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Crystal structure of a β-catenin/Axin complex suggests a mechanism for the β-catenin destruction complex
Open accessAbstract
The “β-catenin destruction complex” is central to canonical Wnt/β-catenin signaling. The scaffolding protein Axin and the tumor suppressor adenomatous polyposis coli protein (APC) are critical components of this complex, required for rapid β-catenin turnover. We determined the crystal structure of a complex between β-catenin and the β-catenin-binding domain of Axin (Axin-CBD). The Axin-CBD forms a helix that occupies the groove formed by the third and fourth armadillo repeats of β-catenin and thus precludes the simultaneous binding of other β-catenin partners in this region. Our biochemical studies demonstrate that, when phosphorylated, the 20-amino acid repeat region of APC competes with Axin for binding to β-catenin. We propose that a key function of APC in the β-catenin destruction complex is to remove phosphorylated β-catenin product from the active site.
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Self-citationSET7/9 regulates cancer cell proliferation by influencing β‐catenin stability
Shen, C., Wang, D., Liu, X., Gu, B., Du, Y., Wei, F., Cao, L., Song, B., Lu, X., Yang, Q., et al. (2015) · The FASEB Journal · doi:10.1096/fj.15-273540 · Cited by 82
“In addition, the phosphorylation of b-catenin at Ser45 by casein kinase (CK)-1a, which primes phosphorylation, induces subsequent phosphorylation by glycogen synthase kinase (GSK)-3b at residues Thr41, Ser37, and Ser33 (15, 16).”
BackgroundInfluentialEnhancing the Cell Permeability of Stapled Peptides with a Cyclic Cell-Penetrating Peptide
Dougherty, P. G., Wen, J., Pan, X., Koley, A., Ren, J.-G., Sahni, A., Basu, R., Salim, H., Kubi, G. A., Qian, Z., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00456 · Cited by 87
Therapeutic stapled peptides: Efficacy and molecular targets
Li, Y., Wu, M., Fu, Y., Xue, J., Yuan, F., Qu, T., Rissanou, A. N., Wang, Y., Li, X., & Hu, H. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107137 · Cited by 86
Xu, P., Ianes, C., Gärtner, F., Liu, C., Burster, T., Bakulev, V. A., Rachidi, N., Knippschild, U., & Bischof, J. (2019) · Gene · doi:10.1016/j.gene.2019.144005 · Cited by 82
Multifunctional arm repeat domains in plants.
Samuel, M., Salt, J. N., Shiu, S., & Goring, D. (2006) · International Review of Cytology · doi:10.1016/s0074-7696(06)53001-3 · Cited by 76
“…its diVerent binding partners, cadherin, TCF, APC, and Axin, have been solved, and interestingly, the binding partners interact with diVerent, but overlapping, regions in the b‐catenin Arm repeat domain (Graham et al., 2000; Harris and Peifer, 2005; Huber and Weis, 2001; Xing et al., 2003, 2004).”
BackgroundCatrow, J. L., Zhang, Y., Zhang, M., & Ji, H. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00223 · Cited by 83
Second hit in cervical carcinogenesis process: involvement of wnt/beta catenin pathway
Pérez‐Plasencia, C., Dueñas‐González, A., & Alatorre, B. (2008) · International Archives of Medicine · doi:10.1186/1755-7682-1-10 · Cited by 78
“When β-catenin binds to APC, it displaces the union of axin because the binding affinity of β-catenin increases dramatically upon phosphorylation and because the binding motifs of APC to axin and β-catenin overlap [47].”
