Induction of Gsk3β-β-TrCP interaction is required for late phase stabilization of β-catenin in canonical Wnt signaling.

A pivotal step in canonical Wnt signaling is Wnt-induced β-catenin stabilization. In the absence of Wnt, β-catenin is targeted for β-transducin repeats-containing proteins (β-TrCP)-mediated degradation due to phosphorylation by glycogen synthase kinase 3 (Gsk3). How canonical Wnt signaling regulates Gsk3 to inhibit β-catenin proteolysis remains largely elusive. This study reveals novel key molecular events in Wnt signaling: induction of Gsk3β ubiquitination and Gsk3β-β-TrCP binding. We found that Wnt stimulation induced prolonged monoubiquitination of Gsk3β and Gsk3β-β-TrCP interaction. Monoubiquitination did not cause Gsk3β degradation nor affects its enzymatic activity. Rather, increased monoubiquitination of Gsk3β/Gsk3β-β-TrCP association suppressed β-catenin recruitment of β-TrCP, leading to long-term inhibition of β-catenin ubiquitination and degradation.