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A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis

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Title: A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis
Authors: Tsukiyama, Tadasuke Browse this author →KAKEN DB
Zou, Juqi Browse this author
Kim, Jihoon Browse this author
Ogamino, Shohei Browse this author
Shino, Yuki Browse this author
Masuda, Takamasa Browse this author
Merenda, Alessandra Browse this author
Matsumoto, Masaki Browse this author
Fujioka, Yoichiro Browse this author →KAKEN DB
Hirose, Tomonori Browse this author
Terai, Sayuri Browse this author
Takahashi, Hidehisa Browse this author →KAKEN DB
Ishitani, Tohru Browse this author →KAKEN DB
Nakayama, Keiichi I. Browse this author →KAKEN DB
Ohba, Yusuke Browse this author →KAKEN DB
Koo, Bon-Kyoung Browse this author
Hatakeyama, Shigetsugu Browse this author →KAKEN DB
Issue Date: 15-Sep-2020
Publisher: Nature Research
Journal Title: Nature communications
Volume: 11
Issue: 1
Start Page: 4586
Publisher DOI: 10.1038/s41467-020-18257-3
Abstract: Frequent mutation of the tumour suppressor RNF43 is observed in many cancers, particularly colon malignancies. RNF43, an E3 ubiquitin ligase, negatively regulates Wnt signalling by inducing degradation of the Wnt receptor Frizzled. In this study, we discover that RNF43 activity requires phosphorylation at a triplet of conserved serines. This phospho-regulation of RNF43 is required for zebrafish development and growth of mouse intestinal organoids. Cancer-associated mutations that abrogate RNF43 phosphorylation cooperate with active Ras to promote tumorigenesis by abolishing the inhibitory function of RNF43 in Wnt signalling while maintaining its inhibitory function in p53 signalling. Our data suggest that RNF43 mutations cooperate with KRAS mutations to promote multi-step tumorigenesis via the Wnt-Ras-p53 axis in human colon cancers. Lastly, phosphomimetic substitutions of the serine trio restored the tumour suppressive activity of extracellular oncogenic mutants. Therefore, harnessing phospho-regulation of RNF43 might be a potential therapeutic strategy for tumours with RNF43 mutations.
Rights: http://creativecommons.org/licenses/by/4.0/
Type: article
URI: http://hdl.handle.net/2115/80529
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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