BackgroundThe Evolutionary Origin of Epithelial Cell–Cell Adhesion Mechanisms
Miller, P. W., Clarke, D. N., Weis, W. I., Lowe, C. J., & Nelson, W. J. (2013) · Current topics in membranes · doi:10.1016/b978-0-12-417027-8.00008-8 · Cited by 80
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Lin, Z., Gao, C., Ning, Y., He, X., Wu, W., & Chen, Y. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804039200 · Cited by 77
de la Roche, M., Ibrahim, A. E. K., Mieszczanek, J., & Bienz, M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2682 · Cited by 71
An Oncogenic Hub: β-Catenin as a Molecular Target for Cancer Therapeutics
Takemaru, K., Ohmitsu, M., & Li, F. Q. (2008) · Handbook of experimental pharmacology · doi:10.1007/978-3-540-72843-6_11 · Cited by 70
Bala, P., Rennhack, J. P., Aitymbayev, D., Morris, C. X., Moyer, S. M., Duronio, G. N., Doan, K. T., Li, Z., Liang, X., Hornick, J. L., et al. (2023) · Science Advances · doi:10.1126/sciadv.adf0927 · Cited by 70
Upadhyay, G., Goessling, W., North, T. E., Xavier, R. J., Zon, L. I., & Yajnik, V. (2008) · Oncogene · doi:10.1038/onc.2008.202 · Cited by 66
“In the literature, phosphorylated APC has been shown to be more efficient in b-catenin binding (Xing et al., 2003).”
BackgroundEnzo, M. V., Rastrelli, M., Rossi, C. R., Hladnik, U., & Segat, D. (2015) · Molecular and Cellular Therapies · doi:10.1186/s40591-015-0038-2 · Cited by 68
“APC can be phosphorylated by CK1/GSK3 increasing its affinity for the same β-catenin domain as Axin, suggesting the role of APC in removing the phosphorylated β-catenin molecules from the complex [20,22,62].”
Ou, C. Y., Kim, J. H., Yang, C. K., & Stallcup, M. R. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.014332 · Cited by 64
Structural basis of coactivation of liver receptor homolog-1 by β-catenin
Yumoto, F., Nguyen, P., Sablin, E. P., Baxter, J. D., Webb, P., & Fletterick, R. J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117036108 · Cited by 63
“X-ray structures of the ARM have been determined with interacting fragments of TCF-4 (41, 42), inhibitor of beta-catenin and TCF-4 (ICAT) (43), Axin (44), B-cell chronic lymphocytic leukemia/lymphoma 9 (BCL9) (45), and others (37, 38).”
MethodFang, W., Chen, W.-W., Fu, A. K. Y., & Ip, N. Y. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.017 · Cited by 65
“Intriguingly, blocking the interaction between nuclear Axin and b-catenin by expressing the Axin point mutant (CIDm) that was unable to bind b-catenin in the nucleus (Xing et al., 2003) inhibited neuronal differentiation and maintained the NPC pool (Figures 7E and 7F), particularly IPs (Figures S7F and S7G).”
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“b-catenin associates with the DC, is phosphorylated by CK1-a and GSK3b [10–12], and subsequently ubiquitinated and degraded [13, 14].”
BackgroundKoelman, E. M. R., Yeste-Vázquez, A., & Grossmann, T. N. (2022) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2022.116920 · Cited by 63
Fujimuro, M., Liu, J., Zhu, J. K., Yokosawa, H., & Hayward, S. D. (2005) · Journal of Virology · doi:10.1128/jvi.79.16.10429-10441.2005 · Cited by 61
“The lower level of phosphorylation supported by CKI may reflect fewer CKI priming sites in LANA(1-340) than for MAPK or, alternatively, CKI priming may be underestimated.”
BackgroundMethodInfluentialThe Role of CTNNB1 in Endometrial Cancer
Ledinek, Ž., Sobočan, M., & Knez, J. (2022) · Disease Markers · doi:10.1155/2022/1442441 · Cited by 61
“It binds with axin on Thr257, Ile296, Ser250, and Trp338 residues [37], none of which were found to be mutated in EC.”
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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
Wnt signaling: the good and the bad
Chen, X., Yang, J., Evans, P. M., & Liu, C. (2008) · Acta Biochimica et Biophysica Sinica · doi:10.1111/j.1745-7270.2008.00440.x · Cited by 56
“The structure of part of this destruction complex has been solved [103–112].”
