BETA-CATENIN IS A TARGET FOR THE UBIQUITIN-PROTEASOME PATHWAY

beta-catenin is a central component of the cadherin cell adhesion comp lex 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 stead y-state level outside the cadherin-catenin complex is low in the absen ce of Wingless/Wnt signal. Here we show that the ubiquitin-dependent p roteolysis system is involved in the regulation of beta-catenin turnov er. beta-catenin, but not E-cadherin, p120(cas) or alpha-catenin, beco mes stabilized when proteasome-mediated proteolysis is inhibited and t his leads to the accumulation of multi-ubiquitinated forms of beta-cat enin. Mutagenesis experiments demonstrate that substitution of the ser ine residues in the glycogen synthase kinase 3 beta (GSK3 beta) phosph orylation consensus motif of beta-catenin inhibits ubiquitination and results in stabilization of the protein. This motif in beta-catenin re sembles a moth in I kappa B (inhibitor of NF kappa B) which is require d for the phosphorylation-dependent degradation of I kappa B via the u biquitin-proteasome pathway, We show that ubiquitination of beta-caten in is greatly reduced in Wnt-expressing cells, providing the first evi dence that the ubiquitin-proteasome degradation pathway may act downst ream of GSK3 beta in the regulation of beta-catenin.