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

Tadasuke Tsukiyama (), Juqi Zou, Jihoon Kim, Shohei Ogamino, Yuki Shino, Takamasa Masuda, Alessandra Merenda, Masaki Matsumoto, Yoichiro Fujioka, Tomonori Hirose, Sayuri Terai, Hidehisa Takahashi, Tohru Ishitani, Keiichi I. Nakayama, Yusuke Ohba, Bon-Kyoung Koo () and Shigetsugu Hatakeyama
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Tadasuke Tsukiyama: Hokkaido University
Juqi Zou: Osaka University
Jihoon Kim: University of Cambridge
Shohei Ogamino: Gunma University
Yuki Shino: Hokkaido University, Kita 15, Nishi 7, Kita-ku
Takamasa Masuda: Kyushu University
Alessandra Merenda: University of Cambridge
Masaki Matsumoto: Kyushu University
Yoichiro Fujioka: Hokkaido University
Tomonori Hirose: Yokohama City University Graduate School of Medical Science
Sayuri Terai: Hokkaido University
Hidehisa Takahashi: Hokkaido University
Tohru Ishitani: Osaka University
Keiichi I. Nakayama: Kyushu University
Yusuke Ohba: Hokkaido University
Bon-Kyoung Koo: Vienna Biocenter (VBC)
Shigetsugu Hatakeyama: Hokkaido University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18257-3

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