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/β‐catenin pathway, and glycogen synthase kinase 3 beta (GSK3β) is a key player for the phosphorylation‐dependent RAS degradation through proteasomes. GSK3β‐mediated RAS degradation does not occur in cells that express a nondegradable mutant (MT) β‐catenin. Here, we show that β‐catenin directly interacts with RAS at the α‐interface region that contains the GSK3β phosphorylation sites, threonine 144 and threonine 148 residues. Exposure of these sites by prior β‐catenin degradation is required for RAS degradation. The introduction of a peptide that blocks the β‐catenin‐RAS interaction by binding to β‐catenin rescues the GSK3β‐mediated RAS degradation in colorectal cancer (CRC) cells that express MT β‐catenin. The coregulation of β‐catenin and RAS stabilities by the modulation of their interaction provides a mechanism for Wnt/β‐catenin and RAS‐ERK pathway cross‐talk and the synergistic transformation of CRC by both APC and KRAS mutations. Synopsis GSK3β promotes phosphorylation‐ and polyubiquitination‐dependent proteasomal RAS degradation. β‐Catenin directly interacts with RAS, thereby preventing GSK3β‐dependent phosphorylation and degradation, defining the basis for the synergistic effect of β‐catenin and RAS on cancer growth. β‐Catenin directly interacts with RAS at the α‐interface that contains GSK3β phosphorylation sites. β‐Catenin degradation is required for subsequent GSK3β‐mediated RAS degradation. Targeting both β‐catenin and RAS for degradation is a potential approach against colorectal cancer. Graphical Abstract GSK3β promotes phosphorylation‐ and polyubiquitination‐dependent proteasomal RAS degradation. β‐Catenin directly interacts with RAS, thereby preventing GSK3β‐dependent phosphorylation and degradation, defining the basis for the synergistic effect of β‐catenin and RAS on cancer growth.