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RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer

M. Spit, N. Fenderico, I. Jordens, T. Radaszkiewicz, RG. Lindeboom, JM. Bugter, A. Cristobal, L. Ootes, M. van Osch, E. Janssen, KE. Boonekamp, K. Hanakova, D. Potesil, Z. Zdrahal, SF. Boj, JP. Medema, V. Bryja, BK. Koo, M. Vermeulen, MM. Maurice

. 2020 ; 39 (18) : e103932. [pub] 20200810

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc21020121

Grantová podpora
Starting Grant 242958 European Research Counsel
Consolidator Grant 771059 European Research Counsel
VICI Grant 91815604 Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
ECHO Grant 711.013.012 Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
TOP Grant 91218050 Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
Marie Curie ITN 608180 EC|Seventh Framework Programme (FP7)
GX19-28347X Czech Science Foundation
CEITEC 2020 (LQ1601) Ministry of Education, Youth and Sports of the Czech Republic
CIISB research infrastructure (LM2018127) Ministry of Education, Youth and Sports of the Czech Republic

Wnt/β-catenin signaling is a primary pathway for stem cell maintenance during tissue renewal and a frequent target for mutations in cancer. Impaired Wnt receptor endocytosis due to loss of the ubiquitin ligase RNF43 gives rise to Wnt-hypersensitive tumors that are susceptible to anti-Wnt-based therapy. Contrary to this paradigm, we identify a class of RNF43 truncating cancer mutations that induce β-catenin-mediated transcription, despite exhibiting retained Wnt receptor downregulation. These mutations interfere with a ubiquitin-independent suppressor role of the RNF43 cytosolic tail that involves Casein kinase 1 (CK1) binding and phosphorylation. Mechanistically, truncated RNF43 variants trap CK1 at the plasma membrane, thereby preventing β-catenin turnover and propelling ligand-independent target gene transcription. Gene editing of human colon stem cells shows that RNF43 truncations cooperate with p53 loss to drive a niche-independent program for self-renewal and proliferation. Moreover, these RNF43 variants confer decreased sensitivity to anti-Wnt-based therapy. Our data demonstrate the relevance of studying patient-derived mutations for understanding disease mechanisms and improved applications of precision medicine.

Citace poskytuje Crossref.org

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$a Spit, Maureen $u Department of Cell Biology and Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
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$a RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer / $c M. Spit, N. Fenderico, I. Jordens, T. Radaszkiewicz, RG. Lindeboom, JM. Bugter, A. Cristobal, L. Ootes, M. van Osch, E. Janssen, KE. Boonekamp, K. Hanakova, D. Potesil, Z. Zdrahal, SF. Boj, JP. Medema, V. Bryja, BK. Koo, M. Vermeulen, MM. Maurice
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$a Wnt/β-catenin signaling is a primary pathway for stem cell maintenance during tissue renewal and a frequent target for mutations in cancer. Impaired Wnt receptor endocytosis due to loss of the ubiquitin ligase RNF43 gives rise to Wnt-hypersensitive tumors that are susceptible to anti-Wnt-based therapy. Contrary to this paradigm, we identify a class of RNF43 truncating cancer mutations that induce β-catenin-mediated transcription, despite exhibiting retained Wnt receptor downregulation. These mutations interfere with a ubiquitin-independent suppressor role of the RNF43 cytosolic tail that involves Casein kinase 1 (CK1) binding and phosphorylation. Mechanistically, truncated RNF43 variants trap CK1 at the plasma membrane, thereby preventing β-catenin turnover and propelling ligand-independent target gene transcription. Gene editing of human colon stem cells shows that RNF43 truncations cooperate with p53 loss to drive a niche-independent program for self-renewal and proliferation. Moreover, these RNF43 variants confer decreased sensitivity to anti-Wnt-based therapy. Our data demonstrate the relevance of studying patient-derived mutations for understanding disease mechanisms and improved applications of precision medicine.
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$a Fenderico, Nicola $u Department of Cell Biology and Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
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$a Boj, Sylvia F $u Hubrecht Organoid Technology, Utrecht, The Netherlands
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$a Bryja, Vitezslav $u Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
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$a Koo, Bon-Kyoung $u Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria
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$a Vermeulen, Michiel $u Department of Molecular Biology and Oncode Institute, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands
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$a Maurice, Madelon M $u Department of Cell Biology and Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
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