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SFRP4 (Secreted Frizzled-Related Protein 4)

Written2009-04Kendra S Carmon, David S Loose
University of Texas Health Science Center Houston, Houston, TX 77030, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namessecreted frizzled-related protein 4
Alias_symbol (synonym)frpHE
FRP-4
FRPHE
Other aliassFRP-4
MGC26498
LOC6424
HGNC (Hugo) SFRP4
LocusID (NCBI) 6424
Atlas_Id 42277
Location 7p14.1  [Link to chromosome band 7p14]
Location_base_pair Starts at 37905933 and ends at 37916923 bp from pter ( according to hg19-Feb_2009)  [Mapping SFRP4.png]
Local_order According to NCBI, SFRP4 is telomeric to EPDR1 (7p14.1) ependymin related protein 1 (zebrafish) and STARD3NL (7p14-p13) StAR-related lipid transfer domain containing 3 N-terminal like and centromeric to TXNDC3 (7p14.1) thioredoxin domain containing 3 (spermatozoa) and GPR141 (7p14.1) G protein-coupled receptor 141.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
TSKU (11q13.5) / SFRP4 (7p14.1)

DNA/RNA

 
  Diagram illustrates SFRP4 gene that contains a total of six exons.
Description The SFRP4 gene spans 10.99 kb on the short arm of chromosome 7 and is transcribed from the minus strand in the centromere-to-telomere orientation. The gene is encoded by six exons with the translation initiation codon in the first exon.
Transcription The SFRP4 mRNA transcript is 2974 bp, 1041 bp are coding sequence. Ensembl data predicts a second transcript from the SFRP4 gene, lacking the 81 bp exon 2, although this has not been demonstrated.

Protein

 
  Diagram illustrates the full length SFRP4 protein which contains a signal peptide sequence of 20-30 amino acids, a cysteine-rich domain (CRD) of approximately 120 amino acids, and a netrin-related motif (NTR) domain. Conserved cysteines of the CRD are indicated by *.
Description SFRP4 protein is comprised of 346 amino acids with a predicted molecular weight of 39.9 kDa and an actual molecular weight of approximately 50-55 kDa.
SFRP4 belongs to a family of five SFRPs; these proteins fold into two independent domains. The N-terminus contains a secretion signal peptide followed by a ~120 amino acid cysteine-rich domain (CRD). The CRD is 30-50% identical to the extracellular putative Wnt-binding domain of frizzled (Fzd) receptors and is characterized by the presence of ten cysteine residues at conserved positions. These cysteines form a pattern of disulfide bridges. The C-terminal portion of the SFRP protein is characterized by segments of positively charged residues that appear to confer heparin-binding properties in at least two SFRPs (SFRP1 and SFRP3) and contains a netrin-related motif (NTR) with six cysteine residues that most likely form three disulfide bridges. NTR domains with similar features are found in a wide range of unrelated proteins, including Netrin-1, tissue inhibitors of metallo-proteinases (TIMPs), complement proteins and type I procollagen C-proteinase enhancer proteins (PCOLCEs). The six conserved cysteines in the NTR of SFRP4 share a similar spacing to SFRP3, whereas those of the SFRP1/SFRP2/SFRP5 subgroup are distinctively different, indicating a disparity in disulfide bond formation. Uniquely, SFRP4 contains two additional cysteine residues. The overall function of the NTR is unknown, yet there is some evidence that the NTR may also play a role in Wnt binding. This implies that multiple Wnt binding sites may exist on SFRP molecules and/or that SFRPs exhibit differential affinities for Wnt ligands according to the different SFRP conformational and post-translational modifications.
Expression SFRP4 is expressed in various normal tissues including endometrium (specifically stromal cells with higher expression during proliferative phase of menstrual cycle), ovary, kidney, heart, brain, mammary gland, cervix, pancreas, stomach, colon, lung, skeletal muscle, testis, eye, bone, prostate, and liver.
Localisation Secreted from cell; extracellular matrix; bound to plasma membrane.
Function Since SFRPs share a similar CRD with the Fzd family of receptors; it is believed that SFRPs may act as soluble modulators that compete with Fzd to bind the Wnt ligands, thereby altering the Wnt signal. Individual SFRPs also have distinct binding specificity for distinct Wnt ligands. Reports have demonstrated that SFRP4 binds Wnt7a and there is conflicting data for SFRP4 binding to Wnt3a. SFRP4 expression is regulated by estrogen and progesterone and may act as a regulator of adult uterine morphology and function. SFRP4 has been shown to increase apoptosis during ovulation. Transgenic studies have found that SFRP4 decreases bone formation and inhibits osteoblast proliferation by attenuating canonical/beta-catenin-Wnt signaling. SFRP4 reportedly exhibits phosphaturic effects by specifically inhibiting sodium-dependent phosphate uptake.
 
