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Wg/Wnt Signal Can Be Transmitted through Arrow/LRP5,6 and Axin Independently of Zw3/Gsk3β Activity
Open accessAbstract
Activation of the Wnt signaling cascade provides key signals during development and in disease. Here we provide evidence, by designing a Wnt receptor with ligand-independent signaling activity, that physical proximity of Arrow (LRP) to the Wnt receptor Frizzled-2 triggers the intracellular signaling cascade. We have uncovered a branch of the Wnt pathway in which Armadillo activity is regulated concomitantly with the levels of Axin protein. The intracellular pathway bypasses Gsk3beta/Zw3, the kinase normally required for controlling beta-catenin/Armadillo levels, suggesting that modulated degradation of Armadillo is not required for Wnt signaling. We propose that Arrow (LRP) recruits Axin to the membrane, and that this interaction leads to Axin degradation. As a consequence, Armadillo is no longer bound by Axin, resulting in nuclear signaling by Armadillo.
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“It is important to note that Wnt stimulation also regulates the stability of Axin for with Wnt stimulation a de-phosphorylation of Axin and a decrease in cytoplasmic levels of Axin has been documented.29–31”
From Wnt signal transduction pathways (2008) · cites this paper as [29]
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“Because LRP can interact with the cytosolic protein Axin (Mao et al. 2001b, Tolwinski et al. 2003) (Figures 2 and 3), Wnts are thought to induce the phosphorylation of LRP on a PPP(S/T)P motif, thus allowing the docking of Axin to the LRP cytoplasmic tail.”
BackgroundWnt signal transduction pathways
Komiya, Y., & Habas, R. (2008) · Organogenesis · doi:10.4161/org.4.2.5851 · Cited by 1,528
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LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling:Arrows point the way
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“Dsh appears to be epistatic to, or downstream of, Arrow, because Dsh overexpression activates β-catenin signaling in arrow mutants (Wehrli et al., 2000) and the constitutively active Dfz2Arrow fusion protein is inactive in dshmutants (Tolwinski et al., 2003).”
BackgroundInfluentialWnt signaling in disease and in development
Nusse, R. (2005) · Cell Research · doi:10.1038/sj.cr.7290260 · Cited by 989
Wnt Induces LRP6 Signalosomes and Promotes Dishevelled-Dependent LRP6 Phosphorylation
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Wnt Signaling through Inhibition of β-Catenin Degradation in an Intact Axin1 Complex
Li, V. S. W., Ng, S. S., Boersema, P. J., Low, T. Y., Karthaus, W. R., Gerlach, J. P., Mohammed, S., Heck, A. J. R., Maurice, M. M., Mahmoudi, T., et al. (2012) · Cell · doi:10.1016/j.cell.2012.05.002 · Cited by 889
GSK3: a multifaceted kinase in Wnt signaling
Wu, D., & Pan, W. (2009) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2009.10.002 · Cited by 862
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Zeng, X., Tamai, K., Doble, B. W., Li, S., Huang, H., Habas, R., Okamura, H., Woodgett, J. R., & He, X. (2005) · Nature · doi:10.1038/nature04185 · Cited by 872
WNT Signaling Pathway and Stem Cell Signaling Network
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Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3–independent β-catenin degradation
Topol, L. Z., Jiang, X., Choi, H., Garrett-Beal, L. J., Carolan, P. J., & Yang, Y. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200303158 · Cited by 724
“The canonical Wnt signaling can also up-regulate -catenin activity through a GSK-3–independent pathway in a recently published work (Tolwinski et al., 2003).”
