論文 - 詳細
| RRC ID | 70327 |
|---|---|
| 著者 | Tsukiyama T, Zou J, Kim J, Ogamino S, Shino Y, Masuda T, Merenda A, Matsumoto M, Fujioka Y, Hirose T, Terai S, Takahashi H, Ishitani T, Nakayama KI, Ohba Y, Koo BK, Hatakeyama S. |
| タイトル | A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis. |
| ジャーナル | Nat Commun |
| 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. |
| 巻・号 | 11(1) |
| ページ | 4586 |
| 公開日 | 2020-9-15 |
| DOI | 10.1038/s41467-020-18257-3 |
| PII | 10.1038/s41467-020-18257-3 |
| PMID | 32934222 |
| PMC | PMC7492264 |
| MeSH | Animals Carcinogenesis / genetics Carcinogenesis / metabolism* Humans Mice Mice, Inbred BALB C Oncogene Protein p21(ras) / genetics Oncogene Protein p21(ras) / metabolism Phosphorylation Proteolysis Receptors, Wnt / genetics Receptors, Wnt / metabolism* Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism* Wnt Signaling Pathway |
| IF | 12.121 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | News |
| 各媒体での言及数の合計 | 26 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ゼブラフィッシュ | Tg(6xTcf/LefBS-miniP:d2EGFP) |
| ヒト・動物細胞 | Cle-H3(RCB0549) |