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The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation
The Wnt/β-catenin signaling pathway plays essential roles in embryonic development and adult tissue homeostasis. Axin is a concentration-limiting factor responsible for the formation of the β-catenin destruction complex. Wnt signaling itself promotes the degradation of Axin. However, the underlying...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458757/ https://www.ncbi.nlm.nih.gov/pubmed/28546513 http://dx.doi.org/10.1101/gad.300053.117 |
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author | Ji, Lei Jiang, Bo Jiang, Xiaomo Charlat, Olga Chen, Amy Mickanin, Craig Bauer, Andreas Xu, Wenqing Yan, Xiaoxue Cong, Feng |
author_facet | Ji, Lei Jiang, Bo Jiang, Xiaomo Charlat, Olga Chen, Amy Mickanin, Craig Bauer, Andreas Xu, Wenqing Yan, Xiaoxue Cong, Feng |
author_sort | Ji, Lei |
collection | PubMed |
description | The Wnt/β-catenin signaling pathway plays essential roles in embryonic development and adult tissue homeostasis. Axin is a concentration-limiting factor responsible for the formation of the β-catenin destruction complex. Wnt signaling itself promotes the degradation of Axin. However, the underlying molecular mechanism and biological relevance of this targeting of Axin have not been elucidated. Here, we identify SIAH1/2 (SIAH) as the E3 ligase mediating Wnt-induced Axin degradation. SIAH proteins promote the ubiquitination and proteasomal degradation of Axin through interacting with a VxP motif in the GSK3-binding domain of Axin, and this function of SIAH is counteracted by GSK3 binding to Axin. Structural analysis reveals that the Axin segment responsible for SIAH binding is also involved in GSK3 binding but adopts distinct conformations in Axin/SIAH and Axin/GSK3 complexes. Knockout of SIAH1 blocks Wnt-induced Axin ubiquitination and attenuates Wnt-induced β-catenin stabilization. Our data suggest that Wnt-induced dissociation of the Axin/GSK3 complex allows SIAH to interact with Axin not associated with GSK3 and promote its degradation and that SIAH-mediated Axin degradation represents an important feed-forward mechanism to achieve sustained Wnt/β-catenin signaling. |
format | Online Article Text |
id | pubmed-5458757 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-54587572017-11-01 The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation Ji, Lei Jiang, Bo Jiang, Xiaomo Charlat, Olga Chen, Amy Mickanin, Craig Bauer, Andreas Xu, Wenqing Yan, Xiaoxue Cong, Feng Genes Dev Research Paper The Wnt/β-catenin signaling pathway plays essential roles in embryonic development and adult tissue homeostasis. Axin is a concentration-limiting factor responsible for the formation of the β-catenin destruction complex. Wnt signaling itself promotes the degradation of Axin. However, the underlying molecular mechanism and biological relevance of this targeting of Axin have not been elucidated. Here, we identify SIAH1/2 (SIAH) as the E3 ligase mediating Wnt-induced Axin degradation. SIAH proteins promote the ubiquitination and proteasomal degradation of Axin through interacting with a VxP motif in the GSK3-binding domain of Axin, and this function of SIAH is counteracted by GSK3 binding to Axin. Structural analysis reveals that the Axin segment responsible for SIAH binding is also involved in GSK3 binding but adopts distinct conformations in Axin/SIAH and Axin/GSK3 complexes. Knockout of SIAH1 blocks Wnt-induced Axin ubiquitination and attenuates Wnt-induced β-catenin stabilization. Our data suggest that Wnt-induced dissociation of the Axin/GSK3 complex allows SIAH to interact with Axin not associated with GSK3 and promote its degradation and that SIAH-mediated Axin degradation represents an important feed-forward mechanism to achieve sustained Wnt/β-catenin signaling. Cold Spring Harbor Laboratory Press 2017-05-01 /pmc/articles/PMC5458757/ /pubmed/28546513 http://dx.doi.org/10.1101/gad.300053.117 Text en © 2017 Ji et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Paper Ji, Lei Jiang, Bo Jiang, Xiaomo Charlat, Olga Chen, Amy Mickanin, Craig Bauer, Andreas Xu, Wenqing Yan, Xiaoxue Cong, Feng The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation |
title | The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation |
title_full | The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation |
title_fullStr | The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation |
title_full_unstemmed | The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation |
title_short | The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation |
title_sort | siah e3 ubiquitin ligases promote wnt/β-catenin signaling through mediating wnt-induced axin degradation |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458757/ https://www.ncbi.nlm.nih.gov/pubmed/28546513 http://dx.doi.org/10.1101/gad.300053.117 |
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