β-Catenin destruction complex: insights and questions from a structural perspective

Kimelman, D; Xu, W

doi:10.1038/sj.onc.1210055

Cited by 632Wnt/β-catenin signaling in development and cancerSignaling Pathways in DiseaseUbiquitin and proteasome pathways

β-Catenin destruction complex: insights and questions from a structural perspective

Kimelman, D, Xu, W·2006·Oncogene

DOI 10.1038/sj.onc.1210055

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Abstract

At the heart of the canonical Wnt signaling pathway is the beta-catenin destruction complex, which functions in the absence of Wnt signaling to keep the cytosolic and nuclear levels of beta-catenin very low by promoting the phosphorylation and ubiquitination of beta-catenin. Structural studies, combined with other experimental approaches, have begun to provide important insights into the mechanism of the destruction complex. We suggest a working model for the destruction complex based on the existing structural and experimental data, and focus on the questions that this model and other studies have raised about the function of the complex in both the normal and Wnt-inhibited states.

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β-catenin proteins undergo proteasomal destruction, which is greatly accelerated by the presence of IDRs in addition to the bound ubiquitin signal.
“Next, the β-catenin proteins undergo proteasomal destruction [259, 260], which is greatly accelerated by the presence of IDRs in addition to the bound ubiquitin signal [262].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [260]
Prior to Wnt signaling, the transcription factor β-catenin is maintained at low levels by the β-catenin destruction complex, an assembly of the 852 residue mostly disordered scaffold protein axin, the 2,843 residue massively disordered protein APC, and the three mostly structured proteins β-catenin, CKI-a, and GSK3b.
“Prior to Wnt signaling, the transcription factor β-catenin is maintained at low levels by the β-catenin destruction complex, which is an assembly of the 852 residue mostly disordered scaffold protein axin, the 2,843 residue massively disordered protein adenomatous polyposis coli (APC), and the three mostly structured proteins β-catenin, casein kinase Ia (CKI-a), and glycogen synthetase kinase 3b (”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [260]
The two kinases phosphorylate residues within a long IDR at β-catenin's amino terminus.
“The two kinases phosphorylate residues within a long IDR at β-catenin’s amino terminus [259, 260].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [260]