BackgroundInfluentialWNTS in the vertebrate nervous system: from patterning to neuronal connectivity
Ciani, L., & Salinas, P. C. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1665 · Cited by 543
“LRP5/6 can also activate the canonical pathway by binding to the intracellular axis inhibitor AXIN, and inducing its degradatio”
BackgroundFrizzled and LRP5/6 Receptors for Wnt/ -Catenin SignalingPreprint
MacDonald, B. T., & He, X. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a007880 · Cited by 640
Boland, G. M., Perkins, G., Hall, D. J., & Tuan, R. S. (2004) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20284 · Cited by 578
“The family of Wnt co-receptors, the low density lipoprotein-related peptides, LRP5 andLRP6, areknown tobe involved in canonical Wnt signal transduction by stabilizing the Wnt–Frizzled interaction, and play a role in intracellular signaling through their interaction with Axin [Mao et al., 2001; Cliffe et al., 2003; Sch…”
BackgroundThe Roles of APC and Axin Derived from Experimental and Theoretical Analysis of the Wnt Pathway
Lee, E., Salic, A., Krüger, R., Heinrich, R., & Kirschner, M. W. (2003) · PLoS Biology · doi:10.1371/journal.pbio.0000010 · Cited by 708
“A number of parameters were set such that the results of the model were in agreement with previous experimental data, specifically with the experimentally determined rate of bcatenin degradation ( Salic et al. 2000; Lee et al. 2001).”
BackgroundMethodResultInfluentialA Mechanism for Wnt Coreceptor Activation
Tamai, K., Zeng, X., Liu, C., Zhang, X., Harada, Y., Chang, Z., & He, X. (2004) · Molecular Cell · doi:10.1016/s1097-2765(03)00484-2 · Cited by 490
“Secondly, forced proximity of Dfz2 and Arrow, by fusing the Arrow cytoplasmic domain with theSignaling by the Wnt family of secreted lipoproteins carboxyl tail of Dfz2, initiates -catenin signaling inplays a central role in development and disease (Wodarz the absence of Wg (Tolwinski et al., 2003).”
BackgroundInfluentialThe contribution of bone to whole-organism physiology
Karsenty, G., & Ferron, M. (2012) · Nature · doi:10.1038/nature10763 · Cited by 537
The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity
Wallingford, J. B., & Habas, R. (2005) · Development · doi:10.1242/dev.02068 · Cited by 509
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
“Indeed, various molecular means to bring Fz and Lrp6 into proximity can activate the -catenin pathway in the absence of any Wnt stimulation (Cong et al., 2004; Liu et al., 2005; Tolwinski et al., 2003; Holmen et al., 2005).”
BackgroundWnt signaling: complexity at the surface
Cadigan, K. M., & Liu, Y. I. (2006) · Journal of Cell Science · doi:10.1242/jcs.02826 · Cited by 486
“There is also evidence that, in Drosophila, axin can retain Arm in the cytoplasm, and that this form of regulation is distinct from regulation of Arm turnover (Tolwinski and Wieschaus, 2001; Tolwinski et al., 2003; Tolwinski and Wieschaus, 2004).”
BackgroundInfluentialSmall-molecule inhibition of Wnt signaling through activation of casein kinase 1α
Thorne, C. A., Hanson, A. J., Schneider, J., Tahinci, E., Orton, D., Cselenyi, C. S., Jernigan, K. K., Meyers, K. C., Hang, B. I., Waterson, A. G., et al. (2010) · Nature Chemical Biology · doi:10.1038/nchembio.453 · Cited by 485
Hino, S., Tanji, C., Nakayama, K. I., & Kikuchi, A. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.20.9063-9072.2005 · Cited by 428
Wnt signaling controls the fate of mesenchymal stem cells
Ling, L., Nurcombe, V., & Cool, S. M. (2008) · Gene · doi:10.1016/j.gene.2008.12.008 · Cited by 417
“APC, Axin1 and Axin2, scaffold proteins of the β-catenin destruction complex, are required for the degradation of β-catenin.”
BackgroundInfluentialCong, F., Schweizer, L., & Varmus, H. (2004) · Development · doi:10.1242/dev.01318 · Cited by 317
“Recent studies have demonstrated that Wnt induces membrane translocation and destabilization of Axin (Cliffe et al., 2003; Mao et al., 2001a; Tolwinski et al., 2003).”
BackgroundInfluentialDkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation
Li, X., Liu, P., Liu, W., Maye, P. F., Zhang, J., Zhang, Y., Hurley, M. M., Guo, C., Boskey, A. L., Sun, L., et al. (2005) · Nature Genetics · doi:10.1038/ng1614 · Cited by 340
“Through mechanisms that are not well characterized but may involve interactions between LRP5/6 and axi”
BackgroundNusse, R. (2003) · Development · doi:10.1242/dev.00821 · Cited by 334
Wnt Signaling from Development to Disease: Insights from Model SystemsPreprint
Cadigan, K. M., & Peifer, M. A. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a002881 · Cited by 312
“Wieschaus’ laboratory found that Wnt signaling alters Axin stability, thus regulating its cytoplasmic anchoring function (Tolwinski et al. 2003).”
BackgroundFZD7 has a critical role in cell proliferation in triple negative breast cancer
Yang, L., Wu, X., Wang, Y., Zhang, K., Wu, J., Yuan, Y.-C., Deng, X., Chen, L., Kim, C. C. H., Lau, S., et al. (2011) · Oncogene · doi:10.1038/onc.2011.145 · Cited by 298
“…Wnt signaling, FZD binds to Dishevelled (DVL) and LRP5/6-binds to AXIN-FRAT to form a complex. b-catenin is prevented from phosphorylation (Tolwinski et al., 2003) and the stabilized b-catenin translocates from the cytoplasm to the nucleus to activate transcription of Wnt-responsive genes…”
BackgroundThe Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice
Kelly, O., Pinson, K. I., & Skarnes, W. C. (2004) · Development · doi:10.1242/dev.01137 · Cited by 295
“The mechanism by which Wnt signals are transduced through Lrp5/6 appears to involve binding of Lrp5/6 to axin, a downstream negative regulator of the pathway that controls degradation of β-catenin (Mao et al., 2001b; Liu et al., 2003; Tolwinski et al., 2003; Tamai et al., 2004).”
BackgroundWnt/Notch signalling and information processing during development
Hayward, P. C., Kalmár, T., & Arias, A. M. (2008) · Development · doi:10.1242/dev.000505 · Cited by 299
“Furthermore, genetic analysis in Drosophila has shown that Axin has a second function in controlling the activity of Armadillo (Drosophila -catenin) (Tolwinski et al., 2003; Tolwinski and Wieschaus, 2004b), supporting the notion that the activity of - catenin is regulated not only through changes…”
BackgroundA Role of Dishevelled in Relocating Axin to the Plasma Membrane during Wingless Signaling
Cliffe, A., Hamada, F., & Bienz, M. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00370-1 · Cited by 289
Nam, J., Turcotte, T. J., Smith, P. F., Choi, S., & Yoon, J. K. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m508324200 · Cited by 288
Multiplicity of the interactions of Wnt proteins and their receptors
Kikuchi, A., Yamamoto, H., & Kishida, S. (2006) · Cellular Signalling · doi:10.1016/j.cellsig.2006.11.001 · Cited by 289
The Frizzled family: receptors for multiple signal transduction pathways.
Huang, H., & Klein, P. S. (2004) · Genome biology · doi:10.1186/gb-2004-5-7-234 · Cited by 283
“In addition, LRP5 and Arrow interact directly with Axin, a cytoplasmic scaffold protein that is the hub of cytoplasmic regulation of Wnt signaling, recruiting Axin to the membrane [ 35 ,36].”
BackgroundWestfall, T. A., Brimeyer, R., Twedt, J., Gladon, J., Olberding, A., Furutani‐Seiki, M., & Slusarski, D. C. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200303107 · Cited by 271
“In particular, PKC (Kuhl et al., 2001) and naked cuticle (Zeng et al., 2000; Yan et al., 2001) proteins, which could lead to -catenin accumulation or those that could influence -catenin nuclear import (Tolwinski et al., 2003), are perhaps required.”
BackgroundWang, L., Li, J., & Di, L. (2021) · Medicinal Research Reviews · doi:10.1002/med.21867 · Cited by 283
New Insights into the Mechanism of Wnt Signaling Pathway Activation
Kikuchi, A., Yamamoto, H., Sato, A., & Matsumoto, S. (2011) · International review of cytology · doi:10.1016/b978-0-12-386035-4.00002-1 · Cited by 275
“In Drosophila although a similar truncated form of Arrow does not activate Wg signaling inDrosophila, a chimera containing the intracellular domain of Arrow fused to the C-terminus of DFz2 activates Wg target genes (Tolwinski et al., 2003).”
