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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]
Citations
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“polyposis coli (APC), both substrates of GSK3, which phosphorylate beta-catenin leading to degradation in the absence of an initial Wnt ligand [65-67].”
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“…cascade results in hyperphosphorylation of disheveled (DVL), which inhibits GSK3β phosphorylation of CTNNB1 (Logan and Nusse, 2004; Clevers, 2006; Kimelman and Xu, 2006; Hoppler and Kavanagh, 2007; Komiya and Habas, 2008), allowing CTNNB1 to accumulate and translocate to the nucleus where it…”
The catenin family at a glance
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“This occurs via inhibition of a multicomponent complex that would otherwise lead to proteasomal destruction of b-catenin (Kimelman and Xu, 2006).”
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Burgess, A. W., Faux, M. C., Layton, M. J., & Ramsay, R. G. (2011) · Experimental Cell Research · doi:10.1016/j.yexcr.2011.08.010 · Cited by 81
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Takemaru, K., Ohmitsu, M., & Li, F. Q. (2008) · Handbook of experimental pharmacology · doi:10.1007/978-3-540-72843-6_11 · Cited by 70
“In the absence of a Wnt ligand, the cytosolic pool of β-catenin is continuously degraded by the action of a large protein complex called the “destruction complex” (Kimelman and Xu 2006).”
BackgroundZhang, L., Liu, J., Liu, F., Liu, W., Wang, Y., Zhu, B., & Yu, B. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.03.092 · Cited by 68
A review of signal pathway induced by virulent protein CagA of Helicobacter pylori
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“The classical Wnt/b-catenin signaling pathway is triggered by the binding of extracellular Wnt ligands to the transmembrane receptor Frizzled family protein (FZD) and its accessory receptor low-density lipoprotein receptor-related protein (LRP) (Kimelman and Xu, 2006).”
BackgroundCUL4B activates Wnt/β‐catenin signalling in hepatocellular carcinoma by repressing Wnt antagonists
Yuan, J., Han, B., Hu, H., Qian, Y., Liu, Z., Wei, Z., Liang, X., Jiang, B., Shao, C., & Gong, Y. (2014) · The Journal of Pathology · doi:10.1002/path.4492 · Cited by 68
WNT2 Regulates DNA Synthesis in Mouse Granulosa Cells Through Beta-Catenin1
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“AXIN, b-catenin, follicular development, FZD, granulosa cells, growth factors, GSK3B, mechanisms of hormone action, proliferation, WNT”
InfluentialStructural and Functional Characterization of the Wnt Inhibitor APC Membrane Recruitment 1 (Amer1)
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Wnt pathway activation by ADP-ribosylation
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Osteopontin induces β-catenin signaling through activation of Akt in prostate cancer cells
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“The increase in β-Catenin protein levels appear to be the result of a decrease in GSK-3β activity and hence a decrease in β-Catenin ubiquitination [44,45].”
Dissecting Major Signaling Pathways throughout the Development of Prostate Cancer
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“In the absence of external stimuli, b-catenin is phosphorylated by GSK-3b, and this retains the b-catenin within the cytoplasm where it undergoes ubiquitination and subsequent degradation (Kimelman and Xu, 2006).”
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“…Wnt signals, b-catenin is bound to a multi-protein degradation complex consisted of the tumor suppressor protein, adenomatosis polyposis coli (APC), the signaling scaffold protein, Axin and the serine-threonine kinase, glycogen synthase kinase 3b (GSK3b) (Moon et al., 2002; Kimelman and Xu, 2006).”
Backgroundβ-Catenin in oral cancer: An update on current knowledge
González‐Moles, M. Á., Ruiz‐Ávila, I., Montoya, J. A. G., Campillo, J. J. P., & Scully, C. M. (2014) · Oral Oncology · doi:10.1016/j.oraloncology.2014.06.005 · Cited by 64
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“APC proteins with their large relative molecular mass can form functional complexes with Axin and GSK-3, among others, to regulate the protein level of β-catenin in the cytoplasm (Kimelman and Xu 2006).”
