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doi: 10.1242/10.1242/jcs.00623

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Secreted antagonists of the Wnt signalling pathway

Department of Cancer Cell Biology, Division of Medicine, Imperial College, London W12 0NN, UK

View larger version (20K): [in a new window]   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.

View larger version (14K): [in a new window]   Fig. 2. Wnt antagonists and related proteins. (a) sFRP family proteins are related to Frizzled receptors in the CRD (Cysteine-rich domain). NTR, netrin-like domain; CD, cytoplasmic domain. (b) Dickkopf family proteins are related to pancreatic colipase in Cys-2 (Cysteine-rich domain-2). The domain containing 10 conserved cysteine residues in colipase is shown in green. Cys-1, Cysteine-rich domain-1. (c) WIF-1 is related to the receptor tyrosine kinase, RYK in the WIF domain (WD). KD, tyrosine kinase domain. Signal peptides, transmembrane domains and EGF-like repeats are shown as red, blue, and hashed boxes, respectively.