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“These complexes include activated transmembrane receptors associated with adaptors and signaling effectors (Hoeller et al., 2005), the β-catenin destruction complex (Kimelman and Xu, 2006), and complexes associated with endosomes (Fischer et al., 2006).”
Background
Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions
Zeng, X., Huang, H., Tamai, K., Zhang, X., Harada, Y., Yokota, C., Almeida, K., Wang, J., Doble, B., Woodgett, J., et al. (2008) · Development · doi:10.1242/dev.013540 · Cited by 492 · see citing works
“, 2000) and in an Arrow (Lrp6) mutant background (Wehrli et al., 2000; Kimelman and Xu, 2006), and this signaling capability by overexpressed Dvl seems to correlate with the propensity of Dvl to multimerize (Schwarz-Romond et al.”
Background
GSK-3: Functional Insights from Cell Biology and Animal Models
Kaidanovich‐Beilin, O., & Woodgett, J. R. (2011) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2011.00040 · Cited by 487 · see citing works
“MOLECULAR NEUROSCIENCE REVIEW ARTICLE published: 16 November 2011 doi: 10.3389/fnmol.2011.00040 GSK-3: functional insights from cell biology and animal models”
Influential
GSK3 and its interactions with the PI3K/AKT/mTOR signalling network
Hermida, M. A., Kumar, J. D., & Leslie, N. R. (2017) · Advances in Biological Regulation · doi:10.1016/j.jbior.2017.06.003 · Cited by 482 · see citing works
Dysregulation of Wnt/β-Catenin Signaling in Gastrointestinal Cancers
White, B. D., Chien, A. J., & Dawson, D. W. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.12.001 · Cited by 471 · see citing works
Wnt/β-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology
Russell, J. O., & Monga, S. P. (2018) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-020117-044010 · Cited by 471 · see citing works
Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex
Jung, Y., & Park, J. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0380-6 · Cited by 423 · see citing works
Wnt/β-catenin signaling: new (and old) players and new insights
Huang, H., & He, X. (2008) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2008.01.009 · Cited by 419 · see citing works
Wilms Tumor Suppressor WTX Negatively Regulates WNT/ß-Catenin Signaling
Major, M. B., Camp, N. D., Berndt, J. D., Yi, X., Goldenberg, S. J., Hubbert, C. C., Biechele, T. L., Gingras, A., Zheng, N., MacCoss, M. J., et al. (2007) · Science · doi:10.1126/science/1141515 · Cited by 405 · see citing works
Wnt signaling in bone formation and its therapeutic potential for bone diseases
Kim, J. H., Liu, X., Wang, J., Chen, X. '., Zhang, H., Kim, S. H., Cui, J., Li, R., Zhang, W., Kong, Y., et al. (2013) · Therapeutic Advances in Musculoskeletal Disease · doi:10.1177/1759720x12466608 · Cited by 357 · see citing works
“GSK3β, axin and APC form the degradation complex which tags β catenin for degradation in the inactive state [Kimelman and Xu, 2006].”
Background
A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice
Waaler, J., Machoň, O., Tůmová, L., Dinh, H., Kořínek, V., Wilson, S. R., Paulsen, J. E., Pedersen, N. M., Eide, T. J., Machoňová, O., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3336 · Cited by 328 · see citing works
“In the cytoplasm, b-catenin can form complexes with a multitude of proteins, including the b-catenin destruc- tion complex consisting of adenomatous polyposis coli (APC), AXIN2, GSK3b, and CK1a (4, 5).”
BackgroundInfluential
β-Catenin induces immortalization of melanocytes by suppressing p16 INK4a expression and cooperates with N-Ras in melanoma developmentPreprint
Delmas, V., Beermann, F., Martinozzi, S., Carreira, S., Ackermann, J., Kumasaka, M. Y., Denat, L., GOODALL, J. C., Luciani, F., Virós, A., et al. (2007) · Genes & Development · doi:10.1101/gad.450107 · Cited by 312 · see citing works
“GENES & DEVELOPMENT 21:2923–2935 © 2007 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/07; www.genesdev.org 2923 cogen synthase kinase-3 (GSK-3 ) on serine (S) and threonine (T) residues and is consequently ubiquitinated and degraded (for review, see Kimelman and Xu 2006).”
Background
Wnt signaling and cellular metabolism in osteoblasts
Karner, C. M., & Long, F. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2425-5 · Cited by 295 · see citing works
“Normally, in cells not exposed to ligand, cytoplasmic levels of b-catenin are kept low through interactions with the b-catenin destruction complex [20].”
Background
Wnt signaling and hepatocarcinogenesis: Molecular targets for the development of innovative anticancer drugs
Pez, F., Lopez, A., Kim, M., Wands, J. R., de Fromentel, C. C., & Merle, P. (2013) · Journal of Hepatology · doi:10.1016/j.jhep.2013.07.001 · Cited by 295 · see citing works
“Ser37 and Ser33 phosphorylations provide a binding site for the E3 ubiquitin ligase b-TRCP (b-transducin repeat containing protein), leading to b-catenin ubiquitination in a b-TRCP/ Skp1/cullin F-box complex (SCF) dependent manner followed by proteasomal degradation [30,31].”