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“In fact, b-catenin is controlled by a protein complex containing the tumor suppressor protein adenomatous polyposis coli (APC), casein kinase 1 (CK1), and glycogen synthase kinase-b (GSK3b) (3, 53, 76).”
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“In fact, β-catenin is controlled by a protein complex containing the tumor suppressor protein adenomatous polyposis coli (APC), casein kinase 1 (CK1), and glycogen synthase kinase-β (GSK-3β) (Barker et al., 2000; Hammond and Giaccia, 2005; Kimelman and Xu, 2006).”
BackgroundThe trimeric G protein Go inflicts a double impact on axin in the Wnt/frizzled signaling pathway
Egger‐Adam, D., & Katanaev, V. L. (2009) · Developmental Dynamics · doi:10.1002/dvdy.22060 · Cited by 61
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“The phosphorylation of β-catenin results in its ubiquitination and proteosomal degradation [15].”
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BackgroundNitric oxide prodrug JS-K inhibits ubiquitin E1 and kills tumor cells retaining wild-type p53
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“In the absence of Wnt signals, b-catenin is ubiquitylated, after phosphorylation by glycogen synthase kinase 3b and casein kinase 1a, and degraded through the proteasome pathway (Kimelman and Xu, 2006).”
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“Phosphorylated b-Catenin could be recognized by the E3 ubiquitin ligase enzyme b-Trcp, and then be de-gradated by proteasome, to ensure the concentrate of the b-catenin maintained at a relatively low level [58].”
BackgroundWong, C. T., Ahmad, E., Li, H., & Crawford, D. A. (2014) · Cell Communication and Signaling · doi:10.1186/1478-811x-12-19 · Cited by 65
“For instance, the phosphorylation of sites Ser33, 37, and Thr41 targets β-catenin for ubiquitination and proteasomal degradation [87,88].”
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Mustafa, M., Abbas, K., Alam, M., Ahmad, W., Moinuddin, M., Usmani, N., Siddiqui, S. A., & Habib, S. (2023) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-023-04772-6 · Cited by 58
“When Wnt is not activated, the transcriptional coactivator β-catenin becomes inactive due to GSK-3 phosphorylation. β-catenin inactivation is characterised by the formation of a “destruction complex” composed of GSK3, APC, Axin, and casein kinase I (CKI) [88].”
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Glycogen Synthase Kinase 3β Involvement in Neuroinflammation and Neurodegenerative Diseases
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“In normal conditions, the epithelial cells maintains adherent junctions, where E-cadherin forms a complex with βcatenin in the cell membrane [3,20].”
BackgroundMethodTankyrase Sterile α Motif Domain Polymerization Is Required for Its Role in Wnt Signaling
Riccio, A. A., McCauley, M., Langelier, M.-F., & Pascal, J. M. (2016) · Structure · doi:10.1016/j.str.2016.06.022 · Cited by 55
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript (Kimelman and Xu, 2006; MacDonald et al., 2009).”
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“Upon phosphorylation, β-catenin is recognized by β-transducin repeat-containing protein for ubiquitination and degradation [35].”
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“This led several authors [23,24,35] to propose that the destruction complex undergoes a cycle of structural rearrangements.”
BackgroundWu, G., Liu, A., Zhu, J., Lei, F., Wu, S., Zhang, X., Ye, L., Cao, L., & He, S. (2015) · Oncotarget · doi:10.18632/oncotarget.4921 · Cited by 53
“Moreover, Axin associates with GSK-3β, CK1α and APC to form the destruction complex that induces β-catenin degradation through ubiquitin-proteasome pathway [22].”
Molecular pathogenesis of desmoid tumor and the role of γ-secretase inhibition
Federman, N. C. (2022) · npj Precision Oncology · doi:10.1038/s41698-022-00308-1 · Cited by 53
The C. elegans SYS-1 Protein Is a Bona Fide β-Catenin
Liu, J., Phillips, B. T., Amaya, M. F., Kimble, J. E., & Xu, W. (2008) · Developmental Cell · doi:10.1016/j.devcel.2008.02.015 · Cited by 52
“and b-catenin/APC complexes demonstrated that the spacing between the TCF-like motif and phosphorylation-dependent motif is flexible (Kimelman and Xu, 2006).”
