Fig. 1. A simplified prevailing view of Wnt/ß-catenin signaling (see Box 1 for some alternative views). (A) Without Wnt, the scaffolding protein Axin assembles a protein complex that contains Apc, Gsk3, Ck1 and ß-catenin. In this complex, ß-catenin is sequentially phosphorylated by Ck1 and Gsk3. Phosphorylated ß-catenin is recognized by ß-Trcp, which is a component of an ubiquitin-ligase complex that conjugates ß-catenin with ubiquitin. Poly-ubiquitinated ß-catenin is degraded by the proteosome. TCF/LEF-associated co-repressors, such as Groucho (Cavallo et al., 1998), and Axin-associated Diversin (Schwarz-Romond et al., 2002), PP2A (Hsu et al., 1999) and other proteins (Kikuchi, 1999) are omitted for simplicity. (B) In the presence of Wnt, ß-catenin phosphorylation and degradation is inhibited. Accumulated ß-catenin forms a nuclear complex with the DNA-bound TCF/LEF transcription factor, and together they activate Wnt-responsive genes. This signaling cascade is perhaps initiated by a Wnt-induced Fz-Lrp5/Lrp6 co-receptor complex, which recruits Axin to the plasma membrane through Lrp5/Lrp6-Axin association. Fz-associated Dishevelled (Dvl) protein may bind Axin and inhibit Axin-Gsk3 phosphorylation of ß-catenin, either directly or indirectly via Dvl-associated proteins. Lrp5/Lrp6-Axin binding may also promote Axin degradation. Either or both of these events can lead to ß-catenin accumulation. This description represents one of several possibilities. The composition of the Axin complex upon Wnt stimulation is not well defined. Gsk3-binding protein (GBP/Frat) (Farr et al., 2000; Salic et al., 2000), and nuclear ß-catenin-associated Legless/Bcl9 and Pygopus (Belenkaya et al., 2002; Kramps et al., 2002; Parker et al., 2002; Thompson et al., 2002) are omitted for simplicity. Modified with permission from He (He, 2003).