A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis
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 phosphorylat...
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Veröffentlicht in: | Nature communications 2020-09, Vol.11 (1), p.1-16, Article 4586 |
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creator | Tsukiyama, Tadasuke Zou, Juqi Kim, Jihoon Ogamino, Shohei Shino, Yuki Masuda, Takamasa Merenda, Alessandra Matsumoto, Masaki Fujioka, Yoichiro Hirose, Tomonori Terai, Sayuri Takahashi, Hidehisa Ishitani, Tohru Nakayama, Keiichi I. Ohba, Yusuke Koo, Bon-Kyoung Hatakeyama, Shigetsugu |
description | 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.
RNF43 is frequently mutated in cancers and negatively regulates Wnt signalling. Here, the authors report that RNF43 phosphorylation at a serine triplet is required for the negative regulation of Wnt signalling and that the phosphorylation of RNF43 suppresses cancer-associated oncogenic RNF43 mutants. |
doi_str_mv | 10.1038/s41467-020-18257-3 |
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RNF43 is frequently mutated in cancers and negatively regulates Wnt signalling. Here, the authors report that RNF43 phosphorylation at a serine triplet is required for the negative regulation of Wnt signalling and that the phosphorylation of RNF43 suppresses cancer-associated oncogenic RNF43 mutants.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/s41467-020-18257-3</identifier><identifier>PMID: 32934222</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/95 ; 631/67/1244 ; 631/80/474/2073 ; 631/80/86/2368 ; 64/116 ; 64/60 ; 692/4028/67/68 ; 692/4028/67/70 ; 96/100 ; Cancer ; Colon ; Colorectal cancer ; Degradation ; Frizzled protein ; Humanities and Social Sciences ; Intestine ; multidisciplinary ; Mutants ; Mutation ; Organoids ; p53 Protein ; Phosphorylation ; Receptors ; Science ; Science (multidisciplinary) ; Serine ; Signaling ; Tumorigenesis ; Tumors ; Ubiquitin ; Ubiquitin-protein ligase ; Wnt protein ; Zebrafish</subject><ispartof>Nature communications, 2020-09, Vol.11 (1), p.1-16, Article 4586</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c627t-b79a94df347d5265233f1e34dd710de6223e7337e130930dfd87c3253520dc5f3</citedby><cites>FETCH-LOGICAL-c627t-b79a94df347d5265233f1e34dd710de6223e7337e130930dfd87c3253520dc5f3</cites><orcidid>0000-0001-7562-3753 ; 0000-0002-3258-6953 ; 0000-0002-7185-1529 ; 0000-0002-6200-7043 ; 0000-0001-5205-8202 ; 0000-0002-6987-0288 ; 0000-0002-4134-8033 ; 0000-0003-2461-8289 ; 0000-0003-2428-0919</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492264/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492264/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,27924,27925,41120,42189,51576,53791,53793</link.rule.ids></links><search><creatorcontrib>Tsukiyama, Tadasuke</creatorcontrib><creatorcontrib>Zou, Juqi</creatorcontrib><creatorcontrib>Kim, Jihoon</creatorcontrib><creatorcontrib>Ogamino, Shohei</creatorcontrib><creatorcontrib>Shino, Yuki</creatorcontrib><creatorcontrib>Masuda, Takamasa</creatorcontrib><creatorcontrib>Merenda, Alessandra</creatorcontrib><creatorcontrib>Matsumoto, Masaki</creatorcontrib><creatorcontrib>Fujioka, Yoichiro</creatorcontrib><creatorcontrib>Hirose, Tomonori</creatorcontrib><creatorcontrib>Terai, Sayuri</creatorcontrib><creatorcontrib>Takahashi, Hidehisa</creatorcontrib><creatorcontrib>Ishitani, Tohru</creatorcontrib><creatorcontrib>Nakayama, Keiichi I.</creatorcontrib><creatorcontrib>Ohba, Yusuke</creatorcontrib><creatorcontrib>Koo, Bon-Kyoung</creatorcontrib><creatorcontrib>Hatakeyama, Shigetsugu</creatorcontrib><title>A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><description>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.
RNF43 is frequently mutated in cancers and negatively regulates Wnt signalling. 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subjects | 13/95 631/67/1244 631/80/474/2073 631/80/86/2368 64/116 64/60 692/4028/67/68 692/4028/67/70 96/100 Cancer Colon Colorectal cancer Degradation Frizzled protein Humanities and Social Sciences Intestine multidisciplinary Mutants Mutation Organoids p53 Protein Phosphorylation Receptors Science Science (multidisciplinary) Serine Signaling Tumorigenesis Tumors Ubiquitin Ubiquitin-protein ligase Wnt protein Zebrafish |
title | A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-07T10%3A32%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_doaj_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20phospho-switch%20controls%20RNF43-mediated%20degradation%20of%20Wnt%20receptors%20to%20suppress%20tumorigenesis&rft.jtitle=Nature%20communications&rft.au=Tsukiyama,%20Tadasuke&rft.date=2020-09-15&rft.volume=11&rft.issue=1&rft.spage=1&rft.epage=16&rft.pages=1-16&rft.artnum=4586&rft.issn=2041-1723&rft.eissn=2041-1723&rft_id=info:doi/10.1038/s41467-020-18257-3&rft_dat=%3Cproquest_doaj_%3E2442689263%3C/proquest_doaj_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2442689263&rft_id=info:pmid/32934222&rft_doaj_id=oai_doaj_org_article_8bbcf86e1ff943ee8f363d3d01a94e7d&rfr_iscdi=true |