  CLUSTAL alignment of the 5 human SFRPs.
Homology Of the five human SFRPs (SFRP1, SFRP2, SFRP3, SFRP4, SFRP5), SFRP4 shares most significant homology with SFRP3.

Mutations

Note It was reported that the T allele of the SFRP4 gene polymorphism ARG262 (CGC to CGT) of exon4 is associated with decreased bone mineral density in post-menopausal Japanese women.

Implicated in

Note
  
Entity Endometrial Carcinoma
Note SFRP4 was more frequently down-regulated in (microsatellite instability). MSI cancers as compared with (microsatellite stable) MSS endometrioid endometrial cancers. Expression of SFRP4 is decreased in both low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma.
  
  
Entity Malignant Pleural Mesothelioma
Note SFRP4 promoter is frequently methylated in this cancer leading to inhibition of expression and is associated with abnormal growth; restoration of SFRP4 results in growth suppression and apoptosis in mesothelioma cell lines.
  
  
Entity Tumor-induced osteomalacia
Note Tumor-induced osteomalacia is a disorder in which there is an increase in renal phosphate excretion and a reduction in serum phosphate levels leading to hyperphosphaturia, hypophosphatemia and rickets. SFRP4 is highly expressed in such tumors and functions as a circulating phosphaturic factor that antagonizes renal Wnt-signaling.
  
  
Entity Breast Cancer
Note Studies have found evidence for SFRP4 overexpression in breast cancer.
  
  
Entity Pancreatic Cancer
Note SFRP4 found to be significantly hypermethylated in the tumors of cancer patients versus matched adjacent tissue controls.
  
  
Entity Gastric Carcinoma
Note The SFRP4 was highly methylated in gastric carcinoma samples with greater instance in H. pylori positive patients.
  
  
Entity Prostate Cancer
Note SFRP4 is overexpressed in prostate cancers and functions to inhibit cell proliferation and metastatic potential.
Prognosis Increased expression of membranous SFRP4 is associated with a good prognosis in human localized androgen-dependent prostate cancer, suggesting a role for sFRP4 in early stage disease.
  
  
Entity B-cell chronic lymphocytic leukemia
Note SFRP4 was found to be frequently methylated and downregulated in CLL samples.
  
  
Entity Colorectal Carcinoma
Note SFRP4 expression was shown to be up-regulated in colorectal cancer.
  
  
Entity8/tD> Esophageal Adenocarcinoma
Note SFRP4 mRNA and protein expression were significantly decreased due to hypermethylation in esophageal adenocarcinoma and Barrett's esophagus patients.
  

Bibliography

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Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent.
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Secreted frizzled-related protein-4 reduces sodium-phosphate co-transporter abundance and activity in proximal tubule cells.
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Hypermethylation and aberrant expression of secreted frizzled-related protein genes in pancreatic cancer.
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Secreted frizzled-related protein 4 regulates two Wnt7a signaling pathways and inhibits proliferation in endometrial cancer cells.
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Disulfide bond assignments of secreted Frizzled-related protein-1 provide insights about Frizzled homology and netrin modules.
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PMID 11741940
 
Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains.
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A secreted frizzled related protein, FrzA, selectively associates with Wnt-1 protein and regulates wnt-1 signaling.
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PMID 10523516
 
The role of sFRP4, a secreted frizzled-related protein, in ovulation.
Drake JM, Friis RR, Dharmarajan AM.
Apoptosis. 2003 Aug;8(4):389-97.
PMID 12815282
 
