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β-Catenin destruction complex: insights and questions from a structural perspective
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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“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]
In the citing paper
“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]
In the citing paper
“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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“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).”
BackgroundWnt 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
“Normally, in cells not exposed to ligand, cytoplasmic levels of b-catenin are kept low through interactions with the b-catenin destruction complex [20].”
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“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].”
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Martín‐Orozco, E., Sanchez-Fernandez, A., Ortiz-Parra, I., & Nicolás, M. A.-S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02854 · Cited by 306
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“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…”
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“However, a small dynamic pool of -catenin shuttles between the cytoplasm and the nucleus to transduce canonical Wnt signals (Kimelman and Xu, 2006).”
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“…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.”
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The Spectrum of Achalasia: Lessons From Studies of Pathophysiology and High-Resolution Manometry
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Wnt Stabilization of β-Catenin Reveals Principles for Morphogen Receptor-Scaffold Assemblies
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“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).”
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“The axin complex is constitutively active in the absence of Wnt stimulation, phosphorylating -catenin and thus promoting its proteasomal degradation (Kimelman and Xu, 2006).”
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“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].”
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“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].”
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Emerging links between CDK cell cycle regulators and Wnt signaling
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Drug Discovery Approaches to Target Wnt Signaling in Cancer Stem Cells
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“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).”
BackgroundInfluentialSnapShot: Wnt/β-Catenin Signaling
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“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),…”
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“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).”
BackgroundMechanistic insights into Wnt–β-catenin pathway activation and signal transduction
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BackgroundFrequent mutations of β‐catenin gene in sporadic secreting adrenocortical adenomas*
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Wnt signaling in Alzheimer's disease: Up or down, that is the question
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“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).”
BackgroundFernandez, 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 152
“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].”
BackgroundTargeting the Wnt pathways for therapies
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“The function of this complex is to phosphorylate cytoplasmic β-catenin, targeting it for ubiquitin-dependent proteasomal degradation [15].”
BackgroundChibby cooperates with 14-3-3 to regulate β-catenin subcellular distribution and signaling activity
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“…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…”
BackgroundThe Ubiquitin-Specific Protease USP34 Regulates Axin Stability and Wnt/β-Catenin Signaling
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“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).”
BackgroundNucleo-cytoplasmic shuttling of PAK4 modulates β-catenin intracellular translocation and signaling
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Integrating developmental signals: a Hippo in the (path)way
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“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)).”
BackgroundWnt 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
Mutant huntingtin‐impaired degradation of β‐catenin causes neurotoxicity in Huntington's disease
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“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).”
BackgroundInfluentialGSK-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 124
“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
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“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).”
BackgroundWnt/β-catenin signaling in heart regeneration
Özhan, G., & Weidinger, G. (2015) · Cell Regeneration · doi:10.1186/s13619-015-0017-8 · Cited by 125
“Phosphorylated β-catenin is ubiquitinated and targeted for degradation by the proteasome pathway [47, 50, 53, 54].”
BackgroundWnt 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 114
“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].”
BackgroundTorres, 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
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
“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].”
BackgroundÖzhan, 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
“Phosphorylated b-catenin is degraded by the ubiquitin-proteasome pathway (Kimelman and Xu, 2006).”
BackgroundMolecular 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 123
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 109
Kaur, M., Balaiya, V., Tyagi, A., Agarwal, C., Singh, R. P., & Agarwal, R. (2010) · Neoplasia · doi:10.1593/neo.10188 · Cited by 110
“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…”
BackgroundDetection 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
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 109
RetractedHuang, 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
Intersection of AHR and Wnt Signaling in Development, Health, and Disease
Schneider, A. J., Branam, A. M., & Peterson, R. E. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms151017852 · Cited by 109
RACK1 Suppresses Gastric Tumorigenesis by Stabilizing the β-Catenin Destruction Complex
Deng, Y., Yao, F., Li, J., Mao, Z., Hu, P., Long, L., Guo, L., Ji, X., Shi, S., Guan, D., et al. (2012) · Gastroenterology · doi:10.1053/j.gastro.2011.12.046 · Cited by 103
Rodriguez, J. P., Coulter, M., Miotke, J., Meyer, R., Takemaru, K., & Levine, J. M. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.4915-13.2014 · Cited by 106
“Consistent with the notion that reducing CSPGs can reduce microglial reactions to injury is the finding that there is reduced inflammation after lysolecithin-induced demyelination in the spinal cords of NG2-null mice (Kucharova et al., 2011).”
BackgroundConstitutive activation of the Wnt canonical pathway in mantle cell lymphoma
Gélébart, P., Anand, M., Armanious, H., Peters, A., Bard, J. D., Amin, H. M., & Lai, R. L. (2008) · Blood · doi:10.1182/blood-2008-02-139212 · Cited by 100
Morrone, S. R., Cheng, Z., Moon, R. T., Cong, F., & Xu, W. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1116618109 · Cited by 100
“The assembly or disassembly of the destruction complex in the cytosol is a central regulatory step of the Wnt/β-catenin pathway (2, 9).”
BackgroundMethodInfluentialSelf-citationAberrant regulation of Wnt signaling in hepatocellular carcinoma
Liu, L., Xie, S., Chen, Y.-T., Xue, J.-L., Zhang, C., & Zhu, F. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i33.7486 · Cited by 102
Wnt/β-Catenin Signaling in Alzheimer’s Disease
Ferrari, G., Avila, M., Medina, M., Perez-Palma, E., Bustos, B., & Alarcon, M. (2014) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527312666131223113900 · Cited by 95
Bernard, P., & Harley, V. R. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2009.10.017 · Cited by 99
“Phosphorylated - atenin is then recognised by the E3 ubiquitin ligase complex nd targeted for degradation (Kimelman and Xu, 2006; Logan and usse, 2004).”
