Structural basis for recruitment of glycogen synthase kinase 3β to the axin—APC scaffold complex
Open accessAbstract
Glycogen synthase kinase 3beta (GSK3beta) is a serine/threonine kinase involved in insulin, growth factor and Wnt signalling. In Wnt signalling, GSK3beta is recruited to a multiprotein complex via interaction with axin, where it hyperphosphorylates beta-catenin, marking it for ubiquitylation and destruction. We have now determined the crystal structure of GSK3beta in complex with a minimal GSK3beta-binding segment of axin, at 2.4 A resolution. The structure confirms the co-localization of the binding sites for axin and FRAT in the C-terminal domain of GSK3beta, but reveals significant differences in the interactions made by axin and FRAT, mediated by conformational plasticity of the 285-299 loop in GSK3beta. Detailed comparison of the axin and FRAT GSK3beta complexes allows the generation of highly specific mutations, which abrogate binding of one or the other. Quantitative analysis suggests that the interaction of GSK3beta with the axin scaffold enhances phosphorylation of beta-catenin by >20 000-fold.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The quantitative requirement that "Axin stimulates the phosphorylation of β-catenin by GSK3β at least 24,000-fold" actually refers to the wet-lab data WD1 obtained in another study by Dajani et al. (2003).
“The quantitative requirement that “Axin stimulates the phosphorylation of β-catenin by GSK3β at least 24,000-fold” [28] actually refers to the wet-lab data WD1 obtained in another study by Dajani et al. (2003) [65].”
From Relating simulation studies by provenance—Developing a family of Wnt signaling models (2021) · cites this paper as [65]
Cites
Polakis, P. (2000) · Genes & Development · doi:10.1101/gad.14.15.1837 · Cited by 3,183 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases
Beurel, E., Grieco, S. F., & Jope, R. S. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.11.016 · Cited by 1,768 · see citing works
Flexible nets: The roles of intrinsic disorder in protein interaction networks
Dunker, A. K., Cortese, M. S., Romero, P., Iakoucheva, L. M., & Uversky, V. N. (2005) · The FEBS Journal · doi:10.1111/j.1742-4658.2005.04948.x · Cited by 1,122 · see citing works
Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling
Uversky, V. N., Oldfield, C. J., & Dunker, A. K. (2005) · Journal of Molecular Recognition · doi:10.1002/jmr.747 · Cited by 847 · see citing works
Wnt/β-catenin signaling in cancers and targeted therapies
Yu, F., Yu, C., Li, F., Zuo, Y., Wang, Y., Yao, L., Wu, C., Wang, C., & Ye, L. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00701-5 · Cited by 734 · see citing works
β-Catenin destruction complex: insights and questions from a structural perspective
Kimelman, D., & Xu, W. (2006) · Oncogene · doi:10.1038/sj.onc.1210055 · Cited by 628 · see citing works
Disorder and Sequence Repeats in Hub Proteins and Their Implications for Network Evolution
Dosztányi, Z., Chen, J., Dunker, A. K., Simon, I., & Tompa, P. (2006) · Journal of Proteome Research · doi:10.1021/pr060171o · Cited by 341 · see citing works
Xing, Y., Clements, W. K., Kimelman, D., & Xu, W. (2003) · Genes & Development · doi:10.1101/gad.1142603 · Cited by 237 · see citing works
Substrate and Docking Interactions in Serine/Threonine Protein Kinases
Goldsmith, E. J., Akella, R., Min, X., Zhou, T., & Humphreys, J. M. (2007) · Chemical Reviews · doi:10.1021/cr068221w · Cited by 143 · see citing works
Basheer, N., Smolek, T., Hassan, I., Liu, F., Iqbal, K., Zilka, N., & Novak, P. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02113-z · Cited by 159 · see citing works
