Mammalian genomes encode 5 secreted Frizzled related proteins (sFRPs) that are proposed to antagonize WNT signaling by binding directly to WNT ligands. Binding is mediated by a cysteine-rich-domain in the N-terminal that is homologous to the one found in FZD receptors and which is also found in the alternative WNT receptors ROR1 and ROR2 (reviewed in Kawano and Kupta, 2003; Boloventa et al, 2008). Direct binding of sFRP1, 2, 3 and 4 to Wnt3a has been demonstrated by surface plasmon resonance, but only sFRP1 and 2 were shown to inhibit Wtn3a-dependent signaling in mouse ES cells (Wawrzak et al, 2007). In addition to binding to WNT ligands, sFRPs are proposed to antagonize WNT signaling in a number of other ways. sFRPs have been shown to bind directly to FZD proteins by virtue of the CRDs: this interaction is postulated to block WNT signaling by inhibiting the WNT:FZD interaction (Bafico et al, 1999; Rodgriguez et al, 2005).