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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...

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Autores principales: Ji, Lei, Jiang, Bo, Jiang, Xiaomo, Charlat, Olga, Chen, Amy, Mickanin, Craig, Bauer, Andreas, Xu, Wenqing, Yan, Xiaoxue, Cong, Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
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.
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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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