PreprintCited by 89Wnt/β-catenin signaling in development and cancerUbiquitin and proteasome pathwaysSignaling Pathways in Disease

The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation

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Ji, Lei, Jiang, Bo, Jiang, Xiaomo, Charlat, Olga, Chen, Amy, Mickanin, Craig, Bauer, Andreas, Xu, Wenqing +2 more·2017·Genes & Development

Abstract

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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Authors
Ji, L., Jiang, B., Jiang, X., Charlat, O., Chen, A., Mickanin, C., Bauer, A., Xu, W., Yan, X., & Cong, F.
Affiliations
  • Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA;
  • Chinese Academy of Sciences (CN)
  • University of Washington (US)
  • National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
Venue
Genes & Development
Published
2017-05-01
Volume
31
Issue
9
Pages
904-915
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
OpenAlex
W2620379607
Cited by
89
References
66
Citations by year
2026: 5 · 2025: 11 · 2024: 13 · 2023: 8 · 2022: 7 · 2021: 21 · 2020: 10 · 2019: 8 · 2018: 5 · 2017: 1
Type
posted content
Language
en
Open access
Licence
cc-by-nc
Locations
  • Genes & Development (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • The Novartis Repository (Novartis) (submittedVersion, cc-by-nc)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • National Natural Science Foundation of China (31570794, 31629002)
  • Chinese Academy of Sciences Pilot Strategic Science and Technology Projects B (XDB08010303)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
SIAH1, SIAH2, E3 ubiquitin ligase, Wnt/β-catenin signaling, ubiquitination, proteasomal degradation, β-catenin stabilization, feed-forward mechanism
MeSH terms
Seven in Absentia Proteins, Amino Acid Sequence, Bone Neoplasms, Gene Expression Regulation, Humans, Nuclear Proteins, Protein Conformation, Osteosarcoma, Tumor Cells, Cultured, Signal Transduction, Sequence Homology, Ubiquitin, Ubiquitin-Protein Ligases, Wnt Proteins, beta Catenin, Ubiquitination, HEK293 Cells, Proteolysis, Axin Protein

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