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SFRP2 (secreted frizzled-related protein 2)

Written2013-08Darragh S O'Donovan, Antoinette S Perry
Prostate Molecular Oncology, Institute of Molecular Medicine, Trinity College, Dublin, Ireland

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)SARP1
SDF-5
FRP-2
Other alias
HGNC (Hugo) SFRP2
LocusID (NCBI) 6423
Atlas_Id 42952
Location 4q31.3  [Link to chromosome band 4q31]
Location_base_pair Starts at 153780590 and ends at 153789076 bp from pter ( according to hg19-Feb_2009)  [Mapping SFRP2.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
SFRP2 (4q31.3) / SFRP2 (4q31.3)
Note Orientation: minus strand.

DNA/RNA

 
  Wnt (wingless-type)/β-catenin signaling is a major regulator of cell proliferation, migration and differentiation, controlling tissue homeostasis and tumor progression (Klaus et al., 2008). A) The binding of a canonical Wnt ligand to its cell-surface receptor complex, consisting of Frizzled (FZD) and one of two low-density-lipoprotein- receptor-related proteins (LRP-5 and LRP-6), initiates a signaling cascade that activates disheveled (DVL), which releases β-catenin from an inhibitory complex consisting of Axin, APC and glycogen synthase kinase 3b (GSK3B). On dephosphorylation and release, β-catenin translocates to the nucleus, where it interacts with members of the T-cell factor/lymphoid enhancer factor (TCF/LEF) families of transcription factors to stimulate expression of genes involved in cell survival, proliferation and osteoblastic differentiation (e.g., MMPs, CCND1, PTGS2, MYC, JUN and VEGFR) (Reya et al., 2005). B) Wnt signaling is regulated by several classes of negative regulators. The Secreted Frizzled-Related Protein (SFRP) class comprises SFRP1-SFRP5, Wnt inhibitory factor 1 (WIF1) and Cerberus. SFRPs are a family of soluble glycoproteins that possess a cysteine- rich domain (CRD) structurally similar to the extracellular Wnt-binding domain of the FZD receptors. SFRPs can thus modulate Wnt signaling by sequestering Wnts through their CRD or by acting as dominant-negative inhibitors, forming inactive complexes with the FZD receptors.
Description Size: 8487 bases. The SFRP2 gene is located on the long arm of Chromosome 4, and consists of 3 coding exons, with exon 2 being significantly smaller than the other two. No known splice variants.
Transcription mRNA size 2005 bp, ORF size 888 bp.

Protein

 
Description SFRP2 contains several domains which potentially govern protein-protein interactions.
- Beginning at the N-terminus there is a 24 aa hydrophobic signal domain, which presumably governs the targeting of SFRP2 to the secretory pathway.
- The CRD/FZ (cysteine-rich/Frizzled) domain allows SFRP proteins to antagonise Wnt/Frizzled binding at the plasma membrane either by sequestration of the Wnt ligand or dominant-negative binding to complimentary regions within the Frizzled protein.
- The C345C/Netrin domain is an accessory binding domain for SFRP2-Wnt interaction.
- The PDZ ligand domain is a short sequence which is recognised by PDZ proteins such as Dishevelled (Dvl), and other proteins which interact with the cytoplasmic portion of Frizzled (Schulte and Bryja, 2007). Notably, a recent study (Zhang et al., 2009) has used synthetic PDZ ligands to interfere with Dvl/FZD cytoplasmic interaction, and thus antagonise canonical Wnt signalling. Additionally, another group subsequently showed that the NSAID Sulindac inhibits canonical Wnt signaling by blocking the PDZ domain of Dvl (Lee et al., 2009). These data suggest that the presence of a PDZ ligand in SFRP2 may indicate a previously-unexplored role for SFRP2 as a cytoplasmic antagonist of Wnt signalling.
- A phosphoproteomic study has revealed phosphorylation of SFRP2 at serine-289 in response to growth factor stimulation (Olsen et al., 2006). Bioinformatic analysis suggests that this site is a motif for recognition and phosphorylation by PKA. Additionally, bioinformatic analysis of the SFRP2 sequence suggests a site for phosphorylation by GSK3β (itself an inhibitor of β-catenin) at either serine-34 or serine-38. Although the potential significance of phosphorylation at this site is unclear, it may overlap with the Nec 1/Nec 2 cleavage site and prevent removal of the N-terminal signal domain. Typically, Nec 1/2 is responsible for the cleavage of pro-proteins into their active form, and perhaps phosphorylation in this region is a mechanism by which GSK3β may regulate SFRP2 activity.
Expression Widely expressed.
Localisation Nucleus, cytoplasm and secreted.
Function SFRP2 is a member of the secreted Frizzled-related protein (SFRP) family of soluble extracellular Wnt antagonists, which act in conjunction with the Dickkopf (DKK) class of Wnt antagonists. SFRP2 is thought to act primarily by binding directly to and sequestering Wnt ligands, but may also act by direct binding to the Wnt-receptor complex. Binding occurs primarily via the cysteine-rich domain, which bears a high degree of homology to similar domains in the Frizzled (Fzd) receptor. SFRP activity may conversely promote Wnt pathway signalling in some contexts, as a consequence of SFRP proteins interacting with each other and titrating each others' activity, or by SFRP binding and stabilising Wnt-Fzd complexes.
Homology SFRP2 has a high degree of homology to both other SFRP family members, as well as Fzd receptors via the cysteine-rich domain.

