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

Autor: Spit M; Department of Cell Biology and Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands., Fenderico N; Department of Cell Biology and Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands., Jordens I; Department of Cell Biology and Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands., Radaszkiewicz T; Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic., Lindeboom RG; Department of Molecular Biology and Oncode Institute, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands., Bugter JM; Department of Cell Biology and Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands., Cristobal A; Department of Cell Biology and Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands., Ootes L; Department of Cell Biology and Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands., van Osch M; Department of Cell Biology and Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands., Janssen E; Department of Cell Biology and Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands., Boonekamp KE; Department of Cell Biology and Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands., Hanakova K; Central European Institute of Technology, Masaryk University, Brno, Czech Republic., Potesil D; Central European Institute of Technology, Masaryk University, Brno, Czech Republic., Zdrahal Z; Central European Institute of Technology, Masaryk University, Brno, Czech Republic., Boj SF; Hubrecht Organoid Technology, Utrecht, The Netherlands., Medema JP; Laboratory for Experimental Oncology and Radiobiology and Oncode Institute, Center for Experimental and Molecular Medicine, Amsterdam UMC, Cancer Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands., Bryja V; Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic., Koo BK; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria., Vermeulen M; Department of Molecular Biology and Oncode Institute, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands., Maurice MM; Department of Cell Biology and Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2020 Sep 15; Vol. 39 (18), pp. e103932. Date of Electronic Publication: 2020 Aug 10.
DOI: 10.15252/embj.2019103932
Abstrakt: 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.
(© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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