β-Catenin-RAS interaction serves as a molecular switch for RAS degradation via GSK3β

RAS proteins play critical roles in various cellular processes, including growth and transformation. RAS proteins are subjected to protein stability regulation via the Wnt/beta-catenin pathway, and glycogen synthase kinase 3 beta (GSK3 beta) is a key player for the phosphorylation-dependent RAS degradation through proteasomes. GSK3 beta-mediated RAS degradation does not occur in cells that express a nondegradable mutant (MT) beta-catenin. Here, we show that beta-catenin directly interacts with RAS at the alpha-interface region that contains the GSK3 beta phosphorylation sites, threonine 144 and threonine 148 residues. Exposure of these sites by prior beta-catenin degradation is required for RAS degradation. The introduction of a peptide that blocks the beta-catenin-RAS interaction by binding to beta-catenin rescues the GSK3 beta-mediated RAS degradation in colorectal cancer (CRC) cells that express MT beta-catenin. The coregulation of beta-catenin and RAS stabilities by the modulation of their interaction provides a mechanism for Wnt/beta-catenin and RAS-ERK pathway cross-talk and the synergistic transformation of CRC by both APC and KRAS mutations.