Implicated in

Note
  
Entity Colorectal cancer and prostate cancer
Note Methylation of SFRP2 and its promoter regions, and consequent loss of SFRP2 expression, is a potential diagnostic and prognostic marker of disease progression in both colorectal and prostate cancers.
  

Bibliography

Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease.
Bovolenta P, Esteve P, Ruiz JM, Cisneros E, Lopez-Rios J.
J Cell Sci. 2008 Mar 15;121(Pt 6):737-46. doi: 10.1242/jcs.026096. (REVIEW)
PMID 18322270
 
Secreted Frizzled-related proteins: searching for relationships and patterns.
Jones SE, Jomary C.
Bioessays. 2002 Sep;24(9):811-20. (REVIEW)
PMID 12210517
 
Wnt signalling and its impact on development and cancer.
Klaus A, Birchmeier W.
Nat Rev Cancer. 2008 May;8(5):387-98. doi: 10.1038/nrc2389.
PMID 18432252
 
Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin.
Lavergne E, Hendaoui I, Coulouarn C, Ribault C, Leseur J, Eliat PA, Mebarki S, Corlu A, Clement B, Musso O.
Oncogene. 2011 Jan 27;30(4):423-33. doi: 10.1038/onc.2010.432. Epub 2010 Sep 20.
PMID 20856206
 
Sulindac inhibits canonical Wnt signaling by blocking the PDZ domain of the protein Dishevelled.
Lee HJ, Wang NX, Shi DL, Zheng JJ.
Angew Chem Int Ed Engl. 2009;48(35):6448-52. doi: 10.1002/anie.200902981.
PMID 19637179
 
The role of secreted frizzled-related protein 2 expression in prostate cancer.
O'Hurley G, Perry AS, O'Grady A, Loftus B, Smyth P, O'Leary JJ, Sheils O, Fitzpatrick JM, Hewitt SM, Lawler M, Kay EW.
Histopathology. 2011 Dec;59(6):1240-8. doi: 10.1111/j.1365-2559.2011.04073.x.
PMID 22175903
 
Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.
Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M.
Cell. 2006 Nov 3;127(3):635-48.
PMID 17081983
 
Gene expression and epigenetic discovery screen reveal methylation of SFRP2 in prostate cancer.
Perry AS, O'Hurley G, Raheem OA, Brennan K, Wong S, O'Grady A, Kennedy AM, Marignol L, Murphy TM, Sullivan L, Barrett C, Loftus B, Thornhill J, Hewitt SM, Lawler M, Kay E, Lynch T, Hollywood D.
Int J Cancer. 2013 Apr 15;132(8):1771-80. doi: 10.1002/ijc.27798. Epub 2012 Sep 28.
PMID 22915211
 
Wnt signalling in stem cells and cancer.
Reya T, Clevers H.
Nature. 2005 Apr 14;434(7035):843-50. (REVIEW)
PMID 15829953
 
The Frizzled family of unconventional G-protein-coupled receptors.
Schulte G, Bryja V.
Trends Pharmacol Sci. 2007 Oct;28(10):518-25. Epub 2007 Sep 19. (REVIEW)
PMID 17884187
 
Inhibition of Wnt signaling by Dishevelled PDZ peptides.
Zhang Y, Appleton BA, Wiesmann C, Lau T, Costa M, Hannoush RN, Sidhu SS.
Nat Chem Biol. 2009 Apr;5(4):217-9. doi: 10.1038/nchembio.152. Epub 2009 Mar 1.
PMID 19252499
 

Citation

This paper should be referenced as such :
O'Donovan, DS ; PerryPS
SFRP2 (secreted frizzled-related protein 2)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(3):180-182.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/SFRP2ID42952ch4q31.html


