Cargando…
The most common RNF43 mutant G659Vfs*41 is fully functional in inhibiting Wnt signaling and unlikely to play a role in tumorigenesis
RNF43 is an E3 ligase that inhibits Wnt signaling by ubiquitinating Wnt receptors for degradation. It is mutated in various cancer types with the most recurrent mutation being the frameshift G659Vfs*41 with frequencies of ~5–8% in colon, stomach and endometrial cancers. This mutation, a deletion of...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898356/ https://www.ncbi.nlm.nih.gov/pubmed/31811196 http://dx.doi.org/10.1038/s41598-019-54931-3 |
_version_ | 1783477001835773952 |
---|---|
author | Tu, Jianghua Park, Soohyun Yu, Wangsheng Zhang, Sheng Wu, Ling Carmon, Kendra Liu, Qingyun J. |
author_facet | Tu, Jianghua Park, Soohyun Yu, Wangsheng Zhang, Sheng Wu, Ling Carmon, Kendra Liu, Qingyun J. |
author_sort | Tu, Jianghua |
collection | PubMed |
description | RNF43 is an E3 ligase that inhibits Wnt signaling by ubiquitinating Wnt receptors for degradation. It is mutated in various cancer types with the most recurrent mutation being the frameshift G659Vfs*41 with frequencies of ~5–8% in colon, stomach and endometrial cancers. This mutation, a deletion of G in a 7-G repeat, has been assumed to encode an inactive enzyme that would lead to increased Wnt signaling and drive tumorigenesis, yet no functional characterization has been reported. We analyzed the distribution of G659Vfs*41 and its association with other cancer gene mutations, and found that the mutation occurred nearly exclusively in tumors with low expression of the DNA mismatch repair gene MLH1. Mutant RNF43-G659Vfs*41 was no different from wild type RNF43 in expression, stability, localization, R-spondin binding, and inhibition of Wnt signaling. No dominant negative activity of the mutant was observed. Colon tumors with RNF43-G659Vfs*41 had low Wnt/β-catenin signaling and were frequently mutated in BRAF. A colon cancer cell line with RNF43-G659Vfs*41 and BRAF-V600E mutations was sensitive to activation of Wnt/β-catenin signaling. These findings suggest that the frequent occurrence of RNF43-G659Vfs*41 may result from error-prone replication of the 7-G repeat in MLH1-deficient tumors and that the mutation itself does not inactivate enzyme. |
format | Online Article Text |
id | pubmed-6898356 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-68983562019-12-12 The most common RNF43 mutant G659Vfs*41 is fully functional in inhibiting Wnt signaling and unlikely to play a role in tumorigenesis Tu, Jianghua Park, Soohyun Yu, Wangsheng Zhang, Sheng Wu, Ling Carmon, Kendra Liu, Qingyun J. Sci Rep Article RNF43 is an E3 ligase that inhibits Wnt signaling by ubiquitinating Wnt receptors for degradation. It is mutated in various cancer types with the most recurrent mutation being the frameshift G659Vfs*41 with frequencies of ~5–8% in colon, stomach and endometrial cancers. This mutation, a deletion of G in a 7-G repeat, has been assumed to encode an inactive enzyme that would lead to increased Wnt signaling and drive tumorigenesis, yet no functional characterization has been reported. We analyzed the distribution of G659Vfs*41 and its association with other cancer gene mutations, and found that the mutation occurred nearly exclusively in tumors with low expression of the DNA mismatch repair gene MLH1. Mutant RNF43-G659Vfs*41 was no different from wild type RNF43 in expression, stability, localization, R-spondin binding, and inhibition of Wnt signaling. No dominant negative activity of the mutant was observed. Colon tumors with RNF43-G659Vfs*41 had