BackgroundDrechsel, G., Bergler, J., Wippel, K., et al. (2010) · Journal of Experimental Botany · doi:10.1093/jxb/erq313 · Cited by 58
“Scale bars in E and F represent 50 lm. 2000; Huber and Weis, 2001; Xing et al., 2003, 2004).”
BackgroundVac8p, an Armadillo Repeat Protein, Coordinates Vacuole Inheritance With Multiple Vacuolar Processes
Tang, F., Peng, Y., Nau, J. J., et al. (2006) · Traffic · doi:10.1111/j.1600-0854.2006.00458.x · Cited by 56
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Identification and in vivo role of the Armadillo-Legless interaction
Hoffmans, R., & Basler, K. (2004) · Development · doi:10.1242/dev.01296 · Cited by 54
“Another stable and thus constitutively active form of Arm is ∆Arm, in which a large N-terminal region comprising the GSK3β phosphorylation and α-catenin-binding sites is replaced by a myristoylation signal (Zecca et al., 1996).”
BackgroundChai, G., Ma, C., Bao, K., Zheng, L., Wang, X., Sun, Z., Saló, E., Adell, T., & Wu, W. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.113662 · Cited by 51
Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope
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The Roles of Intrinsic Disorder in Orchestrating the Wnt-Pathway
Xue, B., Dunker, A. K., & Uversky, V. N. (2012) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/073911012010525024 · Cited by 48
Swarup, S., & Verheyen, E. M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1017548108 · Cited by 47
“These phosphorylation events trigger the APC-mediated extraction of β-catenin/Arm from the complex and its subsequent transfer to the Skp1-Cul1-Fbox (SCF) E3 ubiquitin ligase (9, 10).”
BackgroundHahne, G., & Grossmann, T. N. (2013) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2013.02.050 · Cited by 46
Signaling from the Adherens Junction
McEwen, A. E., Escobar, D. E., & Gottardi, C. J. (2012) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-007-4186-7_8 · Cited by 47
“…et al. 2001) (through binding residues in β-catenin that overlap with those that engage phospho-destruction components, APC and Axin, (Ha et al. 2004; Xing et al. 2003, 2004)), it is easy to see how cadherin cytodomain clipping could potentially liberate a substantial pool of β-catenin/cadherin…”
BackgroundHelical Repeat Structure of Apoptosis Inhibitor 5 Reveals Protein-Protein Interaction Modules
Han, B.-G., Kim, K. H., Lee, S. J., Jeong, K.-C., Cho, J., Noh, K. H., Kim, T. W., Kim, S. J., Yoon, H. J., Suh, S. W., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.317594 · Cited by 45
Metadata
- Authors
- Xing, Y., Clements, W. K., Kimelman, D., & Xu, W.
- Affiliations
- University of Washington (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2003-01-01
- Volume
- 17
- Issue
- 22
- Pages
- 2753-2764
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC280624
- OpenAlex
- W2041827225
- Semantic Scholar
- f02d1678de9728664b949b5fed44792fbdcc704e
- Cited by
- 237
- References
- 50
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 10 · 2023: 9 · 2022: 15 · 2021: 9 · 2020: 10 · 2019: 11 · 2018: 7 · 2017: 10 · 2016: 7 · 2015: 9 · 2014: 16 · 2013: 12 · 2012: 14
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA 90351, R01CA090351)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD027262, HD27262)
- 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 › Ubiquitin and proteasome pathways
- Keywords
- β-catenin, Axin, β-catenin destruction complex, Wnt/β-catenin signaling, adenomatous polyposis coli, armadillo repeats, protein-protein complex structure, β-catenin phosphorylation, protein turnover, tumor suppressor
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Cytoskeletal Proteins, Humans, Models, Molecular, Molecular Sequence Data, Phosphorylation, Protein Binding, Protein Conformation, Proteins, Repressor Proteins, Xenopus laevis, Signal Transduction, Trans-Activators, Sequence Homology, Amino Acid, Crystallography, X-Ray, Adenomatous Polyposis Coli Protein, Xenopus Proteins, beta Catenin, Axin Protein
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