Expression of sFRP-4 and beta-catenin in human colorectal carcinoma.
Feng Han Q, Zhao W, Bentel J, Shearwood AM, Zeps N, Joseph D, Iacopetta B, Dharmarajan A.
Cancer Lett. 2006 Jan 8;231(1):129-37.
PMID 16356838
 
Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action.
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Differential expression of secreted frizzled-related protein 4 in decidual cells during pregnancy.
Fujita M, Ogawa S, Fukuoka H, Tsukui T, Nemoto N, Tsutsumi O, Ouchi Y, Inoue S.
J Mol Endocrinol. 2002 Jun;28(3):213-23.
PMID 12063187
 
Association of a single nucleotide polymorphism in the secreted frizzled-related protein 4 (sFRP4) gene with bone mineral density.
Fujita M, Urano T, Shiraki M, Momoeda M, Tsutsumi O, Hosoi T, Orimo H, Ouchi Y, Inoue S.
Ger. Geront. Int. 2004; 4 (3): 175-180.
 
Secreted frizzled-related protein 4 is silenced by hypermethylation and induces apoptosis in beta-catenin-deficient human mesothelioma cells.
He B, Lee AY, Dadfarmay S, You L, Xu Z, Reguart N, Mazieres J, Mikami I, McCormick F, Jablons DM.
Cancer Res. 2005 Feb 1;65(3):743-8.
PMID 15705870
 
Membranous expression of secreted frizzled-related protein 4 predicts for good prognosis in localized prostate cancer and inhibits PC3 cellular proliferation in vitro.
Horvath LG, Henshall SM, Kench JG, Saunders DN, Lee CS, Golovsky D, Brenner PC, O'Neill GF, Kooner R, Stricker PD, Grygiel JJ, Sutherland RL.
Clin Cancer Res. 2004 Jan 15;10(2):615-25.
PMID 14760084
 
Inverse correlation of secreted frizzled-related protein 4 and beta-catenin expression in endometrial stromal sarcomas.
Hrzenjak A, Tippl M, Kremser ML, Strohmeier B, Guelly C, Neumeister D, Lax S, Moinfar F, Tabrizi AD, Isadi-Moud N, Zatloukal K, Denk H.
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PMID 15307134
 
DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis.
Kang GH, Lee S, Cho NY, Gandamihardja T, Long TI, Weisenberger DJ, Campan M, Laird PW.
Lab Invest. 2008 Feb;88(2):161-70. Epub 2007 Dec 24.
PMID 18158559
 
Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma.
Lee AY, He B, You L, Dadfarmay S, Xu Z, Mazieres J, Mikami I, McCormick F, Jablons DM.
Oncogene. 2004 Aug 26;23(39):6672-6.
PMID 15221014
 
CpG island methylation and expression of the secreted frizzled-related protein gene family in chronic lymphocytic leukemia.
Liu TH, Raval A, Chen SS, Matkovic JJ, Byrd JC, Plass C.
Cancer Res. 2006 Jan 15;66(2):653-8.
PMID 16423993
 
Osteoblast-targeted expression of Sfrp4 in mice results in low bone mass.
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J Bone Miner Res. 2008 Feb;23(2):271-7.
PMID 17907918
 
Gene expression profiling of microsatellite unstable and microsatellite stable endometrial cancers indicates distinct pathways of aberrant signaling.
Risinger JI, Maxwell GL, Chandramouli GV, Aprelikova O, Litzi T, Umar A, Berchuck A, Barrett JC.
Cancer Res. 2005 Jun 15;65(12):5031-7.
PMID 15958545
 
Localization of disulfide bonds in the frizzled module of Ror1 receptor tyrosine kinase.
Roszmusz E, Patthy A, Trexler M, Patthy L.
J Biol Chem. 2001 May 25;276(21):18485-90. Epub 2001 Feb 21.
PMID 11279007
 
Wnt signaling pathway in mammary gland development and carcinogenesis.
Turashvili G, Bouchal J, Burkadze G, Kolar Z.
Pathobiology. 2006;73(5):213-23. (REVIEW)
PMID 17314492
 