Background
WNT Signaling in Tumors: The Way to Evade Drugs and Immunity
Martín-Orozco, E., Sánchez-Fernández, A., Ortiz-Parra, I., & Nicolas, M. A.-S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02854 · Cited by 218 · see citing works
Activating Wnt/β-catenin signaling pathway for disease therapy: Challenges and opportunities
Piao, H., Yan, R., Zhang, X., Wang, L., Ke, X., & Qu, Y. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.11.008 · Cited by 269 · see citing works
Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases
Wang, L., Li, J., & Di, L. (2021) · Medicinal Research Reviews · doi:10.1002/med.21867 · Cited by 273 · see citing works
“Activation of the Wnt signaling pathway does not inhibit the enzymatic activity of GSK3, especially the small amount of GSK3 bound to Axin.272,273 Instead, Axin protein seems to be the rate‐limiting component in regulating the activity of the β‐catenin destruction complex at a very low concentration based on experimen…”
Background
Interactions between SOX factors and Wnt/β‐catenin signaling in development and disease
Kormish, J. D., Sinner, D. I., & Zorn, A. M. (2009) · Developmental Dynamics · doi:10.1002/dvdy.22046 · Cited by 267 · see citing works
“However, a small dynamic pool of -catenin shuttles between the cytoplasm and the nucleus to transduce canonical Wnt signals (Kimelman and Xu, 2006).”
Background
Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance
Mohammed, M. K., Shao, C. C., Wang, J., Wei, Q., Wang, X. W., Collier, Z. J., Tang, S., Liu, H., Zhang, F., Huang, J., et al. (2016) · Genes & Diseases · doi:10.1016/j.gendis.2015.12.004 · Cited by 260 · see citing works
P21 activated kinase signaling in cancer
Rane, C. K., & Minden, A. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.01.006 · Cited by 247 · see citing works
Mechanistic insights from structural studies of β-catenin and its binding partners
Xu, W., & Kimelman, D. (2007) · Journal of Cell Science · doi:10.1242/jcs.013771 · Cited by 246 · see citing works
“…absence of a Wnt signal, cytosolic -catenin is captured and phosphorylated by a cytoplasmic protein complex called the -catenin-destruction complex, which catalyzes the phosphorylation of -catenin and thus labels it for ubiquitindependent degradation by the proteasome (Kimelman and Xu, 2006) (Fig.”
BackgroundSelf-citation
Nuclear Dvl, c-Jun, β-catenin, and TCF form a complex leading to stabiLization of β-catenin–TCF interaction
Gan, X., Wang, J., Xi, Y., Wu, Z., Li, Y.-P., & Li, L. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200710050 · Cited by 235 · see citing works
The Spectrum of Achalasia: Lessons From Studies of Pathophysiology and High-Resolution Manometry
Kahrilas, P. J., & Boeckxstaens, G. E. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.08.038 · Cited by 234 · see citing works
Wnt Stabilization of β-Catenin Reveals Principles for Morphogen Receptor-Scaffold Assemblies
Kim, S., Huang, H., Zhao, M., Zhang, X., Zhang, A., Semonov, M. V., MacDonald, B. T., Zhang, X., Abreu, J. G., Peng, L., et al. (2013) · Science · doi:10.1126/science.1232389 · Cited by 230 · see citing works
“Our experimental evidence and interpretation agree fully with the prevailing model that Wnt signaling stabilizes β-catenin through inhibition of β-catenin phosphorylation (1, 11, 14, 15).”
Dynamic recruitment of axin by Dishevelled protein assemblies
Schwarz, T., Metcalfe, C., & Bienz, M. (2007) · Journal of Cell Science · doi:10.1242/jcs.002956 · Cited by 225 · see citing works
“The axin complex is constitutively active in the absence of Wnt stimulation, phosphorylating -catenin and thus promoting its proteasomal degradation (Kimelman and Xu, 2006).”
Background
Intrinsically disordered proteins play diverse roles in cell signaling
Bondos, S. E., Dunker, A. K., & Uversky, V. N. (2022) · Cell Communication and Signaling · doi:10.1186/s12964-022-00821-7 · Cited by 222 · see citing works
“phosphorylate residues within a long IDR at β-catenin’s amino terminus [259, 260].”
Background
Inhibition of GSK3 Phosphorylation of β-Catenin via Phosphorylated PPPSPXS Motifs of Wnt Coreceptor LRP6
Wu, G., Huang, H., Abreu, J. G., & He, X. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004926 · Cited by 216 · see citing works
The way Wnt works: Components and mechanism
Saito‐Diaz, K., Chen, T. W., Wang, X., Thorne, C. A., Wallace, H. A., Page, A. W., & Lee, E. N. (2012) · Growth Factors · doi:10.3109/08977194.2012.752737 · Cited by 215 · see citing works
“1999), (5) coordinating the phosphorylation and release of b-catenin from the destruction complex to allow its ubiquitination (Kimelman and Xu 2006), (6) blocking dephosphorylation ofb-catenin by protein phosphatase 2A (PP2A) (Su et al.”
BackgroundInfluential
Wnt Signaling in vascular eye diseases
Wang, Z., Liu, C., Huang, S., & Chen, J. (2018) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2018.11.008 · Cited by 211 · see citing works
