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

Published version
Peer-reviewed

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Authors

Tsukiyama, Tadasuke  ORCID logo  https://orcid.org/0000-0001-5205-8202
Zou, Juqi 
Shino, Yuki 

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.

Description

Funder: Japan Foundation for Applied Enzymology; doi: https://doi.org/10.13039/100008695


Funder: Pancreas Research Foundation of Japan Collaborative Research Project Program of the Medical Institute of Bioregulation, Kyushu University, Japan Joint Research Program of the Institute for Molecular and Cellular Regulation, Gunma University, Japan Grant for Joint Research Project of the Research Institute for Microbial Diseases Osaka University


Funder: European Research Council (ERC (639050) and the Interpark Bio-Convergence Center Grant Program.

Keywords

Animals, Carcinogenesis, Humans, Mice, Mice, Inbred BALB C, Oncogene Protein p21(ras), Phosphorylation, Proteolysis, Receptors, Wnt, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Wnt Signaling Pathway

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

11

Publisher

Springer Science and Business Media LLC
Sponsorship
MEXT | Japan Society for the Promotion of Science (JSPS) (25430102, 16K07105, 19K07633, 16H06227, 15H04701, 17K19578, 16H05141, 15H04690, 18H02607)
MEXT | JST | Core Research for Evolutional Science and Technology (CREST) (JPMJCR15G4)
Ministry of Education, Culture, Sports, Science and Technology (MEXT) (26114006, 17H06301)