The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation
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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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The SIAH1 E3 ligase recognizes a VxP motif on substrate proteins.
“The SIAH1 E3 ligase recognizes a VxP motif on substrate proteins25,26”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [26]
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Additional file 2 of An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development
Wang, R., Liu, J., Li, K., Yang, G., Chen, S., Wu, J., Xie, X., Ren, H., & Pang, Y. (2021) · Figshare · doi:10.6084/m9.figshare.16807645
Additional file 10 of An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development
Wang, R., Liu, J., Li, K., Yang, G., Chen, S., Wu, J., Xie, X., Ren, H., & Pang, Y. (2021) · Figshare · doi:10.6084/m9.figshare.16807633
Additional file 4 of An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development
Wang, R., Liu, J., Li, K., Yang, G., Chen, S., Wu, J., Xie, X., Ren, H., & Pang, Y. (2021) · Figshare · doi:10.6084/m9.figshare.16807651
Additional file 8 of An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development
Wang, R., Liu, J., Li, K., Yang, G., Chen, S., Wu, J., Xie, X., Ren, H., & Pang, Y. (2021) · Figshare · doi:10.6084/m9.figshare.16807663
Additional file 12 of An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development
Wang, R., Liu, J., Li, K., Yang, G., Chen, S., Wu, J., Xie, X., Ren, H., & Pang, Y. (2021) · Figshare · doi:10.6084/m9.figshare.16807639
Additional file 3 of An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development
Wang, R., Liu, J., Li, K., Yang, G., Chen, S., Wu, J., Xie, X., Ren, H., & Pang, Y. (2021) · Figshare · doi:10.6084/m9.figshare.16807648
Additional file 9 of An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development
Wang, R., Liu, J., Li, K., Yang, G., Chen, S., Wu, J., Xie, X., Ren, H., & Pang, Y. (2021) · Figshare · doi:10.6084/m9.figshare.16807666
Li, T., Tong, H., Yin, H., Luo, Y., Zhu, J., Qin, Z., Yin, S., & He, W. (2021) · Figshare · doi:10.6084/m9.figshare.16946377
Additional file 1 of An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development
Wang, R., Liu, J., Li, K., Yang, G., Chen, S., Wu, J., Xie, X., Ren, H., & Pang, Y. (2021) · Figshare · doi:10.6084/m9.figshare.16807642
Additional file 6 of An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development
Wang, R., Liu, J., Li, K., Yang, G., Chen, S., Wu, J., Xie, X., Ren, H., & Pang, Y. (2021) · Figshare · doi:10.6084/m9.figshare.16807657
Additional file 7 of An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development
Wang, R., Liu, J., Li, K., Yang, G., Chen, S., Wu, J., Xie, X., Ren, H., & Pang, Y. (2021) · Figshare · doi:10.6084/m9.figshare.16807660
Additional file 5 of An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development
Wang, R., Liu, J., Li, K., Yang, G., Chen, S., Wu, J., Xie, X., Ren, H., & Pang, Y. (2021) · Figshare · doi:10.6084/m9.figshare.16807654
Additional file 1 of R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis
Tan, L., Yan, M., Su, Z., Wang, H., Li, H., Zhao, X., Liu, S., Zhang, L., Sun, Q., & Lu, D. (2024) · Figshare · doi:10.6084/m9.figshare.24953177
Additional file 11 of An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development
Wang, R., Liu, J., Li, K., Yang, G., Chen, S., Wu, J., Xie, X., Ren, H., & Pang, Y. (2021) · Figshare · doi:10.6084/m9.figshare.16807636
A novel variant in SIAH1 associated with autosomal dominant Buratti-Harel syndrome
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Yang, G., Huang, C., Yu, M., Li, W., Wu, D., Li, C., Hu, S., & Wu, J. (2026) · BMC Genomics · doi:10.1186/s12864-026-13314-5
- 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
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2017-05-01
- Volume
- 31
- Issue
- 9
- Pages
- 904-915
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC5458757
- 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
- hybrid
- doi.org
- 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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