Mutations in TP53, CTNNB1 and PIK3CA genes in hepatocellular carcinoma associated with hepatitis B and hepatitis C virus infections
Tornesello, M. L., Buonaguro, L., Tatangelo, F., Botti, G., Izzo, F., & Buonaguro, L. (2013) · Genomics · doi:10.1016/j.ygeno.2013.04.001 · Cited by 196 · see citing works
“In the absence of Wnt, cytoplasmic β-catenin protein is phosphorylated at the N-terminal domain (serine 33, 37 and 45, threonine 41) by the Axin complex (composed of Axin, APC, CK1, and GSK3) and then ubiquitinated and degraded by β-Trcp ubiquitin ligase [81].”
Background
PARP family enzymes: regulation and catalysis of the poly(ADP-ribose) posttranslational modification
Langelier, M.-F., Eisemann, T., Riccio, A. A., & Pascal, J. M. (2018) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2018.11.002 · Cited by 196 · see citing works
“Axin is the limiting factor of a multicomponent assembly of proteins referred to as the “destruction complex,” [55,56], which degrades β-catenin in the cytoplasm to prevent its movement to the nucleus where it activates gene transcription [56].”
Background
Leptin-induced Epithelial-Mesenchymal Transition in Breast Cancer Cells Requires β-Catenin Activation via Akt/GSK3- and MTA1/Wnt1 Protein-dependent Pathways
Yan, D., Avtanski, D. B., Saxena, N. K., & Sharma, D. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.322800 · Cited by 188 · see citing works
Emerging links between CDK cell cycle regulators and Wnt signaling
Davidson, G. R., & Niehrs, C. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.05.002 · Cited by 182 · see citing works
FOXM1 (Forkhead box M1) in Tumorigenesis
Wierstra, I. (2013) · Advances in cancer research · doi:10.1016/b978-0-12-407190-2.00016-2 · Cited by 183 · see citing works
Drug Discovery Approaches to Target Wnt Signaling in Cancer Stem Cells
Curtin, J. C., & Lorenzi, M. V. (2010) · Oncotarget · doi:10.18632/oncotarget.191 · Cited by 182 · see citing works
The WNT signaling pathway from ligand secretion to gene transcription: Molecular mechanisms and pharmacological targets
Baarsma, H. A., Königshoff, M., & Gosens, R. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.01.002 · Cited by 175 · see citing works
“Axin, APC, GSK-3β and CK-1 form the core proteins of the destruction complex and their function will be briefly discussed (Clevers, 2006; Kimelman & Xu, 2006; MacDonald, et al., 2009).”
BackgroundInfluential
SnapShot: Wnt/β-Catenin Signaling
MacDonald, B. T., Semënov, M. V., & He, X. (2007) · Cell · doi:10.1016/j.cell.2007.11.036 · Cited by 169 · see citing works
Wnt signaling: Essential roles in osteoblast differentiation, bone metabolism and therapeutic implications for bone and skeletal disorders
Vlashi, R., Zhang, X., Wu, M., & Chen, G. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2022.07.011 · Cited by 165 · see citing works
“When the canonical Wnt ligand is missing in this specific pathway, it is a destructive complex of proteins, that includes serineethreonine kinases glycogen synthase kinase 3b (GSK-3b) and casein kinase 1a (CK1a), the protein Axin, the cytoplasmic phosphoproteins Dishevelled (DVL) and Adenomatous Polyposis Coli (APC),…”
Background
Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages
Ng, C. K. Y., Dazert, E., Boldanova, T., Coto-Llerena, M., Nuciforo, S., Ercan, C., Suslov, A., Meier, M.-A., Bock, T., Schmidt, A., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-29960-8 · Cited by 165 · see citing works
O ‐GlcNAcylation stabilizes β‐catenin through direct competition with phosphorylation at threonine 41
Stichelen, S. O.-V., Dehennaut, V., Buzy, A., Zachayus, J., Guinez, C., Mir, A., Yazidi‐Belkoura, I. E., Copin, M., Bourême, D., Loyaux, D., et al. (2014) · The FASEB Journal · doi:10.1096/fj.13-243535 · Cited by 161 · see citing works
“First, a destruction complex including the tumor suppressors adenomatous polyposis coli (APC) and axin, as well as the kinases GSK3 and CK1 , sequestrates -catenin (6).”
Background
Mechanistic insights into Wnt–β-catenin pathway activation and signal transduction
Maurice, M. M., & Angers, S. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00823-y · Cited by 161 · see citing works
“241), transfer of phosphorylated β-catenin to the ubiquitin–proteasome system 242 , protection of β-catenin from dephosphorylation 243 or de-ubiquitylation 244 , or recruitment of the SCF–βTrCP E3 ligase 241 .”
The role of autophagy in hepatocellular carcinoma: friend or foe
Liu, L., Liao, J., He, X., & Li, P. (2017) · Oncotarget · doi:10.18632/oncotarget.17202 · Cited by 155 · see citing works
Pyrvinium, a Potent Small Molecule Wnt Inhibitor, Promotes Wound Repair and Post-MI Cardiac Remodeling
Saraswati, S., Alfaro, M. P., Thorne, C. A., Atkinson, J. B., Lee, E. N., & Young, P. P. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015521 · Cited by 154 · see citing works
“This results in the recruitment of a b-TrCPcontaining E3 ubiquitin ligase that targets b-catenin for proteosomal degradation [11].”