External links

Nomenclature
HGNC (Hugo)SFRP2   10777
Cards
AtlasSFRP2ID42952ch4q31
Entrez_Gene (NCBI)SFRP2  6423  secreted frizzled related protein 2
AliasesFRP-2; SARP1; SDF-5
GeneCards (Weizmann)SFRP2
Ensembl hg19 (Hinxton)ENSG00000145423 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000145423 [Gene_View]  chr4:153780590-153789076 [Contig_View]  SFRP2 [Vega]
ICGC DataPortalENSG00000145423
TCGA cBioPortalSFRP2
AceView (NCBI)SFRP2
Genatlas (Paris)SFRP2
WikiGenes6423
SOURCE (Princeton)SFRP2
Genetics Home Reference (NIH)SFRP2
Genomic and cartography
GoldenPath hg38 (UCSC)SFRP2  -     chr4:153780590-153789076 -  4q31.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SFRP2  -     4q31.3   [Description]    (hg19-Feb_2009)
EnsemblSFRP2 - 4q31.3 [CytoView hg19]  SFRP2 - 4q31.3 [CytoView hg38]
Mapping of homologs : NCBISFRP2 [Mapview hg19]  SFRP2 [Mapview hg38]
OMIM604157   
Gene and transcription
Genbank (Entrez)AA449032 AF017986 AF311912 AK075372 AK093922
RefSeq transcript (Entrez)NM_003013
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)SFRP2
Cluster EST : UnigeneHs.481022 [ NCBI ]
CGAP (NCI)Hs.481022
Alternative Splicing GalleryENSG00000145423
Gene ExpressionSFRP2 [ NCBI-GEO ]   SFRP2 [ EBI - ARRAY_EXPRESS ]   SFRP2 [ SEEK ]   SFRP2 [ MEM ]
Gene Expression Viewer (FireBrowse)SFRP2 "[0Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6423
GTEX Portal (Tissue expression)SFRP2
Human Protein AtlasENSG00000145423-SFRP2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ96HF1   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ96HF1  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ96HF1
Splice isoforms : SwissVarQ96HF1
PhosPhoSitePlusQ96HF1
Domaine pattern : Prosite (Expaxy)FZ (PS50038)    NTR (PS50189)   
Domains : Interpro (EBI)Frizzled/SFRP    Frizzled_dom    Netrin_domain        SFRP2    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)SFRP2
DMDM Disease mutations6423
Blocks (Seattle)SFRP2
SuperfamilyQ96HF1
Human Protein Atlas [tissue]ENSG00000145423-SFRP2 [tissue]
Peptide AtlasQ96HF1
HPRD16041
IPIIPI00027596   
Protein Interaction databases
DIP (DOE-UCLA)Q96HF1
IntAct (EBI)Q96HF1
FunCoupENSG00000145423
BioGRIDSFRP2
STRING (EMBL)SFRP2
ZODIACSFRP2
Ontologies - Pathways
QuickGOQ96HF1
Ontology : AmiGObranching involved in blood vessel morphogenesis  fibronectin binding  chondrocyte development  outflow tract morphogenesis  cardiac left ventricle morphogenesis  integrin binding  extracellular space  extracellular space  apoptotic process  cell-cell signaling  response to nutrient  positive regulation of cell proliferation  negative regulation of cell proliferation  negative regulation of cell proliferation  male gonad development  negative regulation of gene expression  negative regulation of cardiac muscle cell apoptotic process  negative regulation of epithelial to mesenchymal transition  positive regulation of endopeptidase activity  regulation of neuron projection development  Wnt-protein binding  negative regulation of Wnt signaling pathway  negative regulation of Wnt signaling pathway  collagen fibril organization  positive regulation of cell growth  negative regulation of cell growth  negative regulation of cell migration  negative regulation of BMP signaling pathway  extracellular matrix  cellular response to extracellular stimulus  positive regulation of peptidyl-serine phosphorylation  positive regulation of cell adhesion mediated by integrin  positive regulation of catenin import into nucleus  post-anal tail morphogenesis  response to drug  negative regulation of mesodermal cell fate specification  embryonic digit morphogenesis  positive regulation of apoptotic process  negative regulation of cysteine-type endopeptidase activity involved in apoptotic process  negative regulation of JUN kinase activity  positive regulation of fat cell differentiation  positive regulation of osteoblast differentiation  positive regulation of angiogenesis  negative regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  receptor agonist activity  digestive tract morphogenesis  negative regulation of epithelial cell proliferation  negative regulation of peptidyl-tyrosine phosphorylation  convergent extension involved in axis elongation  bone morphogenesis  sclerotome development  endopeptidase activator activity  negative regulation of dermatome development  hematopoietic stem cell proliferation  cellular response to X-ray  negative regulation of canonical Wnt signaling pathway  planar cell polarity pathway involved in neural tube closure  Wnt signaling pathway involved in somitogenesis  positive regulation of canonical Wnt signaling pathway  negative regulation of extrinsic apoptotic signaling pathway via death domain receptors  negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage  regulation of midbrain dopaminergic neuron differentiation  regulation of stem cell division  negative regulation of planar cell polarity pathway involved in axis elongation  