Preclinical efficacy on GSK‐3 inhibitors: Towards a future generation of powerful drugs
Martı́nez, A. (2008) · Medicinal Research Reviews · doi:10.1002/med.20119 · Cited by 98
“Thus, in the absence of GSK-3 the cell may harbor other independent mechanism to regulate b-catenin degradation.(137)”
Molecular regulation and pharmacological targeting of the β‐catenin destruction complex
van Kappel, E. C., & Maurice, M. M. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13922 · Cited by 96
“In this model, PP2A-mediated dephosphorylation of APC resets the system for binding and processing a new β-catenin (Kimelman and Xu, 2006; Xu and Kimelman, 2007).”
Jin, R., Liu, W., Menezes, S. V., Yue, F., Zheng, M., Kovačević, Ž., & Richardson, D. R. (2014) · Journal of Cell Science · doi:10.1242/jcs.147835 · Cited by 99
“polyubiquitylation and proteasomal degradation (Kimelman and Xu, 2006; MacDonald et al., 2009; Wu and Pan, 2010; Stamos and Weis, 2013).”
BackgroundShrivastava, S., Jeengar, M. K., Thummuri, D., Koval, A., Katanaev, V. L., Marepally, S. K., & Naidu, V. G. M. (2016) · BioFactors · doi:10.1002/biof.1315 · Cited by 94
Ranes, M., Zaleska, M., Sakalas, S., Knight, R., & Guettler, S. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.07.013 · Cited by 100
The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway
Zhao, B., Schlesiger, C., Masucci, M. G., & Lindsten, K. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00682.x · Cited by 93
Roberts, D. M., Pronobis, M. I., Poulton, J. S., Waldmann, J. D., Stephenson, E. M., Hanna, S., & Peifer, M. A. (2011) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-11-0871 · Cited by 90
“This model builds on earlier suggestions of a catalytic cycle (Kimelman and Xu, 2006), of the role of multiple ßcat-binding sites as docking sites to accommodate different ßcat levels (Ha et al.”
BackgroundMethodInfluentialFu, D.-Y., Wang, Z.-M., Li-Chen, Wang, B.-L., Shen, Z., Huang, W., & Shao, Z. (2009) · Breast Cancer Research and Treatment · doi:10.1007/s10549-009-0339-8 · Cited by 89
“The b-catenin is a key effector in the Wnt signaling pathway [40].”
BackgroundShould I stay or should I go: β-catenin decides under stress
Hoogeboom, D., & Burgering, B. M. T. (2009) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2009.02.002 · Cited by 90
Lane, D. J. R., Mills, T. M., Shafie, N. H., Merlot, A. M., Moussa, R., Kalinowski, D. S., Kovačević, Ž., & Richardson, D. R. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2014.01.005 · Cited by 90
Wnt/β-catenin signaling pathway in trophoblasts and abnormal activation in preeclampsia
Zhang, Z., Wang, X., Zhang, L., Shi, Y., Wang, J., & Yan, H. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.6718 · Cited by 89
“…axin and adenomatous polyposis coli (APC), and the kinases that phosphorylate β -catenin, glycogen synthase kinase 3 β (GSK3 β ), casein kinase 1 (CK1) and protein phosphatase 2A], which contributes to the degradation of β -catenin in the cytoplasm through the addition of phosphate groups (45,46).”
Identification of targets of the Wnt pathway destruction complex in addition to β-catenin
Kim, N., Xu, C. B., & Gumbiner, B. M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810185106 · Cited by 94
Cha, B., Kim, W., Kim, Y., Hwang, B. N., Park, S. Y., Yoon, J., Park, W. S., Cho, J. W., Bedford, M. T., & Jho, E. (2011) · Oncogene · doi:10.1038/onc.2010.610 · Cited by 85
“In the absence of Wnt activation, cytoplasmic b-catenin is assembled in a multimeric protein complex comprising Axin, adenomatous polyposis coli, casein kinase 1 (CK1) and glycogen synthase kinase 3b (GSK3b; Kimelman and Xu, 2006), after which it is sequentially phosphorylated at its Ser and Thr residues by CK1 and GS…”
BackgroundGSK3β: a master player in depressive disorder pathogenesis and treatment responsiveness
Duda, P., Hajka, D., Wójcicka, O., Rakus, D., & Gizak, A. (2020) · Cells · doi:10.3390/cells9030727 · Cited by 84
“This results in GSK3β-dependent phosphorylation of β-catenin and leads to its subsequent proteasomal degradation [115].”
BackgroundAldolase positively regulates of the canonical Wnt signaling pathway
Caspi, M., Perry, G., Skalka, N., Meisel, S., Firsow, A., Amit, M., & Rosin‐Arbesfeld, R. (2014) · Molecular Cancer · doi:10.1186/1476-4598-13-164 · Cited by 84
“This destruction complex consists of the scaffold protein Axin, the tumor suppressor adenomatous polyposis coli (APC) and the kinases glycogen synthase kinase-3 (GSK-3) α/β and casein kinase-1α (CKIα) [2,3].”
Background
Metadata
- Authors
- Kimelman, D., & Xu, W.
- Affiliations
- University of Washington (US)
- Corresponding author
- Kimelman, D
- ORCID
- Venue
- Oncogene
- Published
- 2006-12-04
- Volume
- 25
- Issue
- 57
- Pages
- 7482-7491
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- 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
- 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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