Wnt3a binds to several sFRPs in the nanomolar range

Laboratory for Cell Genetics, Vrije Universiteit Brussel (VUB), Pleinlaan 2, B-1050 Brussels, Belgium.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 07/2007; 357(4):1119-23. DOI: 10.1016/j.bbrc.2007.04.069
Source: PubMed


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.

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    • "Axin2, although strong, was only found in the most lateral aspect of the EmT in its entire rostrocaudal axis. This restricted expression may be due to the strong expression of Sfrp2, an antagonist of Wnt signalling (Wawrzak et al. 2007), expressed in a high-medial to lowlateral gradient complementary to that of Axin2. Very low Lef1 expression in the EmT with high levels in the neighbouring prethalamus resembles lack of Lef1 expression in the cortical hem with high expression levels in the adjacent dorsomedial pallium (Fotaki et al. 2011; Galceran et al. 2000). "
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    ABSTRACT: The mammalian eminentia thalami (EmT) (or thalamic eminence) is an embryonic forebrain structure of unknown function. Here, we examined the molecular and cellular properties of the mouse EmT. We first studied mRNA expression of signalling molecules and found that the EmT is a structure, rich in expression of secreted factors, with Wnts being the most abundantly detected. We then examined whether EmT tissue could induce cell fate changes when grafted ectopically. For this, we transplanted EmT tissue from a tau-GFP mouse to the ventral telencephalon of a wild type host, a telencephalic region where Wnt signalling is not normally active but which we showed in culture experiments is competent to respond to Wnts. We observed that the EmT was able to induce in adjacent ventral telencephalic cells ectopic expression of Lef1, a transcriptional activator and a target gene of the Wnt/β-catenin pathway. These Lef1-positive;GFP-negative cells expressed the telencephalic marker Foxg1 but not Ascl1, which is normally expressed by ventral telencephalic cells. These results suggest that the EmT has the capacity to activate Wnt/β-catenin signalling in the ventral telencephalon and to suppress ventral telencephalic gene expression. Altogether, our data support a role of the EmT as a signalling centre in the developing mouse forebrain.
    Brain Structure and Function 10/2015; DOI:10.1007/s00429-015-1127-3 · 5.62 Impact Factor
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    • "However, truncated forms of sFRP1 lacking the CRD retain strong interaction with Wingless and Wnt8 and mimic the function of the entire protein in both cell culture and fish embryos (Lopez-Rios et al., 2008; Uren et al., 2000). These data suggest that sFRPs have multiple Wnt binding sites (Figure 13.1a), which may be crucial to establish specific sFRP–Wnt pairs with different affinities (Wawrzak et al., 2007). Furthermore, sFRPs cannot be considered as simple Wnt scavengers because there is increasing evidence that they also have important functions in the activation of the pathway. "
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    ABSTRACT: Modulators of Wnt signaling can be divided into two classes. The first class consists of secreted and in general highly diffusible molecules that bind directly to Wnt ligands and thereby either prevent pathway activation or influence their activity and signaling range. These factors fall into four distinct groups based on their protein structure: secreted Frizzled-related proteins (sFRPs), Cerberus (Cer), Wnt-inhibitory factor 1 (WIF-1), and secreted wingless interacting molecules (Swim). Molecules that do not bind directly to Wnt ligands but essentially interfere with the formation of active ligand/receptor/coreceptor complexes compose the second class. These modulators can be grouped as Dickkopf (Dkk), Wnt modulator in surface ectoderm (Wise), IGFbinding protein-4 (IGFBP-4), Tsukushi (TSK), Notum, Serpina3k, connective tissue growth factor (CTGF), Sclerostin/SOST, Shisa, and Norrin. This chapter discusses the evidence supporting the role and action mechanism of these modulators and summarizes the pathological conditions that have been so far associated with their dysfunction.
    Wnt Signaling in Development and Disease, 03/2014: pages 177-193; , ISBN: 9781118444160
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    • "Finch et al., purified and cloned the SFRP gene for the first time [20], 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 [21] [22] [23] [24] [25]. These papers also summarized the antagonizing effects of SFRP molecules on Wnt-induced increases in free β-catenin levels and morphological alterations. "
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    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
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