Background
Frequent mutations of <i>β‐catenin</i> gene in sporadic secreting adrenocortical adenomas*
Tadjine, M., Lampron, A., Ouadi, L., & Bourdeau, I. (2008) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2007.03033.x · Cited by 153 · see citing works
Small molecule-based disruption of the Axin/β-catenin protein complex regulates mesenchymal stem cell differentiation
Gwak, J., Hwang, S. G., Park, H. S., CHoi, S. R., Park, S.-H., Kim, H., Ha, N., Bae, S. J., Han, J., Kim, D., et al. (2011) · Cell Research · doi:10.1038/cr.2011.127 · Cited by 150 · see citing works
Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma
Wu, X., Li, J., Gassa, A., Buchner, D., Alakus, H., Dong, Q., Ren, N., Liu, M., Odenthal, M., Stippel, D. L., et al. (2020) · International Journal of Biological Sciences · doi:10.7150/ijbs.44024 · Cited by 147 · see citing works
Wnt signaling in Alzheimer's disease: Up or down, that is the question
Boonen, R. A. C. M., van Tijn, P., & Živković, D. (2008) · Ageing Research Reviews · doi:10.1016/j.arr.2008.11.003 · Cited by 143 · see citing works
“Phosphorylation of b-catenin promotes its ubiquitination and subsequent degradation by the ubiquitin-proteasome system, whereas dephosphorylation potentially by PP2A, stimulates transduction of the Wnt/b-catenin-dependent signal (Kimelman and Xu, 2006).”
Background
Survivin expression promotes VEGF-induced tumor angiogenesis via PI3K/Akt enhanced β-catenin/Tcf-Lef dependent transcription
Fernandez, J. G., Rodríguez, D. A., Valenzuela, M., Calderón, C. C., Urzúa, U., Munroe, D. J., Rosas, C., David Lemus, A., Díaz‐Valdivia, N., Wright, M. C., et al. (2014) · Molecular Cancer · doi:10.1186/1476-4598-13-209 · Cited by 145 · see citing works
“In the absence of Wnt ligands, β-catenin is phosphorylated and targeted for degradation by the multi-protein complex that includes Glycogen Synthase Kinase 3β (GSK-3β), APC, Axin, β-catenin, Casein Kinase 1 and others [24,25].”
Background
Targeting the Wnt pathways for therapies
Blagodatski, A. S., Poteryaev, D. A., & Katanaev, V. L. (2014) · Molecular and Cellular Therapies · doi:10.1186/2052-8426-2-28 · Cited by 141 · see citing works
“The function of this complex is to phosphorylate cytoplasmic β-catenin, targeting it for ubiquitin-dependent proteasomal degradation [15].”
Background
Chibby cooperates with 14-3-3 to regulate β-catenin subcellular distribution and signaling activity
Li, F., Mofunanya, A., Harris, K., & Takemaru, K. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200709091 · Cited by 140 · see citing works
“…APC, adenomatous polyposis coli; Cby, Chibby; CRM-1, chromosome region maintenance protein 1; DN-14-3-3, dominantnegative 14-3-3; GSK3, glycogen synthase kinase 3; hRluc, synthetic Renilla luciferase; KD, kinase-dead; Lef, lymphoid enhancer factor; MBP, maltose-binding protein; NES, nuclear export…”
Background
The Ubiquitin-Specific Protease USP34 Regulates Axin Stability and Wnt/β-Catenin Signaling
Lui, T. T. H., Lacroix, C., Ahmed, S. M., Goldenberg, S. J., Leach, C. A., Daulat, A. M., & Angers, S. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.01094-10 · Cited by 138 · see citing works
“APC and axin are the core components of a cellular machinery dubbed the “destruction complex” that promotes the phosphorylation of the cytoplasmic pool of -catenin (24).”
Background
Nucleo-cytoplasmic shuttling of PAK4 modulates β-catenin intracellular translocation and signaling
Li, Y., Shao, Y., Tong, Y., Shen, T., Zhang, J., Li, Y., Gu, H., & Li, F. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.11.013 · Cited by 130 · see citing works
Integrating developmental signals: a Hippo in the (path)way
Mauviel, A., Nallet-Staub, F., & Varelas, X. (2011) · Oncogene · doi:10.1038/onc.2011.363 · Cited by 129 · see citing works
“This complex mediates the phosphorylation of b-catenin by GSK3b and recruits the SCF/bTrCP complex, which targets b-catenin for ubiquitination and subsequent proteasomal degradation (reviewed in Kimelman and Xu (2006)).”
Background
Wnt Signalling Pathway Parameters for Mammalian Cells
Tan, C. W., Gardiner, B. S., Hirokawa, Y., Layton, M. J., Smith, D. W., & Burgess, A. W. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031882 · Cited by 127 · see citing works
Mutant huntingtin‐impaired degradation of β‐catenin causes neurotoxicity in Huntington's disease
Godin, J. D., Poizat, G., Hickey, M. A., Maschat, F., & Humbert, S. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.117 · Cited by 126 · see citing works
“Under unstimulated conditions, a multiprotein complex known as the destruction complex is required for the processing of b-catenin through the generation of ubiquitinated b-catenin (Kimelman and Xu, 2006).”
BackgroundInfluential
GSK-3 Inhibitors: A Ray of Hope for the Treatment of Alzheimer's Disease?
Martı́nez, A., & Pérez, D. I. (2008) · Journal of Alzheimer s Disease · doi:10.3233/jad-2008-15204 · Cited by 125 · see citing works
