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

Sang Kyu Lee, Woo Jeong Jeong, Yong Hee Cho, Pu Hyeon Cha, Jeong Su Yoon, Eun Ji Ro, Sooho Choi, Jeong Min Oh, Yunseok Heo, Hyuntae Kim, Do Sik Min, Gyoonhee Han, Weontae Lee, Kang Yell Choi

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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/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.

Original languageEnglish
Article numbere46060
JournalEMBO Reports
Volume19
Issue number12
DOIs
Publication statusPublished - 2018 Dec

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Lee, S. K., Jeong, W. J., Cho, Y. H., Cha, P. H., Yoon, J. S., Ro, E. J., Choi, S., Oh, J. M., Heo, Y., Kim, H., Min, D. S., Han, G., Lee, W., & Choi, K. Y. (2018). β-Catenin-RAS interaction serves as a molecular switch for RAS degradation via GSK3β. EMBO Reports, 19(12), [e46060]. https://doi.org/10.15252/embr.201846060