Secreted Frizzled-related proteins (sFRPs) are modulators of the Wnt signaling pathway that plays important roles in both embryogenesis and oncogenesis. sFRPs have been proposed to antagonize Wnt activity by binding to Wnts. However, the affinity of this binding is unknown. Here we show, using surface plasmon resonance and purified proteins, that sFRP1, sFRP2, sFRP4, and Frzb bind directly to Wnt3a with affinities in the nanomolar range. However, only sFRP1 and sFRP2 antagonize Wnt3a activity by blocking Wnt3a induced beta-catenin accumulation in L cells. Furthermore, sFRP2, but not Frzb, antagonizes Wnt3a signaling in an ES cell model of mesoderm differentiation. These results provide the first measurement of binding affinity of sFRPs for a Wnt, which together with the measurement of antagonistic activity of sFRPs could help understand how sFRPs regulate Wnt signaling.
"Finch et al., purified and cloned the SFRP gene for the first time , and they confirmed it to be antagonistic to Wnt signalling. Further evidence to their antagonistic role came from studies where SFRPs had been shown to interact with and bind to Wnt ligands     . These papers also summarized the antagonizing effects of SFRP molecules on Wnt-induced increases in free β-catenin levels and morphological alterations. "
[Show abstract][Hide abstract] ABSTRACT: The Wnt (wingless-type) signalling pathway plays an important role in embryonic development, tissue homeostasis, and tumour progression because of its effect on cell proliferation, migration, and differentiation. Secreted frizzled-related proteins (SFRPs) are extracellular inhibitors of Wnt signalling that act by binding directly to Wnt ligands or to Frizzled receptors. In recent years, aberrant expression of SFRPs has been reported to be associated with numerous cancers. As gene expression of SFRP members is often lost through promoter hypermethylation, inhibition of methylation through the use of epigenetic modifying agents could renew the expression of SFRP members and further antagonize deleterious Wnt signalling. Several reports have described epigenetic silencing of these Wnt signalling antagonists in various human cancers, suggesting their possible role as tumour suppressors. SFRP family members thus come across as potential tools in combating Wnt-driven tumourigenesis. However, little is known about SFRP family members and their role in different cancers. This review comprehensively covers all the available information on the role of SFRP molecules in various human cancers.
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 01/2014; 1845(1):53-65. DOI:10.1016/j.bbcan.2013.11.004 · 7.85 Impact Factor
"Structurally, each SFRP protein consists of two distinct domains, an N-terminal cysteine rich domain (CRD), which is homologous to the extracellular domain of Frizzled proteins, and a second, C-terminal cysteine rich domain with homology to netrin proteins . Both CRD and NTR domains can bind to Wnt signaling molecules , , , with different SFRP proteins binding a different subset of Wnt molecules –. "
[Show abstract][Hide abstract] ABSTRACT: Sfrp5 belongs to the family of secreted frizzled related proteins (Sfrp), secreted inhibitors of Wingless-MMTV Integration Site (Wnt) signaling, which play an important role in cancer and development. We selected sfrp5 because of its compelling expression profile in the developing endoderm in zebrafish, Danio rerio. In this study, overexpression of sfrp5 in embryos results in defects in both convergent extension (CE) by inhibition of non-canonical Wnt signaling and defects in dorsoventral patterning by inhibition of Tolloid-mediated proteolysis of the BMP inhibitor Chordin. From 25 hours post fertilization (hpf) to 3 days post fertilization (dpf), both overexpression and knockdown of Sfrp5 decrease the size of the endoderm, significantly reducing liver cell number. At 3 dpf, insulin-positive endodermal cells fail to coalesce into a single pancreatic islet. We show that Sfrp5 inhibits both canonical and non-canonical Wnt signaling during embryonic and endodermal development, resulting in endodermal abnormalities.
PLoS ONE 09/2013; 8(4):e62470. DOI:10.1371/journal.pone.0062470 · 3.23 Impact Factor
"Although the concentration of soluble FZC18 in the conditioned medium was several fold lower than that of FZD8_CRD, a well-known partner of Wnt3a , Wnt3a was efficiently pulled down by FZC18. Accordingly, Wnts bind to FZD CRDs with affinities lower than 90 nM , , , , . In the present report, the use of soluble FZC18 at very low concentrations and a Wnt3a concentration within the physiological range (2.7 nM) indicates that spurious interactions of highly concentrated cysteine-rich proteins are unlikely. "
[Show abstract][Hide abstract] ABSTRACT: The Wnt/β-catenin pathway controls cell proliferation, death and differentiation. Several families of extracellular proteins can antagonize Wnt/β-catenin signaling, including the decoy receptors known as secreted frizzled related proteins (SFRPs), which have a cysteine-rich domain (CRD) structurally similar to the extracellular Wnt-binding domain of the frizzled receptors. SFRPs inhibit Wnt signaling by sequestering Wnts through the CRD or by forming inactive complexes with the frizzled receptors. Other endogenous molecules carrying frizzled CRDs inhibit Wnt signaling, such as V3Nter, which is proteolytically derived from the cell surface component collagen XVIII and contains a biologically active frizzled domain (FZC18) inhibiting in vivo cell proliferation and tumor growth in mice. We recently showed that FZC18 expressing cells deliver short-range signals to neighboring cells, decreasing their proliferation in vitro and in vivo through the Wnt/β-catenin signaling pathway. Here, using low concentrations of soluble FZC18 and Wnt3a, we show that they physically interact in a cell-free system. In addition, soluble FZC18 binds the frizzled 1 and 8 receptors' CRDs, reducing cell sensitivity to Wnt3a. Conversely, inhibition of Wnt/β-catenin signaling was partially rescued by the expression of full-length frizzled 1 and 8 receptors, but enhanced by the expression of a chimeric cell-membrane-tethered frizzled 8 CRD. Moreover, soluble, partially purified recombinant FZC18_CRD inhibited Wnt3a-induced β-catenin activation. Taken together, the data indicate that collagen XVIII-derived frizzled CRD shifts Wnt sensitivity of normal cells to a lower pitch and controls their growth.
PLoS ONE 01/2012; 7(1):e30601. DOI:10.1371/journal.pone.0030601 · 3.23 Impact Factor
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