Self-citationGiakoustidis, A. E., Giakoustidis, D. E., Mudan, S., Sklavos, A., & Williams, R. L. (2015) · Canadian Journal of Gastroenterology and Hepatology · doi:10.1155/2015/172356 · Cited by 54
“In the absence of activated Wnt/β-catenin signalling, cytosolic β-catenin is phosphorylated by the core proteins axin, adenomatous polyposis coli (APC), glycogen synthase kinase 3 (GSK3) and casein kinase 1 (13).”
BackgroundNaghibalhossaini, F., Zamani, M., Mokarram, P., Khalili, I., Rasti, M., & Mostafavi‐Pour, Z. (2011) · Molecular Biology Reports · doi:10.1007/s11033-011-1434-6 · Cited by 51
Chai, 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
Nuclear-Cytoplasmic Shuttling of Chibby Controls β-Catenin Signaling
Li, F., Mofunanya, A., Fischer, V., Hall, J. C., & Takemaru, K. (2009) · Molecular Biology of the Cell · doi:10.1091/mbc.e09-05-0437 · Cited by 52
“This constantly targets -catenin for ubiquitin-mediated proteasomal degradation, keeping the cytosolic pool of -catenin low (Kimelman and Xu, 2006; Macdonald et al., 2007).”
BackgroundKohler, E. M., Chandra, S. H. V., Behrens, J., & Schneikert, J. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn338 · Cited by 66
Structure, Dynamics, and Functionality of Tankyrase Inhibitor-Induced Degradasomes
Thorvaldsen, T. E., Pedersen, N. M., Wenzel, E. M., Schultz, S. W., Brech, A., Liestøl, K., Waaler, J., Krauss, S. J. K., & Stenmark, H. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0125 · Cited by 51
“The structural proteins adenomatous polyposis coli (APC) and axis inhibition protein 1 and 2 (AXIN1/2), and the kinases casein kinase 1a (CK1a) and glycogen synthase kinase 3 (GSK3) are regarded as the core complex components (5).”
BackgroundZhao, Q., Bi, Y., Zhong, J., Ren, Z., Liu, Y., Jia, J., Yu, M., Tan, Y. L., Zhang, Q., & Yu, X. (2019) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2019.114813 · Cited by 51
Wnt Signaling Inhibitors and Their Promising Role in Tumor Treatment
Pećina‐Šlaus, N., Aničić, S., Bukovac, A., & Kafka, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076733 · Cited by 53
“The N-terminal domain of β-catenin, which is nota bene targeted by the majority of mutations, contains phosphorylation sites for GSK3β, CK-1α, and Bcl9 [8,30,33].”
BackgroundSexually Dimorphic Fin Regeneration in Zebrafish Controlled by Androgen/GSK3 Signaling
Nachtrab, G. T., Czerwinski, M. J., & Poss, K. D. (2011) · Current Biology · doi:10.1016/j.cub.2011.09.050 · Cited by 52
Rough surface topography enhances the activation of Wnt/β‐catenin signaling in mesenchymal cells
Galli, C., Passeri, G., Ravanetti, F., Elezi, E., Pedrazzoni, M., & Macaluso, G. M. (2010) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.32887 · Cited by 50
Modulation of Wnt signaling pathway by hepatitis B virus
Daud, M., Rana, M. A., Husnaın, T., & Ijaz, B. (2017) · Archives of Virology · doi:10.1007/s00705-017-3462-6 · Cited by 51
Wnt Signaling in Cardiac Disease
Hermans, K. C. M., & Blankesteijn, W. M. (2015) · Comprehensive physiology · doi:10.1002/cphy.c140060 · Cited by 56
Sileo, P., Simonin, C., Melnyk, P., Chartier‐Harlin, M., & Cotelle, P. (2022) · Cells · doi:10.3390/cells11223631 · Cited by 56
Kirby, L. A., Schott, J. T., Noble, B. L., Mendez, D. C., Caseley, P. S., Peterson, S. C., Routledge, T. J., & Patel, N. V. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039329 · Cited by 49
“Normally, the transcriptional co-activator b-catenin is recruited to the axin-GSK3 complex by APC, where b-catenin is phosphorylated by GSK3 and targeted for proteosomal degradation [20–22].”
