Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783584326617661440 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7503102 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT spitmaureen rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT fendericonicola rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT jordensingrid rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT radaszkiewicztomasz rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT lindeboomrikgh rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT bugterjeroenm rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT cristobalalba rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT ooteslars rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT vanoschmax rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT jansseneline rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT boonekampkime rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT hanakovakaterina rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT potesildavid rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT zdrahalzbynek rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT bojsylviaf rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT medemajanpaul rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT bryjavitezslav rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT koobonkyoung rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT vermeulenmichiel rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer AT mauricemadelonm rnf43truncationstrapck1todrivenicheindependentselfrenewalincancer |