Ontology : EGO-EBIbranching involved in blood vessel morphogenesis  fibronectin binding  chondrocyte development  outflow tract morphogenesis  cardiac left ventricle morphogenesis  integrin binding  extracellular space  extracellular space  apoptotic process  cell-cell signaling  response to nutrient  positive regulation of cell proliferation  negative regulation of cell proliferation  negative regulation of cell proliferation  male gonad development  negative regulation of gene expression  negative regulation of cardiac muscle cell apoptotic process  negative regulation of epithelial to mesenchymal transition  positive regulation of endopeptidase activity  regulation of neuron projection development  Wnt-protein binding  negative regulation of Wnt signaling pathway  negative regulation of Wnt signaling pathway  collagen fibril organization  positive regulation of cell growth  negative regulation of cell growth  negative regulation of cell migration  negative regulation of BMP signaling pathway  extracellular matrix  cellular response to extracellular stimulus  positive regulation of peptidyl-serine phosphorylation  positive regulation of cell adhesion mediated by integrin  positive regulation of catenin import into nucleus  post-anal tail morphogenesis  response to drug  negative regulation of mesodermal cell fate specification  embryonic digit morphogenesis  positive regulation of apoptotic process  negative regulation of cysteine-type endopeptidase activity involved in apoptotic process  negative regulation of JUN kinase activity  positive regulation of fat cell differentiation  positive regulation of osteoblast differentiation  positive regulation of angiogenesis  negative regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  receptor agonist activity  digestive tract morphogenesis  negative regulation of epithelial cell proliferation  negative regulation of peptidyl-tyrosine phosphorylation  convergent extension involved in axis elongation  bone morphogenesis  sclerotome development  endopeptidase activator activity  negative regulation of dermatome development  hematopoietic stem cell proliferation  cellular response to X-ray  negative regulation of canonical Wnt signaling pathway  planar cell polarity pathway involved in neural tube closure  Wnt signaling pathway involved in somitogenesis  positive regulation of canonical Wnt signaling pathway  negative regulation of extrinsic apoptotic signaling pathway via death domain receptors  negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage  regulation of midbrain dopaminergic neuron differentiation  regulation of stem cell division  negative regulation of planar cell polarity pathway involved in axis elongation  
Pathways : KEGGWnt signaling pathway   
REACTOMEQ96HF1 [protein]
REACTOME PathwaysR-HSA-3772470 [pathway]   
NDEx NetworkSFRP2
Atlas of Cancer Signalling NetworkSFRP2
Wikipedia pathwaysSFRP2
Orthology - Evolution
OrthoDB6423
GeneTree (enSembl)ENSG00000145423
Phylogenetic Trees/Animal Genes : TreeFamSFRP2
HOVERGENQ96HF1
HOGENOMQ96HF1
Homologs : HomoloGeneSFRP2
Homology/Alignments : Family Browser (UCSC)SFRP2
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSFRP2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SFRP2
dbVarSFRP2
ClinVarSFRP2
1000_GenomesSFRP2 
Exome Variant ServerSFRP2
ExAC (Exome Aggregation Consortium)ENSG00000145423
GNOMAD BrowserENSG00000145423
Genetic variants : HAPMAP6423
Genomic Variants (DGV)SFRP2 [DGVbeta]
DECIPHERSFRP2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSFRP2 
Mutations
ICGC Data PortalSFRP2 
TCGA Data PortalSFRP2 
Broad Tumor PortalSFRP2
OASIS PortalSFRP2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSFRP2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSFRP2
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 SFRP2
DgiDB (Drug Gene Interaction Database)SFRP2
DoCM (Curated mutations)SFRP2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SFRP2 (select a term)
intoGenSFRP2
NCG5 (London)SFRP2
Cancer3DSFRP2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM604157   
Orphanet
MedgenSFRP2
Genetic Testing Registry SFRP2
NextProtQ96HF1 [Medical]
TSGene6423
GENETestsSFRP2
Target ValidationSFRP2
Huge Navigator SFRP2 [HugePedia]
snp3D : Map Gene to Disease6423
BioCentury BCIQSFRP2
ClinGenSFRP2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD6423
Chemical/Pharm GKB GenePA35693
Clinical trialSFRP2
Miscellaneous
canSAR (ICR)SFRP2 (select the gene name)
Probes
Litterature
PubMed87 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSFRP2
EVEXSFRP2
GoPubMedSFRP2
iHOPSFRP2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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