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

Autor: Michiel Vermeulen, Madelon M. Maurice, Lars Ootes, Maureen Spit, Jeroen M. Bugter, Sylvia F. Boj, Tomasz Witold Radaszkiewicz, Jan Paul Medema, Alba Cristobal, Katerina Hanakova, Max van Osch, Eline Janssen, Vitezslav Bryja, Bon-Kyoung Koo, David Potesil, Zbynek Zdrahal, Kim E. Boonekamp, Rik G.H. Lindeboom, Ingrid Jordens, Nicola Fenderico
Přispěvatelé: Center of Experimental and Molecular Medicine, Radiotherapy, CCA - Cancer biology and immunology
Rok vydání: 2019
Předmět:
Ubiquitin-Protein Ligases
Endocytosis
General Biochemistry
Genetics and Molecular Biology
Article
03 medical and health sciences
All institutes and research themes of the Radboud University Medical Center
0302 clinical medicine
Downregulation and upregulation
Transcription (biology)
Neoplasms
Humans
Molecular Biology
Wnt Signaling Pathway
beta Catenin
030304 developmental biology
Cancer
0303 health sciences
PORCN inhibitors
General Immunology and Microbiology
biology
cancer mutations
Casein Kinase I
Proteomics and Chromatin Biology
General Neuroscience
Wnt signaling pathway
Articles
Wnt signaling
3. Good health
Ubiquitin ligase
Cell biology
human colon organoids
HEK293 Cells
RNF43
biology.protein
Phosphorylation
Casein kinase 1
Stem cell
Tumor Suppressor Protein p53
Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]
030217 neurology & neurosurgery
Signal Transduction
Zdroj: The EMBO Journal
EMBO journal, 39(18):e103932. Wiley-Blackwell
EMBO Journal, 39
EMBO Journal, 39, 18
ISSN: 1460-2075
0261-4189
Popis: 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.
C‐terminal shortening of RNF43 promotes Wnt/β‐catenin by decreasing destruction complex activity without effects on its ubiquitin ligase activity.
Databáze: OpenAIRE
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