Ji, L., Jiang, B., Jiang, X., Charlat, O., Chen, A., Mickanin, C., Bauer, A., Xu, W., Yan, X., & Cong, F. (2017) · Genes & Development · doi:10.1101/gad.300053.117 · Cited by 89 · see citing works
van Leeuwen, I. M. M., Byrne, H. M., Jensen, O. E., & King, J. R. (2007) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2007.01.019 · Cited by 59 · see citing works
Critical Scaffolding Regions of the Tumor Suppressor Axin1 Are Natively Unfolded
Noutsou, M., Duarte, A. M. S., Anvarian, Z., Didenko, T., Minde, D. P., Kuper, I., de Ridder, I., Oikonomou, C., Friedler, A., Boelens, R., et al. (2011) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.11.013 · Cited by 58 · see citing works
Stochastic machines as a colocalization mechanism for scaffold protein function
Xue, B., Romero, P. R., Noutsou, M., Maurice, M. M., Rüdiger, S. G. D., William, A. M., Mizianty, M. J., Kurgan, L., Uversky, V. N., & Dunker, A. K. (2013) · FEBS Letters · doi:10.1016/j.febslet.2013.04.006 · Cited by 47 · see citing works
Jiang, L., Yamashita, Y., Chew, S., Akatsuka, S., Ukai, S., Wang, S., Nagai, H., Okazaki, Y., Takahashi, T., & Toyokuni, S. (2014) · The Journal of Pathology · doi:10.1002/path.4377 · Cited by 34 · see citing works
Relating simulation studies by provenance—Developing a family of Wnt signaling models
Budde, K., Smith, J., Wilsdorf, P., Haack, F., & Uhrmacher, A. M. (2021) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1009227 · Cited by 23 · see citing works
Elucidation of the GSK3α Structure Informs the Design of Novel, Paralog-Selective Inhibitors
Amaral, B., Capacci, A., Anderson, T., Tezer, C., Bajrami, B., Lulla, M., Lucas, B., Chodaparambil, J. V., Marcotte, D., Kumar, P. R., et al. (2023) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.2c00476 · Cited by 22 · see citing works
The Landscape of Glycogen Synthase Kinase-3 Beta Genomic Alterations in Cancer
Borden, B. A., Baca, Y., Xiu, J., Tavora, F., Winer, I., Weinberg, B. A., Vanderwalde, A. M., Darabi, S., Korn, W. M., Mazar, A. P., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0497 · Cited by 15 · see citing works
- Authors
- Dajani, R., Fraser, E., Roe, S. M., Yeo, M., Good, V. M., Thompson, V., Dale, T. C., & Pearl, L. H.
- Affiliations
- Institute of Cancer Research (GB)
- Corresponding author
- Pearl, Laurence H.
- Venue
- The EMBO Journal
- Published
- 2003-02-03
- Volume
- 22
- Issue
- 3
- Pages
- 494-501
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC140752
- OpenAlex
- W2160003033
- Cited by
- 315
- References
- 1
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 13 · 2023: 14 · 2022: 12 · 2021: 12 · 2020: 15 · 2019: 10 · 2018: 4 · 2017: 20 · 2016: 8 · 2015: 7 · 2014: 13 · 2013: 14 · 2012: 18
- FWCI
- 5.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research UK
- 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 › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- glycogen synthase kinase-3β, Axin, Wnt signaling, β-catenin phosphorylation, protein-protein interaction, crystal structure, conformational plasticity, C-terminal domain, ubiquitination, destruction complex
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Binding Sites, Carrier Proteins, Cell Line, Cytoskeletal Proteins, Humans, Models, Molecular, Mutation, Neoplasm Proteins, Phosphorylation, Proteins, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Repressor Proteins, Tyrosine, Molecular Structure, Signal Transduction, Trans-Activators, Protein Structure, Tertiary, Crystallography, X-Ray, Adenomatous Polyposis Coli Protein, Zebrafish Proteins, Glycogen Synthase Kinase 3, Macromolecular Substances, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Wnt Proteins, beta Catenin, Axin Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
