| SPIT, Maureen, Nicola FENDERICO, Ingrid JORDENS, Tomasz Witold RADASZKIEWICZ, Rik G. H. LINDEBOOM, Jeroen M. BUGTER, Alba CRISTOBAL, Lars OOTES, Max VAN OSCH, Eline JANSSEN, Kim E. BOONEKAMP, Kateřina HANÁKOVÁ, David POTĚŠIL, Zbyněk ZDRÁHAL, Sylvia F. BOJ, Jan Paul MEDEMA, Vítězslav BRYJA, Bon-Kyoung KOO, Michiel VERMEULEN and Madelon M. MAURICE. RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer. EMBO Journal. Hoboken (USA): Wiley, 2020, vol. 39, No 18, p. 1-15. ISSN 0261-4189. Available from: https://dx.doi.org/10.15252/embj.2019103932. |
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@article{1710476,
author = {Spit, Maureen and Fenderico, Nicola and Jordens, Ingrid and Radaszkiewicz, Tomasz Witold and Lindeboom, Rik G. H. and Bugter, Jeroen M. and Cristobal, Alba and Ootes, Lars and van Osch, Max and Janssen, Eline and Boonekamp, Kim E. and Hanáková, Kateřina and Potěšil, David and Zdráhal, Zbyněk and Boj, Sylvia F. and Medema, Jan Paul and Bryja, Vítězslav and Koo, BonandKyoung and Vermeulen, Michiel and Maurice, Madelon M.},
article_location = {Hoboken (USA)},
article_number = {18},
doi = {http://dx.doi.org/10.15252/embj.2019103932},
keywords = {cancer mutations; human colon organoids; PORCNinhibitors; RNF43; Wnt signaling},
language = {eng},
issn = {0261-4189},
journal = {EMBO Journal},
title = {RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer},
url = {https://doi.org/10.15252/embj.2019103932},
volume = {39},
year = {2020}
}
TY - JOUR
ID - 1710476
AU - 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.
PY - 2020
TI - RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer
JF - EMBO Journal
VL - 39
IS - 18
SP - 1-15
EP - 1-15
PB - Wiley
SN - 02614189
KW - cancer mutations
KW - human colon organoids
KW - PORCNinhibitors
KW - RNF43
KW - Wnt signaling
UR - https://doi.org/10.15252/embj.2019103932
L2 - https://doi.org/10.15252/embj.2019103932
N2 - 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.
ER -
SPIT, Maureen, Nicola FENDERICO, Ingrid JORDENS, Tomasz Witold RADASZKIEWICZ, Rik G. H. LINDEBOOM, Jeroen M. BUGTER, Alba CRISTOBAL, Lars OOTES, Max VAN OSCH, Eline JANSSEN, Kim E. BOONEKAMP, Kateřina HANÁKOVÁ, David POTĚŠIL, Zbyněk ZDRÁHAL, Sylvia F. BOJ, Jan Paul MEDEMA, Vítězslav BRYJA, Bon-Kyoung KOO, Michiel VERMEULEN and Madelon M. MAURICE. RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer. \textit{EMBO Journal}. Hoboken (USA): Wiley, 2020, vol.~39, No~18, p.~1-15. ISSN~0261-4189. Available from: https://dx.doi.org/10.15252/embj.2019103932.
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