BackgroundWnt and the Wnt signaling pathway in bone development and disease
Wang, Y. (2014) · Frontiers in bioscience · doi:10.2741/4214 · Cited by 255
The links between axin and carcinogenesis
Salahshor, S., & Woodgett, J. R. (2005) · Journal of Clinical Pathology · doi:10.1136/jcp.2003.009506 · Cited by 256
Wnt Signaling and Drug Resistance in Cancer
Zhong, Z., & Virshup, D. M. (2019) · Molecular Pharmacology · doi:10.1124/mol.119.117978 · Cited by 243
“…bodies (MVBs) that restricts GSK39s access to substrates (Taelman et al., 2010), 3) dissociation of the ubiquitination machinery from the b-catenin destruction complex (Li et al., 2012), and 4) degradation of AXIN and disassembly of the destruction complex (Tolwinski et al., 2003).”
BackgroundXing, Y., Clements, W. K., Kimelman, D., & Xu, W. (2003) · Genes & Development · doi:10.1101/gad.1142603 · Cited by 237
“Although -catenin levels may also be regulated by other Axinindependent pathways (Kang et al. 2002; Tolwinski et al. 2003), phosphorylation of -catenin by the -catenin destruction complex is the central regulatory step of the canonical Wnt/ -catenin signaling pathway.”
BackgroundExon 3 mutations of CTNNB1 drive tumorigenesis: a review
Gao, C., Wang, Y., Broaddus, R. R., Sun, L., Xue, F., & Zhang, W. (2017) · Oncotarget · doi:10.18632/oncotarget.23695 · Cited by 227
“The cytoplasmic tail of LRP may combine with Axin directly [36, 37].”
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Semënov, M. V., & He, X. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m609509200 · Cited by 221
Wnt/beta-Catenin Signaling and Small Molecule Inhibitors
Voronkov, A. E., & Krauss, S. J. K. (2012) · Current Pharmaceutical Design · doi:10.2174/138161213804581837 · Cited by 227
Han, C., Yan, D., Belenkaya, T. Y., & Lin, X. (2005) · Development · doi:10.1242/dev.01636 · Cited by 221
“The following UAS constructs were used to overexpress the corresponding transgenes in the posterior compartment of the wing disc: UAS-dlp (Baeg et al., 2001), UAS-dally (Tsuda et al., 1999), UAS-fz and UAS-fz2 (Zhang and Carthew, 1998), and UAS-gfp-arr.”
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 223
“The low level of intracellular Axin is due, in part, to its ubiquitin- mediated turnover that is promoted by LRP5/6 (Yamamoto et al. 1999; Mao et al. 2001; Tolwinski et al. 2003; Kofron et al. 2007; Cselenyi et al. 2008).”
BackgroundInfluentialLRP5 and Wnt Signaling: A Union Made for Bone
Johnson, M. L., Harnish, K., Nusse, R., & Hul, W. V. (2004) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.040816 · Cited by 211
Cselenyi, C. S., Jernigan, K. K., Tahinci, E., Thorne, C. A., Lee, L. A., & Lee, E. N. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803025105 · Cited by 207
“These data are consistent with evidence in Drosophila embryos that Arrow, the Drosophila LRP5/6 ortholog, can promote Axin degradation in the absence of GSK3 activity (7).”
BackgroundMethodResultInfluentialHayward, P., Brennan, K. R., Sanders, P., Balayo, T., DasGupta, R., Perrimon, N., & Arias, A. M. (2005) · Development · doi:10.1242/dev.01724 · Cited by 204
“This form of Armadillo lacks the Shaggy/GSK3β phosphorylation sites and provides Wingless-independent signalling by escaping degradation by the Axin-based destruction complex (Pai et al., 1997).”
