Journal
EMBO JOURNAL
Volume 39, Issue 18, Pages -Publisher
WILEY
DOI: 10.15252/embj.2019103932
Keywords
cancer mutations; human colon organoids; PORCNinhibitors; RNF43; Wnt signaling
Categories
Funding
- Dutch Cancer Society
- European Research Council [242958]
- Netherlands Organization for Scientific Research NWO VICI Grant [91815604]
- ECHO [91815604]
- European Union Grant FP7 Marie Curie ITN [711.013.012]
- Czech Science Foundation [608180]
- CIISB research infrastructure [GX19-28347X, LQ1601]
- Ministry of Education, Youth and Sports of the Czech Republic [LM2018127]
- TOP [91218050]
- [771059]
- European Research Council (ERC) [242958] Funding Source: European Research Council (ERC)
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Wnt/beta-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 ligaseRNF43 gives rise to Wnt-hypersensitive tumors that are susceptible to anti-Wnt-based therapy. Contrary to this paradigm, we identify a class ofRNF43 truncating cancer mutations that induce beta-catenin-mediated transcription, despite exhibiting retained Wnt receptor downregulation. These mutations interfere with a ubiquitin-independent suppressor role of theRNF43 cytosolic tail that involves Casein kinase 1 (CK1) binding and phosphorylation. Mechanistically, truncatedRNF43 variants trapCK1 at the plasma membrane, thereby preventing beta-catenin turnover and propelling ligand-independent target gene transcription. Gene editing of human colon stem cells shows thatRNF43 truncations cooperate with p53 loss to drive a niche-independent program for self-renewal and proliferation. Moreover, theseRNF43 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.
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