BackgroundInfluentialThe roles of ubiquitin modifying enzymes in neoplastic disease
Kumari, N., Jaynes, P. W., Saei, A., Iyengar, P. V., Richard, J. L. C., & Eichhorn, P. J. A. (2017) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2017.09.002 · Cited by 51
Trimeric G protein-dependent signaling by Frizzled receptors in animal development
Egger‐Adam, D. (2008) · Frontiers in bioscience · doi:10.2741/3036 · Cited by 48
“The function of this complex is to induce phosphorylation, followed by proteasomal degradation of the cytoplasmic pool of betacatenin (35).”
BackgroundSwarup, S., & Verheyen, E. M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1017548108 · Cited by 47
“In the absence of pathway activity, the members of the destruction complex interact with one another to direct the entry, phosphorylation, and exit of β-catenin/Arm from the complex (6).”
BackgroundOkada-Iwasaki, R., Takahashi, Y., Watanabe, Y., Ishida, H., Saito, J., Nakai, R., & Asai, A. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0938 · Cited by 47
“K-756 stabilizes Axin1 and 2 by inhibiting TNKS1 and 2 Next, to examine the mechanism of action of K-756, DLD-1/ TCF-Luc cellswere treatedwithK-756 and the expressionof Axin1, Axin2, and the unphosphorylated active formofb-catenin protein were detected by Western blot analysis.”
BackgroundInfluentialAjayi, B., Adedara, I. A., & Farombi, E. (2018) · Human & Experimental Toxicology · doi:10.1177/0960327117751235 · Cited by 48
“This pathway is critically regulated by APC, glycogen synthase kinase 3 (GSK 3), and -catenin protein levels.(62) Activation of the pathway occurs by inactivation of APC which allows the nuclear translocation of -catenin and downstream activation of its targets genes such as lymphoid Figure 10.”
BackgroundStriking the target in Wnt-y conditions: Intervening in Wnt signaling during cancer progression
Camilli, T. C., & Weeraratna, A. T. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.03.002 · Cited by 47
“In the absence of Wnt ligand, this Axin-containing destruction complex is constitutively active, resulting in the phosphorylation and degradation of β-catenin [18].”
BackgroundTargeting DDX3 in Medulloblastoma Using the Small Molecule Inhibitor RK-33
Tantravedi, S., Vesuna, F., Winnard, P. T., Martin, A. M., Lim, M. K., Eberhart, C. G., Berlinicke, C. A., Raabe, E. H., van Diest, P. J., & Raman, V. (2018) · Translational Oncology · doi:10.1016/j.tranon.2018.09.002 · Cited by 47
“In a normal cell, the cytoplasmic β-catenin levels are maintained by the phosphorylation of β-catenin by a cytoplasmic destruction complex consisting of APC, axin, casein kinase 1α (CK1α), and glycogen synthase kinase (GSK3β), and further β-catenin is degraded by the ubiquitin proteasome complex [38,39].”
Signaling Pathways Induced by Leptin during Epithelial–Mesenchymal Transition in Breast Cancer
Olea‐Flores, M., Juárez-Cruz, J. C., Catalán, M. A. M., Padilla‐Benavides, T., & Navarro‐Tito, N. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113493 · Cited by 48
“A hallmark of EMT is the dysregulation of E-cadherin, occludin, claudins, and cytokeratins which leads to the loss of the apico-basolateral polarity, mediated by the TFs Snail, Slug, Zeb, and Twist [10], which are discussed below.”
