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

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 thera...

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Autores principales: Spit, Maureen, Fenderico, Nicola, Jordens, Ingrid, Radaszkiewicz, Tomasz, Lindeboom, Rik GH, Bugter, Jeroen M, Cristobal, Alba, Ootes, Lars, van Osch, Max, Janssen, Eline, Boonekamp, Kim E, Hanakova, Katerina, Potesil, David, Zdrahal, Zbynek, Boj, Sylvia F, Medema, Jan Paul, Bryja, Vitezslav, Koo, Bon‐Kyoung, Vermeulen, Michiel, Maurice, Madelon M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503102/
https://www.ncbi.nlm.nih.gov/pubmed/32965059
http://dx.doi.org/10.15252/embj.2019103932
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author Spit, Maureen
Fenderico, Nicola
Jordens, Ingrid
Radaszkiewicz, Tomasz
Lindeboom, Rik GH
Bugter, Jeroen M
Cristobal, Alba
Ootes, Lars
van Osch, Max
Janssen, Eline
Boonekamp, Kim E
Hanakova, Katerina
Potesil, David
Zdrahal, Zbynek
Boj, Sylvia F
Medema, Jan Paul
Bryja, Vitezslav
Koo, Bon‐Kyoung
Vermeulen, Michiel
Maurice, Madelon M
author_facet Spit, Maureen
Fenderico, Nicola
Jordens, Ingrid
Radaszkiewicz, Tomasz
Lindeboom, Rik GH
Bugter, Jeroen M
Cristobal, Alba
Ootes, Lars
van Osch, Max
Janssen, Eline
Boonekamp, Kim E
Hanakova, Katerina
Potesil, David
Zdrahal, Zbynek
Boj, Sylvia F
Medema, Jan Paul
Bryja, Vitezslav
Koo, Bon‐Kyoung
Vermeulen, Michiel
Maurice, Madelon M
author_sort Spit, Maureen
collection PubMed
description 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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spelling pubmed-75031022020-09-28 RNF43 truncations trap CK1 to drive niche‐independent self‐renewal in cancer Spit, Maureen Fenderico, Nicola Jordens, Ingrid Radaszkiewicz, Tomasz Lindeboom, Rik GH Bugter, Jeroen M Cristobal, Alba Ootes, Lars van Osch, Max Janssen, Eline Boonekamp, Kim E Hanakova, Katerina Potesil, David Zdrahal, Zbynek Boj, Sylvia F Medema, Jan Paul Bryja, Vitezslav Koo, Bon‐Kyoung Vermeulen, Michiel Maurice, Madelon M EMBO J Articles 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. John Wiley and Sons Inc. 2020-08-10 2020-09-15 /pmc/articles/PMC7503102/ /pubmed/32965059 http://dx.doi.org/10.15252/embj.2019103932 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Spit, Maureen
Fenderico, Nicola
Jordens, Ingrid
Radaszkiewicz, Tomasz
Lindeboom, Rik GH
Bugter, Jeroen M
Cristobal, Alba
Ootes, Lars
van Osch, Max
Janssen, Eline
Boonekamp, Kim E
Hanakova, Katerina
Potesil, David
Zdrahal, Zbynek
Boj, Sylvia F
Medema, Jan Paul
Bryja, Vitezslav
Koo, Bon‐Kyoung
Vermeulen, Michiel
Maurice, Madelon M
RNF43 truncations trap CK1 to drive niche‐independent self‐renewal in cancer
title RNF43 truncations trap CK1 to drive niche‐independent self‐renewal in cancer
title_full RNF43 truncations trap CK1 to drive niche‐independent self‐renewal in cancer
title_fullStr RNF43 truncations trap CK1 to drive niche‐independent self‐renewal in cancer
title_full_unstemmed RNF43 truncations trap CK1 to drive niche‐independent self‐renewal in cancer
title_short RNF43 truncations trap CK1 to drive niche‐independent self‐renewal in cancer
title_sort rnf43 truncations trap ck1 to drive niche‐independent self‐renewal in cancer
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503102/
https://www.ncbi.nlm.nih.gov/pubmed/32965059
http://dx.doi.org/10.15252/embj.2019103932
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