low Wnt/β-catenin signaling and were frequently mutated in BRAF. A colon cancer cell line with RNF43-G659Vfs*41 and BRAF-V600E mutations was sensitive to activation of Wnt/β-catenin signaling. These findings suggest that the frequent occurrence of RNF43-G659Vfs*41 may result from error-prone replication of the 7-G repeat in MLH1-deficient tumors and that the mutation itself does not inactivate enzyme. Nature Publishing Group UK 2019-12-06 /pmc/articles/PMC6898356/ /pubmed/31811196 http://dx.doi.org/10.1038/s41598-019-54931-3 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Tu, Jianghua Park, Soohyun Yu, Wangsheng Zhang, Sheng Wu, Ling Carmon, Kendra Liu, Qingyun J. The most common RNF43 mutant G659Vfs*41 is fully functional in inhibiting Wnt signaling and unlikely to play a role in tumorigenesis |
title | The most common RNF43 mutant G659Vfs*41 is fully functional in inhibiting Wnt signaling and unlikely to play a role in tumorigenesis |
title_full | The most common RNF43 mutant G659Vfs*41 is fully functional in inhibiting Wnt signaling and unlikely to play a role in tumorigenesis |
title_fullStr | The most common RNF43 mutant G659Vfs*41 is fully functional in inhibiting Wnt signaling and unlikely to play a role in tumorigenesis |
title_full_unstemmed | The most common RNF43 mutant G659Vfs*41 is fully functional in inhibiting Wnt signaling and unlikely to play a role in tumorigenesis |
title_short | The most common RNF43 mutant G659Vfs*41 is fully functional in inhibiting Wnt signaling and unlikely to play a role in tumorigenesis |
title_sort | most common rnf43 mutant g659vfs*41 is fully functional in inhibiting wnt signaling and unlikely to play a role in tumorigenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898356/ https://www.ncbi.nlm.nih.gov/pubmed/31811196 http://dx.doi.org/10.1038/s41598-019-54931-3 |
work_keys_str_mv | AT tujianghua themostcommonrnf43mutantg659vfs41isfullyfunctionalininhibitingwntsignalingandunlikelytoplayaroleintumorigenesis AT parksoohyun themostcommonrnf43mutantg659vfs41isfullyfunctionalininhibitingwntsignalingandunlikelytoplayaroleintumorigenesis AT yuwangsheng themostcommonrnf43mutantg659vfs41isfullyfunctionalininhibitingwntsignalingandunlikelytoplayaroleintumorigenesis AT zhangsheng themostcommonrnf43mutantg659vfs41isfullyfunctionalininhibitingwntsignalingandunlikelytoplayaroleintumorigenesis AT wuling themostcommonrnf43mutantg659vfs41isfullyfunctionalininhibitingwntsignalingandunlikelytoplayaroleintumorigenesis AT carmonkendra themostcommonrnf43mutantg659vfs41isfullyfunctionalininhibitingwntsignalingandunlikelytoplayaroleintumorigenesis AT liuqingyunj themostcommonrnf43mutantg659vfs41isfullyfunctionalininhibitingwntsignalingandunlikelytoplayaroleintumorigenesis AT tujianghua mostcommonrnf43mutantg659vfs41isfullyfunctionalininhibitingwntsignalingandunlikelytoplayaroleintumorigenesis AT parksoohyun mostcommonrnf43mutantg659vfs41isfullyfunctionalininhibitingwntsignalingandunlikelytoplayaroleintumorigenesis AT yuwangsheng mostcommonrnf43mutantg659vfs41isfullyfunctionalininhibitingwntsignalingandunlikelytoplayaroleintumorigenesis AT zhangsheng mostcommonrnf43mutantg659vfs41isfullyfunctionalininhibitingwntsignalingandunlikelytoplayaroleintumorigenesis AT wuling mostcommonrnf43mutantg659vfs41isfullyfunctionalininhibitingwntsignalingandunlikelytoplayaroleintumorigenesis AT carmonkendra mostcommonrnf43mutantg659vfs41isfullyfunctionalininhibitingwntsignalingandunlikelytoplayaroleintumorigenesis AT liuqingyunj mostcommonrnf43mutantg659vfs41isfullyfunctionalininhibitingwntsignalingandunlikelytoplayaroleintumorigenesis |