Several unrelated families of secreted proteins antagonize WNT signaling. Secreted frizzled-related proteins (sFRPs) have a cysteine rich domain (CRD) that is also found in FZD and ROR receptors, while WNT inhibitory factor (WIF) proteins contain a WIF domain also present in the WNT-receptor RYK. Both these classes of secreted WNT antagonists inhibit signaling by binding to WNTs and preventing their interaction with the FZD receptors. sFRPs may also able to bind the receptors, blocking ligand binding (Bafico et al, 1999; reviewed in Kawano and Kypta, 2003). The interaction of WIF and sFRPs with WNT ligand may also play a role in regulating WNT diffusion and gradient formation (reviewed in Boloventa et al, 2008).
Dickkopf (DKK) and Sclerostin (SOST) family members, in contrast, antagonize WNT signaling by binding to LRP5/6. There are four DKK family members in vertebrates; the closely related DKK1, 2 and 4 proteins have been shown to have roles in WNT signaling, while the more divergent DKK3 appears not to (Glinka et al, 1998; Fedi et al, 1999; Mao et al, 2001; Semenov et al, 2001; reviewed in Niehrs, 2006). Secreted DKK proteins bind to LRP6 in conjunction with the single-pass transmembrane proteins Kremen 1 and 2, and this interaction is thought to disrupt the WNT-induced FZD-LRP5/6 complex. In some cases, DKK2 has also been shown to function as a WNT agonist (reviewed in N (reviewed in Niehrs, 2006).
Like DKK proteins, SOST binds LRP5/6 and disrupts WNT-dependent receptor activation (Semenov et al, 2005).