FIGURE 2.

The Canonical Wnt/β-catenin signaling pathway. In the absence of Wnt ligands or in the presence of Wnt antagonists such as DKK1, WIF1, or SFRPs, the Wnt signaling pathway is kept in the off state by the dynamic degradation of β-catenin mediated by the β-catenin destruction complex. This multiprotein complex is composed of the scaffolding proteins AXIN1/2 and APC and the kinases CK1α and GSK3β. The two kinases sequentially phosphorylate β-catenin, targeting it for proteasomal degradation. Conversely, when Wnt ligands bind the FZD/LRP co-receptor complex, the β-catenin destruction complex is disassembled. Consequently, β-catenin accumulates in the cytoplasm and translocates to the nucleus, where it displaces co-repressors bound to TCF/LEF transcription factors, thereby initiating Wnt-target gene expression. R-spondins can amplify Wnt ligand response and increase cellular sensitivity to Wnt ligands by inhibiting the recycling of FZD receptors.