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

J 2020

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

SPIT, Maureen, Nicola FENDERICO, Ingrid JORDENS, Tomasz Witold RADASZKIEWICZ, Rik G. H. LINDEBOOM et. al.

Basic information

Original name

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

Authors

SPIT, Maureen, Nicola FENDERICO, Ingrid JORDENS, Tomasz Witold RADASZKIEWICZ (616 Poland, belonging to the institution), Rik G. H. LINDEBOOM, Jeroen M. BUGTER, Alba CRISTOBAL, Lars OOTES, Max VAN OSCH, Eline JANSSEN, Kim E. BOONEKAMP, Kateřina HANÁKOVÁ (203 Czech Republic, belonging to the institution), David POTĚŠIL (203 Czech Republic, belonging to the institution), Zbyněk ZDRÁHAL (203 Czech Republic, belonging to the institution), Sylvia F. BOJ, Jan Paul MEDEMA, Vítězslav BRYJA (203 Czech Republic, belonging to the institution), Bon-Kyoung KOO, Michiel VERMEULEN and Madelon M. MAURICE

Edition

EMBO Journal, Hoboken (USA), Wiley, 2020, 0261-4189

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10601 Cell biology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 11.598

RIV identification code

RIV/00216224:14310/20:00114578

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.15252/embj.2019103932

UT WoS

000557439600001

Keywords in English

cancer mutations; human colon organoids; PORCNinhibitors; RNF43; Wnt signaling

Abstract

V originále

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.

Links

GX19-28347X, research and development project

Name: Molekulární a funkční analýza biologie kasein kinázy 1

Investor: Czech Science Foundation

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

90127, large research infrastructures

Name: CIISB II

Citovat

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.

@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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