Intracellular Signals Activated by Canonical Wnt Ligands Independent of GSK3 Inhibition and β-Catenin Stabilization

In contrast to non-canonical ligands, canonical Wnts promote the stabilization of β-catenin, which is a prerequisite for formation of the TCF4/β-catenin transcriptional complex and activation of its target genes. This pathway is initiated by binding of Wnt ligands to the Frizzled/LRP5/6 receptor complex, and it increases the half-life of β-catenin by precluding the phosphorylation of β-catenin by GSK3 and its binding to the βTrCP1 ubiquitin ligase. Other intercellular signals are also activated by Wnt ligands that do not inhibit GSK3 and increase β-catenin protein but that either facilitate β-catenin transcriptional activity or stimulate other transcriptional factors that cooperate with it. In this review, we describe the layers of complexity of these signals and discuss their crosstalk with β-catenin in activation of transcriptional targets.