Premium
RNF 43 truncations trap CK 1 to drive niche‐independent self‐renewal in cancer
Author(s) -
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 BonKyoung,
Vermeulen Michiel,
Maurice Madelon M
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019103932
Subject(s) - wnt signaling pathway , ubiquitin ligase , casein kinase 1 , biology , endocytosis , microbiology and biotechnology , cancer research , downregulation and upregulation , signal transduction , phosphorylation , receptor , ubiquitin , genetics , gene , protein kinase a
Abstract 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 RNF 43 gives rise to Wnt‐hypersensitive tumors that are susceptible to anti‐Wnt‐based therapy. Contrary to this paradigm, we identify a class of RNF 43 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 RNF 43 cytosolic tail that involves Casein kinase 1 ( CK 1) binding and phosphorylation. Mechanistically, truncated RNF 43 variants trap CK 1 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 RNF 43 truncations cooperate with p53 loss to drive a niche‐independent program for self‐renewal and proliferation. Moreover, these RNF 43 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.