Phosphorylation-Dependent Regulation of WNT/Beta-Catenin Signaling

WNT/beta-catenin signaling is a highly complex pathway that plays diverse roles in various cellular processes. While WNT ligands usually signal through their dedicated Frizzled receptors, the decision to signal in a beta-catenin-dependent or -independent manner rests upon the type of co-receptors used. Canonical WNT signaling is beta-catenin-dependent, whereas non-canonical WNT signaling is beta-catenin-independent according to the classical definition. This still holds true, albeit with some added complexity, as both the pathways seem to cross-talk with intertwined networks that involve the use of different ligands, receptors, and co-receptors. beta-catenin can be directly phosphorylated by various kinases governing its participation in either canonical or non-canonical pathways. Moreover, the co-activators that associate with beta-catenin determine the output of the pathway in terms of induction of genes promoting proliferation or differentiation. In this review, we provide an overview of how protein phosphorylation controls WNT/beta-catenin signaling, particularly in human cancer.