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RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer.
- Source :
-
The EMBO journal [EMBO J] 2020 Sep 15; Vol. 39 (18), pp. e103932. Date of Electronic Publication: 2020 Aug 10. - Publication Year :
- 2020
-
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 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.<br /> (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
- Subjects :
- Casein Kinase I genetics
HEK293 Cells
Humans
Neoplasms genetics
Neoplasms pathology
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Ubiquitin-Protein Ligases genetics
beta Catenin genetics
beta Catenin metabolism
Casein Kinase I metabolism
Neoplasms metabolism
Ubiquitin-Protein Ligases metabolism
Wnt Signaling Pathway
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2075
- Volume :
- 39
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- The EMBO journal
- Publication Type :
- Academic Journal
- Accession number :
- 32965059
- Full Text :
- https://doi.org/10.15252/embj.2019103932