RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer
| Authors | |
|---|---|
| Year of publication | 2020 |
| Type | Article in Periodical |
| Magazine / Source | EMBO Journal |
| MU Faculty or unit | |
| Citation | |
| Web | https://doi.org/10.15252/embj.2019103932 |
| Doi | http://dx.doi.org/10.15252/embj.2019103932 |
| Keywords | cancer mutations; human colon organoids; PORCNinhibitors; RNF43; Wnt signaling |
| Description | 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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