β‐catenin is a target for the ubiquitin–proteasome pathway

TLDR: It is shown that ubiquitination of β‐catenin is greatly reduced in Wnt‐expressing cells, providing the first evidence that the ubiquitin–proteasome degradation pathway may act downstream of GSK3β in the regulation ofβ‐ catenin.

Abstract: beta-catenin is a central component of the cadherin cell adhesion complex and plays an essential role in the Wingless/Wnt signaling pathway. In the current model of this pathway, the amount of beta-catenin (or its invertebrate homolog Armadillo) is tightly regulated and its steady-state level outside the cadherin-catenin complex is low in the absence of Wingless/Wnt signal. Here we show that the ubiquitin-dependent proteolysis system is involved in the regulation of beta-catenin turnover. beta-catenin, but not E-cadherin, p120(cas) or alpha-catenin, becomes stabilized when proteasome-mediated proteolysis is inhibited and this leads to the accumulation of multi-ubiquitinated forms of beta-catenin. Mutagenesis experiments demonstrate that substitution of the serine residues in the glycogen synthase kinase 3beta (GSK3beta) phosphorylation consensus motif of beta-catenin inhibits ubiquitination and results in stabilization of the protein. This motif in beta-catenin resembles a motif in IkappaB (inhibitor of NFkappaB) which is required for the phosphorylation-dependent degradation of IkappaB via the ubiquitin-proteasome pathway. We show that ubiquitination of beta-catenin is greatly reduced in Wnt-expressing cells, providing the first evidence that the ubiquitin-proteasome degradation pathway may act downstream of GSK3beta in the regulation of beta-catenin.