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- W3048286720 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." @default.
- W3048286720 created "2020-08-13" @default.
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- W3048286720 date "2020-08-10" @default.
- W3048286720 modified "2023-10-15" @default.
- W3048286720 title "<scp>RNF</scp> 43 truncations trap <scp>CK</scp> 1 to drive niche‐independent self‐renewal in cancer" @default.
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- W3048286720 doi "https://doi.org/10.15252/embj.2019103932" @default.
- W3048286720 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7503102" @default.
- W3048286720 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/32965059" @default.
- W3048286720 hasPublicationYear "2020" @default.
- W3048286720 type Work @default.