TY - JOUR
T1 - A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis
AU - Tsukiyama, Tadasuke
AU - Zou, Juqi
AU - Kim, Jihoon
AU - Ogamino, Shohei
AU - Shino, Yuki
AU - Masuda, Takamasa
AU - Merenda, Alessandra
AU - Matsumoto, Masaki
AU - Fujioka, Yoichiro
AU - Hirose, Tomonori
AU - Terai, Sayuri
AU - Takahashi, Hidehisa
AU - Ishitani, Tohru
AU - Nakayama, Keiichi I.
AU - Ohba, Yusuke
AU - Koo, Bon Kyoung
AU - Hatakeyama, Shigetsugu
N1 - Funding Information:
(16H05141, 26114006), K.N. (17H06301) and S.H. (15H04690, 18H02607) by the Ministry of Education, Culture, Sports, Science and Technology in Japan, JST CREST to M.M. (JPMJCR15G4), the Japan Foundation for Applied Enzymology and the Pancreas Research Foundation of Japan to T.T., and by the European Research Council (ERC (639050) and the Interpark Bio-Convergence Center Grant Program to B-K.K. This work was partly performed with the collaborative Research Project Program of the Medical Institute of Bioregulation, Kyushu University, with the joint research program of the Institute for Molecular, Cellular Regulation, Gunma University and with the Grant for Joint Research Project of the Research Institute for Microbial Diseases Osaka University.
Funding Information:
The authors thank M. Uchiumi,Y. Matsuzaki, M. Fujioka and S. Sakata for administrative and technical assistance. We also thank S. Takada, T. Oikawa, T. Kitamura and A. Gurney for providing materials, M. Oda for data analysis, Y. Yamaguchi and N. Kato for suggestions. This work was supported by KAKENHI to T.T. (25430102, 16K07105, 19K07633), Y.F. (16H06227), H.T. (15H04701, 17K19578), Y.O. (17H04016), T.I.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85091055310&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85091055310&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-18257-3
DO - 10.1038/s41467-020-18257-3
M3 - Article
C2 - 32934222
AN - SCOPUS:85091055310
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4586
ER -
