Fig. 2. The spatial and functional organization of the core mechanism of Wnt/β-catenin signalling. (A) In the absence of ligand, a destruction complex assembles around the scaffolding protein Axin (see C for details), which binds and then labels β-catenin for proteolysis via phosphorylation of specific residues at its N-terminus. (B) Wnt binds to Frizzled (a) and triggers signalling by initiating a chain of events, which at a biochemical level are not well characterized. At the cell surface, the Wnt-Frizzled complex forms a trimeric complex with LRP5/6 (Arrow in Drosophila) and this triggers the activity of Dishevelled (Dsh), which promotes the association of the destruction complex with the LRP5/6-Frizzled complex (b,c). A chain of events (detailed in C) leads to the LRP5/6-mediated degradation of Axin (d) and the release of β-catenin from Axin (e). Free hypophosphorylated β-catenin can then enter the nucleus (f), where it nucleates a transcription modulator complex around TCF. (C) Structure and function of the Axin-based destruction complex. In the absence of Wnt, the complex is assembled and can bind β-catenin, which is then phosphorylated by GSK3β. Phosphorylated β-catenin is targeted for ubiquitination and proteasomal degradation. In the presence of Wnt, the destruction complex is recruited to the cell surface, where a series of phosphorylation events results in the degradation of Axin and the release of β-catenin. For further details, see text and published literature (Logan and Nusse, 2004; Tolwinski and Wieschaus, 2004b). APC, Adenomatous polyposis coli; β-TrCP, β-transducin repeat-containing protein (also known as Ebi); CKI, Casein kinase; DSH, Dishevelled; CtBP, C-terminal-binding protein; GSK3β, Glycogen synthase kinase 3β; Lgs, Legless; LRP, Low density lipoprotein receptor-related protein; Pol II, RNA polymerase II; PP2A, Protein phosphatase 2A; TCF, T cell factor (also known as Pangolin); Ub, ubiquitination.