SFRP2 (secreted frizzled-related protein 2)

2013-08-01   Darragh S ODonovan , Antoinette S Perry 

Prostate Molecular Oncology, Institute of Molecular Medicine, Trinity College, Dublin, Ireland




Atlas Image
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.


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.


mRNA size 2005 bp, ORF size 888 bp.


Atlas Image


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.


Widely expressed.


Nucleus, cytoplasm and secreted.


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.


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

Entity name
Colorectal cancer and prostate cancer
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.


Pubmed IDLast YearTitleAuthors
183222702008Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease.Bovolenta P et al
122105172002Secreted Frizzled-related proteins: searching for relationships and patterns.Jones SE et al
184322522008Wnt signalling and its impact on development and cancer.Klaus A et al
208562062011Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin.Lavergne E et al
196371792009Sulindac inhibits canonical Wnt signaling by blocking the PDZ domain of the protein Dishevelled.Lee HJ et al
221759032011The role of secreted frizzled-related protein 2 expression in prostate cancer.O'Hurley G et al
170819832006Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.Olsen JV et al
229152112013Gene expression and epigenetic discovery screen reveal methylation of SFRP2 in prostate cancer.Perry AS et al
158299532005Wnt signalling in stem cells and cancer.Reya T et al
178841872007The Frizzled family of unconventional G-protein-coupled receptors.Schulte G et al
192524992009Inhibition of Wnt signaling by Dishevelled PDZ peptides.Zhang Y et al

Other Information

Locus ID:

NCBI: 6423
MIM: 604157
HGNC: 10777
Ensembl: ENSG00000145423


dbSNP: 6423
ClinVar: 6423
TCGA: ENSG00000145423


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Wnt signaling pathwayKEGGko04310
Wnt signaling pathwayKEGGhsa04310
Signal TransductionREACTOMER-HSA-162582
Signaling by WntREACTOMER-HSA-195721
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Negative regulation of TCF-dependent signaling by WNT ligand antagonistsREACTOMER-HSA-3772470


Pubmed IDYearTitleCitations
270429332016sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance.71
150942742004Methylation changes in faecal DNA: a marker for colorectal cancer screening?62
166090232006Combination analysis of hypermethylated Wnt-antagonist family genes as a novel epigenetic biomarker panel for bladder cancer detection.53
190952962009SFRP1 and SFRP2 suppress the transformation and invasion abilities of cervical cancer cells through Wnt signal pathway.50
194580752009Secreted frizzle-related protein 2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway.47
202085692010The SFRP family of WNT inhibitors function as novel tumor suppressor genes epigenetically silenced in medulloblastoma.44
178489502007Frequent epigenetic inactivation of secreted frizzled-related protein 2 (SFRP2) by promoter methylation in human gastric cancer.42
164078292006Alterations of the Wnt signaling pathway during the neoplastic progression of Barrett's esophagus.39
185921562008Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma.37
214909612011Down-regulation of the canonical Wnt β-catenin pathway in the airway epithelium of healthy smokers and smokers with COPD.35


Darragh S ODonovan ; Antoinette S Perry

SFRP2 (secreted frizzled-related protein 2)

Atlas Genet Cytogenet Oncol Haematol. 2013-08-01

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