| 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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