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

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Publikace nespadá pod Lékařskou fakultu, ale pod Přírodovědeckou fakultu. Oficiální stránka publikace je na webu muni.cz.
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SPIT Maureen FENDERICO Nicola JORDENS Ingrid RADASZKIEWICZ Tomasz Witold LINDEBOOM Rik G. H. BUGTER Jeroen M. CRISTOBAL Alba OOTES Lars VAN OSCH Max JANSSEN Eline BOONEKAMP Kim E. HANÁKOVÁ Kateřina POTĚŠIL David ZDRÁHAL Zbyněk BOJ Sylvia F. MEDEMA Jan Paul BRYJA Vítězslav KOO Bon-Kyoung VERMEULEN Michiel MAURICE Madelon M.

Rok publikování 2020
Druh Článek v odborném periodiku
Časopis / Zdroj EMBO Journal
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
www https://doi.org/10.15252/embj.2019103932
Doi http://dx.doi.org/10.15252/embj.2019103932
Klíčová slova cancer mutations; human colon organoids; PORCNinhibitors; RNF43; Wnt signaling
Popis 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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