Figure 5.

The canonical Wnt pathway regulates gene expression by modulating β-catenin levels. (A) In the absence of Wnt ligands, the Axin/CK1α/APC/GSK3β degradation complex binds and phosphorylates cytoplasmic β-catenin, leading to ubiquitin-dependent degradation of β-catenin. This prevents the accumulation of β-catenin and keeps Wnt pathway target gene expression switched off. (B) Upon binding of extracellular Wnt ligands to transmembrane frizzled receptors and the co-receptors LRP5/6, the Axin/CK1α/APC/GSK3β degradation complex is diverted to the plasma membrane and binds to LRP5/6. Wnt ligand binding also causes disheveled to interact with frizzled receptors and LRP5/6. Phosphorylated LRP5/6 and disheveled then sequester and induce phosphorylation of the Axin/CK1α/APC/GSK3β degradation complex, which inhibits its ability to phosphorylate β-catenin, leading to β-catenin stabilization and accumulation in the cytoplasm. Accumulated β-catenin is then able to translocate into the nucleus and bind to TCF/LEF, activating the expression of the Wnt pathway target genes. CK, casein kinase; APC, adenomatous polyposis coli; GSK, glycogen synthase kinase; LRP, low-density lipoprotein receptor; TCF, transcription factor; LEF, lymphoid enhancing binding factor.