RNF 43 truncations trap CK 1 to drive niche‐independent self‐renewal in cancer

• DOI: 10.15252/embj.2019103932
• Publication Date: 2020-08-10T10:05:45Z
• Authors: Maureen Spit; Nicola Fenderico; Ingrid Jordens; Tomasz Radaszkiewicz; Rik GH Lindeboom; Jeroen M Bugter; Alba Cristobal; Lars Ootes; Max van Osch; Eline Janssen; Kim E Boonekamp; Katerina Hanakova; David Potesil; Zbynek Zdrahal; Sylvia F Boj; Jan Paul Medema; Vitezslav Bryja; Bon‐Kyoung Koo; Michiel Vermeulen; Madelon M Maurice
• Keywords: 0301 basic medicine; Ubiquitin-Protein Ligases; General Biochemistry,Genetics and Molecular Biology; Radboud University Medical Center; 03 medical and health sciences; Neoplasms; Journal Article; Humans; Molecular Biology; Wnt Signaling Pathway; beta Catenin; PORCN inhibitors; cancer mutations; General Immunology and Microbiology; Casein Kinase I; Radboudumc 19: Nanomedicine RIMLS: Radboud Institute for Molecular Life Sciences; Proteomics and Chromatin Biology; General Neuroscience; Articles; Wnt signaling; 3. Good health; human colon organoids; HEK293 Cells; RNF43; Tumor Suppressor Protein p53

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