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

Tsukiyama, Tadasuke; Zou, Juqi; Kim, Jihoon et al.

Nature communications, 2020, 11(1), 4586

Permalink : https://hdl.handle.net/2115/80529

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https://doi.org/10.1038/s41467-020-18257-3     16

論文情報

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アクセス権
open access
URI
https://hdl.handle.net/2115/80529
タイトル
A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis
著者
Tsukiyama, Tadasuke ; Zou, Juqi ; Kim, Jihoon ; Ogamino, Shohei ; Shino, Yuki ; Masuda, Takamasa ; Merenda, Alessandra ; Matsumoto, Masaki ; Fujioka, Yoichiro ; Hirose, Tomonori ; Terai, Sayuri ; Takahashi, Hidehisa ; Ishitani, Tohru ; Nakayama, Keiichi I. ; Ohba, Yusuke ; Koo, Bon-Kyoung ; Hatakeyama, Shigetsugu
e-Rad_Researcher
20399819
著者名
Tsukiyama, Tadasuke
著者名
Zou, Juqi
著者名
Kim, Jihoon
著者名
Ogamino, Shohei
著者名
Shino, Yuki
著者名
Masuda, Takamasa
著者名
Merenda, Alessandra
著者名
Matsumoto, Masaki
e-Rad_Researcher
70597492
著者名
Fujioka, Yoichiro
著者名
Hirose, Tomonori
著者名
Terai, Sayuri
e-Rad_Researcher
30423544
著者名
Takahashi, Hidehisa
e-Rad_Researcher
40448428
著者名
Ishitani, Tohru
e-Rad_Researcher
80291508
著者名
Nakayama, Keiichi I.
e-Rad_Researcher
30333503
著者名
Ohba, Yusuke
著者名
Koo, Bon-Kyoung
e-Rad_Researcher
70294973
著者名
Hatakeyama, Shigetsugu
言語
英語
発行日
2020-09-15
出版者
Nature Research
収録物名
Nature communications
巻(号)
11(1)
ページ
4586
抄録
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.
資源タイプ
学術雑誌論文
出版タイプ
Version of Record
権利情報
Creative Commons Attribution 4.0 International
PISSN
2041-1723
関連情報 (isIdenticalTo)
出版社版DOI
https://doi.org/10.1038/s41467-020-18257-3