Secreted frizzled-related protein-1 binds directly to Wingless and is a biphasic modulator of Wnt signaling.
Uren A, Reichsman F, Anest V, Taylor WG, Muraiso K, Bottaro DP, Cumberledge S, Rubin JS.
J Biol Chem. 2000 Feb 11;275(6):4374-82.
PMID 10660608
 
Wnt3a binds to several sFRPs in the nanomolar range.
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Biochem Biophys Res Commun. 2007 Jun 15;357(4):1119-23. Epub 2007 Apr 19.
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Citation

This paper should be referenced as such :
Carmon, KS ; Loose, DS
SFRP4 (Secreted Frizzled-Related Protein 4)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(3):296-300.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/SFRP4ID42277ch7p14.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Lung: Non-small cell carcinoma


External links

Nomenclature
HGNC (Hugo)SFRP4   10778
Cards
AtlasSFRP4ID42277ch7p14
Entrez_Gene (NCBI)SFRP4  6424  secreted frizzled related protein 4
AliasesFRP-4; FRPHE; PYL; sFRP-4
GeneCards (Weizmann)SFRP4
Ensembl hg19 (Hinxton)ENSG00000106483 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000106483 [Gene_View]  chr7:37905933-37916923 [Contig_View]  SFRP4 [Vega]
ICGC DataPortalENSG00000106483
TCGA cBioPortalSFRP4
AceView (NCBI)SFRP4
Genatlas (Paris)SFRP4
WikiGenes6424
SOURCE (Princeton)SFRP4
Genetics Home Reference (NIH)SFRP4
Genomic and cartography
GoldenPath hg38 (UCSC)SFRP4  -     chr7:37905933-37916923 -  7p14.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SFRP4  -     7p14.1   [Description]    (hg19-Feb_2009)
EnsemblSFRP4 - 7p14.1 [CytoView hg19]  SFRP4 - 7p14.1 [CytoView hg38]
Mapping of homologs : NCBISFRP4 [Mapview hg19]  SFRP4 [Mapview hg38]
OMIM265900   606570   
Gene and transcription
Genbank (Entrez)AF026692 AK302357 AK303977 AK313029 BC032828
RefSeq transcript (Entrez)NM_003014
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)SFRP4
Cluster EST : UnigeneHs.658169 [ NCBI ]
CGAP (NCI)Hs.658169
Alternative Splicing GalleryENSG00000106483
Gene ExpressionSFRP4 [ NCBI-GEO ]   SFRP4 [ EBI - ARRAY_EXPRESS ]   SFRP4 [ SEEK ]   SFRP4 [ MEM ]
Gene Expression Viewer (FireBrowse)SFRP4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6424
GTEX Portal (Tissue expression)SFRP4
Human Protein AtlasENSG00000106483-SFRP4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ6FHJ7   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ6FHJ7  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ6FHJ7
Splice isoforms : SwissVarQ6FHJ7
PhosPhoSitePlusQ6FHJ7
Domaine pattern : Prosite (Expaxy)FZ (PS50038)    NTR (PS50189)   
Domains : Interpro (EBI)Frizzled/SFRP    Frizzled_dom    Netrin_domain    Netrin_module_non-TIMP    SFRP4    TIMP-like_OB-fold   
Domain families : Pfam (Sanger)Fz (PF01392)    NTR (PF01759)   
Domain families : Pfam (NCBI)pfam01392    pfam01759   
Domain families : Smart (EMBL)C345C (SM00643)  FRI (SM00063)  
Conserved Domain (NCBI)SFRP4
DMDM Disease mutations6424
Blocks (Seattle)SFRP4
SuperfamilyQ6FHJ7
Human Protein Atlas [tissue]ENSG00000106483-SFRP4 [tissue]
Peptide AtlasQ6FHJ7
HPRD07357
IPIIPI00017557   IPI00910202   IPI00926016   
Protein Interaction databases
DIP (DOE-UCLA)Q6FHJ7
IntAct (EBI)Q6FHJ7
FunCoupENSG00000106483
BioGRIDSFRP4
STRING (EMBL)SFRP4
ZODIACSFRP4
Ontologies - Pathways
QuickGOQ6FHJ7