InfluentialKeikhosravani, P., Maleki‐Ghaleh, H., Kahaie‐Khosrowshahi, A., Bodaghi, M., Dargahi, Z., Kavanlouei, M., Khademi-Azandehi, P., Fallah, A., Beygi‐Khosrowshahi, Y., & Siadati, M. H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179214 · Cited by 47
“This destruction complex is composed of the proteins Axin, protein phosphate 2A (PP2A), adenomatous polyposis coli (APC), glycogen synthase kinase 3 (GSK-3), and casein kinase 1a (CK1a) [62,63].”
BackgroundSchneikert, J., Brauburger, K., & Behrens, J. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr273 · Cited by 45
“In the absence of a wnt signal, b-catenin is recruited in the so-called destruction complex (14) comprising the core components axin/conductin (15), casein kinase 1 and glycogen synthase kinase 3b (GSK3b).”
Backgroundβ-catenin inhibitors in cancer therapeutics: intricacies and way forward
Dev, A. J. R., Vachher, M., & Prasad, C. P. (2023) · Bioengineered · doi:10.1080/21655979.2023.2251696 · Cited by 47
Physiopathological aspects of the Wnt/β-catenin signaling pathway in the male reproductive system
Lombardi, A. P. G., Royer, C., Pisolato, R., Cavalcanti, F. N., Lucas, T. F. G., Lazari, M. F. M., & Porto, C. S. (2013) · Spermatogenesis · doi:10.4161/spmg.23181 · Cited by 46
“The scaffolding protein Axin has separate domains that interact with glycogen synthase kinase 3 (GSK3), casein kinase 1 (CK1) and β-catenin, and coordinates sequential phosphorylation of β-catenin at serine 45 by CK1α, and threonine 41, serine 37 and serine 33 by GSK3.”
BackgroundInfluentialWnt/β-catenin signaling plays a distinct role in methyl gallate–mediated inhibition of adipogenesis
Jeon, M., Rahman, N., & Kim, Y. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.08.178 · Cited by 46
Perspectives on miRNAs Targeting DKK1 for Developing Hair Regeneration Therapy
Papukashvili, D., Rcheulishvili, N., Liu, C., Xie, F., Tyagi, D., He, Y., & Wang, P. G. (2021) · Cells · doi:10.3390/cells10112957 · Cited by 51
“As a result, the destruction complex is inactivated, which protects β-catenin from targeting by the proteasome [37].”
BackgroundInfluentialThe Wnt/Frizzled pathway as a therapeutic target for cardiac hypertrophy: where do we stand?
ter Horst, P., Smits, J. F. M., & Blankesteijn, W. M. (2011) · Acta Physiologica · doi:10.1111/j.1748-1716.2011.02309.x · Cited by 45
“The phosphorylated b-catenin is then ubiquitinated and degraded by the proteasome (Kimelman & Xu 2006), which results in low levels of b-catenin in the cytoplasm under baseline conditions.”
BackgroundEpigenetic regulation of the Hedgehog and Wnt pathways in cancer
Wils, L. J., & Bijlsma, M. F. (2017) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2017.11.013 · Cited by 46
Yang, J., Han, F., Liu, W., Chen, H., Hao, X., JIANG, X. H., Yin, L., Huang, Y., Cao, J., Zhang, H., et al. (2017) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-017-0643-9 · Cited by 48
Wnt Signaling and Its Impact on Mitochondrial and Cell Cycle Dynamics in Pluripotent Stem Cells
Rasmussen, M. L., Ortolano, N. A., Romero-Morales, A. I., & Gama, V. (2018) · Genes · doi:10.3390/genes9020109 · Cited by 44
“Wnt/STOP seems to be the predominant Wnt pathway in many cancer cells, where it may play a key role in promoting cell growth [11]. receptor and the co ‐ receptor LRP5/6, which induces the recruitment of Dishevelled (DVL)and inhibits the β‐ catenin destruction complex formed by AXIN, APC, GSK3, and CK1.”
InfluentialShailesh, H., Siveen, K. S., & Sif, S. (2021) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.16260 · Cited by 45
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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