FIGURE 16-30 “Canonical” Wnt signaling pathway. (a) In the absence of Wnt, the transcription factor TCF is bound to promoters or enhancers of target genes, but its association with transcriptional repressors such as Groucho (Gro) inhibits gene activation. β-catenin is bound in a complex with Axin (a scaffold protein), APC, and the kinases CK1 and GSK3, which sequentially phosphorylate β-catenin at multiple serine and threonine residues. In particular, Axin-mediated formation of this complex facilitates phosphorylation of β-catenin by GSK3 by an estimated factor of 20,000. The E3 TrCP ubiquitin ligase then binds to two phosphorylated β-catenin residues, leading to β-catenin ubiquitinylation and degradation in proteasomes. (b) Binding of Wnt to its receptor Frizzled (Fz) and to the LRP co-receptor triggers phosphorylation of LRP by GSK3 and CK1, allowing subsequent binding of the Dishevelled scaffold protein. Binding of Axin to the phosphorylated LRP protein and to Dishevelled disrupts the Axin–APC–CK1–GSK3–β-catenin complex, preventing phosphorylation of β-catenin by CK1 and GSK3 and leading to accumulation of β-catenin in the cell. After translocation to the nucleus, β-catenin binds to TCF to displace the Gro repressor and recruits co-activator proteins including Pygo, LGS, and others to activate gene expression. See R. van Amerongen and R. Nusse, 2009, Development 136:3205; E. Verheyen and C. Gottardi, 2010, Dev. Dynam. 239:34; and J. Holland et al., 2013, Curr. Opin. Cell Biol. 25:254. See also the Wnt Homepage, http://web.stanford.edu/group/nusselab/cgi-bin/wnt.