 1.
DR SMART; SM00063; FRI; 1.
DR SUPFAM; SSF50242; SSF50242; 1.
DR SUPFAM; SSF63501; SSF63501; 1.
DR PROSITE; PS50038; FZ; 1.
DR PROSITE; PS50189; NTR; 1.
PE 1: Evidence at protein level;
KW Developmental protein; Differentiation; Disulfide bond; Glycoprotein;
KW Reference proteome; Secreted; Signal; Wnt signaling pathway.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..346
FT /note="Secreted frizzled-related protein 4"
FT /id="PRO_0000032550"
FT DOMAIN 19..139
FT /note="FZ"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090"
FT DOMAIN 178..307
FT /note="NTR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT REGION 292..346
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 292..307
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 38
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 68
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 116
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 194
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 240
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 24..85
FT /evidence="ECO:0000250"
FT DISULFID 32..78
FT /evidence="ECO:0000250"
FT DISULFID 69..108
FT /evidence="ECO:0000250"
FT DISULFID 97..136
FT /evidence="ECO:0000250"
FT DISULFID 101..125
FT /evidence="ECO:0000250"
FT VARIANT 320
FT /note="P -> T (in dbSNP:rs1802073)"
FT /evidence="ECO:0000269|PubMed:12690205,
FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:15489334,
FT ECO:0000269|Ref.3"
FT /id="VAR_051964"
FT VARIANT 340
FT /note="R -> K (in dbSNP:rs1802074)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334"
FT /id="VAR_051965"
FT CONFLICT 19
FT /note="V -> M (in Ref. 5; CAG46532)"
FT /evidence="ECO:0000305"
FT CONFLICT 77
FT /note="L -> F (in Ref. 1; AAC04617)"
FT /evidence="ECO:0000305"
FT CONFLICT 141
FT /note="A -> V (in Ref. 5; CAG46555)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 346 AA; 39827 MW; 75D04089E446CE80 CRC64;
MFLSILVALC LWLHLALGVR GAPCEAVRIP MCRHMPWNIT RMPNHLHHST QENAILAIEQ
YEELVDVNCS AVLRFFLCAM YAPICTLEFL HDPIKPCKSV CQRARDDCEP LMKMYNHSWP
ESLACDELPV YDRGVCISPE AIVTDLPEDV KWIDITPDMM VQERPLDVDC KRLSPDRCKC
KKVKPTLATY LSKNYSYVIH AKIKAVQRSG CNEVTTVVDV KEIFKSSSPI PRTQVPLITN
SSCQCPHILP HQDVLIMCYE WRSRMMLLEN CLVEKWRDQL SKRSIQWEER LQEQRRTVQD
KKKTAGRTSR SNPPKPKGKP PAPKPASPKK NIKTRSAQKR TNPKRV
