PUBLICATION
A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis
- Authors
- 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, K.I., Ohba, Y., Koo, B.K., Hatakeyama, S.
- ID
- ZDB-PUB-201002-70
- Date
- 2020
- Source
- Nature communications 11: 4586 (Journal)
- Registered Authors
- Ishitani, Tohru, Ogamino, Shohei, Zou, Juqi
- Keywords
- none
- MeSH Terms
-
- 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
- PubMed
- 32934222 Full text @ Nat. Commun.
Citation
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, K.I., Ohba, Y., Koo, B.K., Hatakeyama, S. (2020) A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis. Nature communications. 11:4586.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping