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.This research was funded by grants from the Ministerio de Ciencia, Innovación y Universidades (RTI2018-099719-B-100 cofunded by Fondos Feder, SAF2013-40922-R1 and SAF2016-76461-R). Support from ICREA Academia is also appreciated