한빛사 논문
Tadasuke Tsukiyama1,*, Juqi Zou2, Jihoon Kim3,4, Shohei Ogamino5, Yuki Shino6, Takamasa Masuda7, Alessandra Merenda3, Masaki Matsumoto8,9, Yoichiro Fujioka10, Tomonori Hirose11, Sayuri Terai1, Hidehisa Takahashi1,11, Tohru Ishitani2,5,7, Keiichi I. Nakayama8,12, Yusuke Ohba10, Bon-Kyoung Koo4,* & Shigetsugu Hatakeyama1
1 Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan. 2 Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan. 3 Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK. 4 Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, 1030 Vienna, Austria. 5 Laboratory of Integrated Signaling Systems, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8512, Japan. 6 Faculty of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan. 7 Division of Cell Regulation Systems, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. 8 Division of Proteomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. 9 Department of Omics and Systems Biology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-douri, Chuo-ku, Niigata, Niigata 951-8510, Japan. 10 Department of Cell Physiology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan. 11 Department of Molecular Biology, Yokohama City University Graduate School of Medical Science, Fukuura 3-9, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan. 12 Division of Cell Biology, Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
*Correspondence to Tadasuke Tsukiyama or Bon-Kyoung Koo.
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.
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