“Therefore, in the absence of GSK-3 the cell may harbor other independent mechanism to regulate β -catenin degradation [51].”
The Wnt Signal Transduction Pathway in Stem Cells and Cancer Cells: Influence on Cellular Invasion
Neth, P., Ries, C., Karow, M., Egea, V., Ilmer, M., & Jochum, M. (2007) · Stem Cell Reviews and Reports · doi:10.1007/s12015-007-0001-y · Cited by 122 · see citing works
Trabid, a new positive regulator of Wnt-induced transcription with preference for binding and cleaving K63-linked ubiquitin chainsPreprint
Tran, H., Hamada, F., Schwarz, T., & Bienz, M. (2008) · Genes & Development · doi:10.1101/gad.463208 · Cited by 122 · see citing works
“In the absence of Wnt stimulation, an active mechanism operates to down-regulate -catenin, the key effector of the canonical Wnt pathway (Kimelman and Xu 2006).”
Background
Wnt/β-catenin signaling in heart regeneration
Özhan, G., & Weidinger, G. (2015) · Cell Regeneration · doi:10.1186/s13619-015-0017-8 · Cited by 122 · see citing works
“Phosphorylated β-catenin is ubiquitinated and targeted for degradation by the proteasome pathway [47, 50, 53, 54].”
Background
Wnt signaling in multiple myeloma: a central player in disease with therapeutic potential
Spaan, I., Raymakers, R. A. P., van de Stolpe, A., & Peperzak, V. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-018-0615-3 · Cited by 115 · see citing works
“This destruction complex phosphorylates β-catenin at specific and highly conserved serine and threonine residues, thereby marking it for ubiquitination by the E3 ligase β-TrCP and subsequent proteasomal degradation [32].”
Background
E-Cadherin Is Required for Caveolin-1-Mediated Down-Regulation of the Inhibitor of Apoptosis Protein Survivin via Reduced β-Catenin-Tcf/Lef-Dependent Transcription
Torres, V. A., Tapia, J. C., Rodríguez, D. A., Lladser, Á., Arredondo, C., Leyton, L., & Quest, A. F. G. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01991-06 · Cited by 115 · see citing works
MicroRNA roles in beta-catenin pathway
Huang, K., Zhang, J., Han, L., You, Y., Jiang, T., Pu, P., & Kang, C. (2010) · Molecular Cancer · doi:10.1186/1476-4598-9-252 · Cited by 113 · see citing works
“In turn, bcatenin accumulates in the cytoplasm and nucleus, where it interacts with coregulators of transcription including T cell factor/lymphocyte enhancer factor (Tcf/ Lef) to form a b-catenin/Lef/Tcf complex [10].”
Background
Lypd6 Enhances Wnt/β-Catenin Signaling by Promoting Lrp6 Phosphorylation in Raft Plasma Membrane Domains
Özhan, G., Sezgin, E., Wehner, D., Pfister, A. S., Kühl, S. J., Kagermeier-Schenk, B., Kühl, M., Schwille, P., & Weidinger, G. (2013) · Developmental Cell · doi:10.1016/j.devcel.2013.07.020 · Cited by 112 · see citing works
“Phosphorylated b-catenin is degraded by the ubiquitin-proteasome pathway (Kimelman and Xu, 2006).”
Background
Molecular mechanisms in colitis-associated colorectal cancer
Zhou, R. W., Harpaz, N., Itzkowitz, S. H., & Parsons, R. E. (2023) · Oncogenesis · doi:10.1038/s41389-023-00492-0 · Cited by 118 · see citing works
The EDD E3 ubiquitin ligase ubiquitinates and up-regulates β-catenin
Hay-Koren, A., Caspi, M., Zilberberg, A., & Rosin‐Arbesfeld, R. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-05-0440 · Cited by 111 · see citing works
Silibinin Suppresses Growth of Human Colorectal Carcinoma SW480 Cells in Culture and Xenograft through Down-regulation of β-Catenin-Dependent Signaling
Kaur, M., Balaiya, V., Tyagi, A., Agarwal, C., Singh, R. P., & Agarwal, R. (2010) · Neoplasia · doi:10.1593/neo.10188 · Cited by 110 · see citing works
“The first canonical pathway involves multiprotein destruction complex, consisting of GSK-3β, casein kinase 1, APC, and axin, which targets β-catenin for proteasomal degradation [36]; the second pathway involves p53/Siah1 [37]; and the third pathway involves nuclear hormone receptor–mediated degradation of β-catenin [3…”
Background
Detection of somatic β-catenin mutations in primary pigmented nodular adrenocortical disease (PPNAD)
Tadjine, M., Lampron, A., Ouadi, L., Horvath, A., Stratakis, C. A., & Bourdeau, I. (2008) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2008.03273.x · Cited by 108 · see citing works
RETRACTED ARTICLE: Taxifolin, a natural flavonoid interacts with cell cycle regulators causes cell cycle arrest and causes tumor regression by activating Wnt/ β -catenin signaling pathway
Razak, S., Afsar, T., Ullah, A., Almajwal, A. M., Alkholief, M. A., Alshamsan, A., & Jahan, S. (2018) · BMC Cancer · doi:10.1186/s12885-018-4959-4 · Cited by 108 · see citing works
Retracted
The COP9 Signalosome Mediates β-Catenin Degradation by Deneddylation and Blocks Adenomatous Polyposis coli Destruction via USP15
Huang, X., Langelotz, C., Hetfeld, B. K. J., Schwenk, W., & Dubiel, W. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.06.066 · Cited by 107 · see citing works
Intersection of AHR and Wnt Signaling in Development, Health, and Disease
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Self-citation

