?-Catenin-RAS interaction serves as a molecular switch for RAS degradation via GSK3?.

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

SUBMITTER: Lee SK 

PROVIDER: S-EPMC6280641 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature