Fig. 1. Regulation of Wnt signalling by antagonists. (a) Activation of the canonical pathway is initiated when Wnt associates with Frizzled (Fz) and LRP5/6. Subsequent events include the recruitment of Axin to LRP5/6 and its degradation, and the phosphorylation of dishevelled, resulting in disruption of the link between ß-catenin and GSK-3ß. ß-catenin is no longer phosphorylated and is thus stabilised. Activation of the noncanonical pathway may involve interaction of Wnt with Fz in the absence of LRP5/6. (b) Antagonists such as sFRPs, Cerberus (CER) and WIF-1 prevent Wnt from binding to its receptors. In this case, both the canonical and the noncanonical pathways are inactivated. sFRPs may also inhibit Wnt by binding to Frizzled. (c) Dkk-1 interacts with LRP5/6 and the co-receptor Kremen 1/2 (Krm, green), and this triggers LRP5/6 endocytosis, thereby preventing formation of the LRP5/6–Wnt–Frizzled complex. Axin brings together the proteins that promote ß-catenin phosphorylation, enabling ß-catenin degradation and inhibition of the canonical pathway. The Wnt-Fz complex can still activate the noncanonical pathway.