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

被引：50

作者：

Tsukiyama, Tadasuke ^{[1
,2
]}

Zou, Juqi ^{[3
]}

Kim, Jihoon ^{[4
,5
]}

Ogamino, Shohei ^{[6
]}

Shino, Yuki ^{[7
]}

Masuda, Takamasa ^{[8
]}

Merenda, Alessandra ^{[4
]}

Matsumoto, Masaki ^{[9
,10
]}

Fujioka, Yoichiro ^{[2
,11
]}

Hirose, Tomonori ^{[12
]}

Terai, Sayuri ^{[1
,2
]}

Takahashi, Hidehisa ^{[1
,2
,12
]}

Ishitani, Tohru ^{[3
,6
,8
]}

Nakayama, Keiichi I. ^{[9
,13
]}

Ohba, Yusuke ^{[2
,11
]}

Koo, Bon-Kyoung ^{[5
]}

Hatakeyama, Shigetsugu ^{[1
,2
]}

机构：

[1] Hokkaido Univ, Dept Biochem, Fac Med, Kita Ku, Kita 15,Nishi 7, Sapporo, Hokkaido 0608638, Japan

[2] Hokkaido Univ, Grad Sch Med, Kita Ku, Kita 15,Nishi 7, Sapporo, Hokkaido 0608638, Japan

[3] Osaka Univ, Microbial Dis Res Inst, Dept Homeostat Regulat, 3-1 Yamadaoka, Suita, Osaka 5650871, Japan

[4] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England

[5] Austrian Acad Sci IMBA, Inst Mol Biotechnol, Vienna Bioctr VBC, Dr Bohr Gasse 3, A-1030 Vienna, Austria

[6] Gunma Univ, Inst Mol & Cellular Regulat, Dept Mol Med, Lab Integrated Signaling Syst, 3-39-15 Showa Machi, Maebashi, Gunma 3718512, Japan

[7] Hokkaido Univ, Fac Med, Kita Ku, Kita 15,Nishi 7, Sapporo, Hokkaido 0608638, Japan

[8] Kyushu Univ, Med Inst Bioregulat, Div Cell Regulat Syst, Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan

[9] Kyushu Univ, Med Inst Bioregulat, Res Ctr Trans Med, Div Prote,Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan

[10] Niigata Univ, Grad Sch Med & Dent Sci, Dept Omics & Syst Biol, Chuo Ku, 1-757 Asahimachi Douri, Niigata, Niigata 9518510, Japan

[11] Hokkaido Univ, Dept Cell Physiol, Fac Med, Kita Ku, Kita 15,Nishi 7, Sapporo, Hokkaido 0608638, Japan

[12] Yokohama City Univ, Dept Mol Biol, Grad Sch Med Sci, Kanazawa Ku, Fukuura 3-9, Yokohama, Kanagawa 2360004, Japan

[13] Kyushu Univ, Med Inst Bioregulat, Dept Mol & Cellular Biol, Div Cell Biol,Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

欧洲研究理事会;

关键词：

WNT/BETA-CATENIN; BETA-CATENIN; RNF43; UBIQUITIN; PROTEIN; PHOSPHORYLATION; MUTATIONS; PATHWAY; GROWTH; IDENTIFICATION;

D O I：

10.1038/s41467-020-18257-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：16

共 61 条

[1] beta-catenin is a target for the ubiquitin-proteasome pathway [J].

Aberle, H ;

Bauer, A ;

Stappert, J ;

Kispert, A ;

Kemler, R .

EMBO JOURNAL, 1997, 16 (13) :3797-3804

[2]

AKIMENKO MA, 1994, J NEUROSCI, V14, P3475

[3] Axin-mediated CKI phosphorylation of β-catenin at Ser 45:: a molecular switch for the Wnt pathway [J].

Amit, S ;

Hatzubai, A ;

Birman, Y ;

Andersen, JS ;

Ben-Shushan, E ;

Mann, M ;

Ben-Neriah, Y ;

Alkalay, I .

GENES & DEVELOPMENT, 2002, 16 (09) :1066-1076

[4] WNT signalling pathways as therapeutic targets in cancer [J].

Anastas, Jamie N. ;

Moon, Randall T. .

NATURE REVIEWS CANCER, 2013, 13 (01) :11-26

[5] A Video Protocol of Retroviral Infection in Primary Intestinal Organoid Culture [J].

Andersson-Rolf, Amanda ;

Fink, Juergen ;

Mustata, Roxana C. ;

Koo, Bon-Kyoung .

JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, 2014, (90)

[6] p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells [J].

Bailey, J. M. ;

Hendley, A. M. ;

Lafaro, K. J. ;

Pruski, M. A. ;

Jones, N. C. ;

Alsina, J. ;

Younes, M. ;

Maitra, A. ;

McAllister, F. ;

Iacobuzio-Donahue, C. A. ;

Leach, S. D. .

ONCOGENE, 2016, 35 (32) :4282-4288

[7] RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis [J].

Bond, Catherine E. ;

McKeone, Diane M. ;

Kalimutho, Murugan ;

Bettington, Mark L. ;

Pearson, Sally-Ann ;

Dumenil, Troy D. ;

Wockner, Leesa F. ;

Burge, Matthew ;

Leggett, Barbara A. ;

Whitehall, Vicki L. J. .

ONCOTARGET, 2016, 7 (43) :70589-70600

[8] Wnt/β-Catenin Signaling and Disease [J].

Clevers, Hans ;

Nusse, Roel .

CELL, 2012, 149 (06) :1192-1205

[9] The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength [J].

de Lau, Wim ;

Peng, Weng Chuan ;

Gros, Piet ;

Clevers, Hans .

GENES & DEVELOPMENT, 2014, 28 (04) :305-316

[10] Visualization of a short-range Wnt gradient in the intestinal stem-cell niche [J].

Farin, Homier F. ;

Jordens, Ingrid ;

Mosa, Mohammed H. ;

Basak, Onur ;

Korving, Jeroen ;

Tauriello, Daniele V. F. ;

de Punder, Karin ;

Angers, Stephane ;

Peters, Peter J. ;

Maurice, Madelon M. ;

Clevers, Hans .

NATURE, 2016, 530 (7590) :340-+

← 1 2 3 4 5 6 7 →