Ontology : AmiGOpositive regulation of receptor internalization  protein binding  extracellular space  nucleus  cytoplasm  negative regulation of cell proliferation  response to hormone  cell surface  positive regulation of gene expression  Wnt signaling pathway  Wnt-protein binding  Wnt-protein binding  Wnt-protein binding  cell differentiation  negative regulation of Wnt signaling pathway  regulation of BMP signaling pathway  positive regulation of apoptotic process  negative regulation of sequence-specific DNA binding transcription factor activity  positive regulation of epidermal cell differentiation  phosphate ion homeostasis  bone morphogenesis  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  positive regulation of canonical Wnt signaling pathway  positive regulation of keratinocyte apoptotic process  negative regulation of non-canonical Wnt signaling pathway  negative regulation of sodium-dependent phosphate transport  
Ontology : EGO-EBIpositive regulation of receptor internalization  protein binding  extracellular space  nucleus  cytoplasm  negative regulation of cell proliferation  response to hormone  cell surface  positive regulation of gene expression  Wnt signaling pathway  Wnt-protein binding  Wnt-protein binding  Wnt-protein binding  cell differentiation  negative regulation of Wnt signaling pathway  regulation of BMP signaling pathway  positive regulation of apoptotic process  negative regulation of sequence-specific DNA binding transcription factor activity  positive regulation of epidermal cell differentiation  phosphate ion homeostasis  bone morphogenesis  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  positive regulation of canonical Wnt signaling pathway  positive regulation of keratinocyte apoptotic process  negative regulation of non-canonical Wnt signaling pathway  negative regulation of sodium-dependent phosphate transport  
Pathways : KEGGWnt signaling pathway   
NDEx NetworkSFRP4
Atlas of Cancer Signalling NetworkSFRP4
Wikipedia pathwaysSFRP4
Orthology - Evolution
OrthoDB6424
GeneTree (enSembl)ENSG00000106483
Phylogenetic Trees/Animal Genes : TreeFamSFRP4
HOVERGENQ6FHJ7
HOGENOMQ6FHJ7
Homologs : HomoloGeneSFRP4
Homology/Alignments : Family Browser (UCSC)SFRP4
Gene fusions - Rearrangements
Fusion : MitelmanTSKU/SFRP4 [11q13.5/7p14.1]  [t(7;11)(p14;q13)]  
Fusion: TCGATSKU 11q13.5 SFRP4 7p14.1 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSFRP4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SFRP4
dbVarSFRP4
ClinVarSFRP4
1000_GenomesSFRP4 
Exome Variant ServerSFRP4
ExAC (Exome Aggregation Consortium)ENSG00000106483
GNOMAD BrowserENSG00000106483
Genetic variants : HAPMAP6424
Genomic Variants (DGV)SFRP4 [DGVbeta]
DECIPHERSFRP4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSFRP4 
Mutations
ICGC Data PortalSFRP4 
TCGA Data PortalSFRP4 
Broad Tumor PortalSFRP4
OASIS PortalSFRP4 [ Somatic mutations - Copy number]
Cancer Gene: CensusSFRP4 
Somatic Mutations in Cancer : COSMICSFRP4  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSFRP4
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch SFRP4
DgiDB (Drug Gene Interaction Database)SFRP4
DoCM (Curated mutations)SFRP4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SFRP4 (select a term)
intoGenSFRP4
NCG5 (London)SFRP4
Cancer3DSFRP4(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM265900    606570   
Orphanet2703   
MedgenSFRP4
Genetic Testing Registry SFRP4
NextProtQ6FHJ7 [Medical]
TSGene6424
GENETestsSFRP4
Target ValidationSFRP4
Huge Navigator SFRP4 [HugePedia]
snp3D : Map Gene to Disease6424
BioCentury BCIQSFRP4
ClinGenSFRP4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD6424
Chemical/Pharm GKB GenePA35694
Clinical trialSFRP4
Miscellaneous
canSAR (ICR)SFRP4 (select the gene name)
Probes
Litterature
PubMed72 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSFRP4
EVEXSFRP4
GoPubMedSFRP4
iHOPSFRP4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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