Authors: Kimelman, D., & Xu, W.
Affiliations: University of Washington (US)
Corresponding author: Kimelman, D
ORCID: Kimelman, D
Xu, W
Venue: Oncogene
Publisher: Springer Science and Business Media LLC
Published: 2006-12-04
Volume: 25
Issue: 57
Pages: 7482-7491
ISSN: 0950-9232 (ISSN-L)
1476-5594
DOI: 10.1038/sj.onc.1210055
OpenAlex: W2072335762
Cited by: 628
References: 72
Citations by year: 2026: 8 · 2025: 21 · 2024: 23 · 2023: 27 · 2022: 41 · 2021: 52 · 2020: 19 · 2019: 25 · 2018: 37 · 2017: 40 · 2016: 28 · 2015: 36 · 2014: 51 · 2013: 33 · 2012: 40
FWCI: 1.99
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Oncogene (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 destruction complex, Wnt/β-catenin signaling, β-catenin phosphorylation, β-catenin ubiquitination, protein complex structure, Wnt signaling inhibition
MeSH terms: Animals, Cell Nucleus, Colonic Neoplasms, Cytosol, Humans, Models, Biological, Phosphorylation, Protein Conformation, Stem Cells, Ubiquitin, beta Catenin

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β-Catenin destruction complex: insights and questions from a structural perspective

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