BackgroundInfluentialThe role of microtubule actin cross-linking factor 1 (MACF1) in the Wnt signaling pathway
Chen, H.-J., Lin, C.-M., Lin, C.-S., Perez-Olle, R., Leung, C. L., & Liem, R. K. H. (2006) · Genes & Development · doi:10.1101/gad.1411206 · Cited by 191
“The levels of Axin are reduced by Wnt stimulation (Willert et al. 1999; Yamamoto et al. 1999), Wg overexpression (Tolwinski et al. 2003), and Lrp5 N overexpression (Mao et al. 2001) in mammalian and Drosophila cells, suggesting that inhibition of Wnt/ -catenin signaling would increase the total…”
BackgroundWnt/Beta-Catenin Signaling Regulation and a Role for Biomolecular Condensates
Schaefer, K. N., & Peifer, M. A. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.01.025 · Cited by 195
“One common consequence of long-term Wnt signaling is down-regulation of Axin protein levels (Kofron et al., 2007; Liu et al., 2005; Mao et al., 2001; Tolwinski et al., 2003; Yang et al., 2016).”
BackgroundRegulation of Lrp6 phosphorylation
Niehrs, C., & Shen, J. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0329-3 · Cited by 195
“Axin binding to Lrp6 is very likely direct, since truncated Axin interacts with the Lrp6 cytoplasmic domain in yeast two-hybrid assays [41, 118 ].”
BackgroundInfluentialNuclear-cytoplasmic shuttling of Axin regulates subcellular localization of β-catenin
Cong, F., & VARMUS, H. E. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307344101 · Cited by 189
Wei, Q., Yokota, C., Semënov, M. V., Doble, B. W., Woodgett, J. R., & He, X. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m701927200 · Cited by 182
Baarsma, H. A., Königshoff, M., & Gosens, R. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.01.002 · Cited by 179
“Activation of LRP5/6 has been proposed to inhibit the formation of the destruction complex and/or cause disruption of this complex by promoting the degradation of Axin (Kofron et al., 2007; Tolwinski et al., 2003).”
BackgroundThe Wnt signaling pathway: Aging gracefully as a protectionist?
Maiese, K., Li, F., Chong, Z. Z., & Shang, Y. (2008) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2008.01.004 · Cited by 171
“Wnt signaling also can be transmitted through the binding of extracellular domain of LRP-5/6 to Axin, a key component in the GSK-3β complex, indicating that the LRP-5/6 receptor is an important part of the Wnt-FZD signaling pathway (Mao et al., 2001; Tolwinski et al., 2003).”
BackgroundThe LRP5 High-Bone-Mass G171V Mutation Disrupts LRP5 Interaction with Mesd
Zhang, Y., Wang, Y., Li, X., Zhang, J., Mao, J., Li, Z., Zheng, J., Li, L., Harris, S., & Wu, D. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.11.4677-4684.2004 · Cited by 142
“Furthermore, LRP5 and Arrow were found to be involved in transducing the canonical Wnt signals by binding Axin and leading to Axin degradation and -catenin stabilization (24, 35 ).”
BackgroundRegulation of Wnt/β‐catenin signaling by protein kinases
Verheyen, E. M., & Gottardi, C. J. (2009) · Developmental Dynamics · doi:10.1002/dvdy.22019 · Cited by 165
“, 2000), and a constitutively active Fz2-Arrow fusion cannot transduce signaling in a dsh mutant background (Tolwinski et al., 2003).”
BackgroundMechanistic 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 180
“CK1α is an obligatory component of the β-catenin destruction complex that is recruited to the plasma membrane by Wnt-stimulated receptors 193,194 .”
Potential role of the low-density lipoprotein receptor family as mediators of cellular drug uptake
Chung, N., & Wasan, K. M. (2004) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2003.12.003 · Cited by 165
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
“This interaction recruits axin2 and disheveled to the LRP protein and frizzled receptor, respectively [12,13,14], and further inhibits the kinase activity of the b-catenin destruction complex [15].”
BackgroundAxin: A Master Scaffold for Multiple Signaling Pathways
Luo, W., & Lin, S. (2004) · Neurosignals · doi:10.1159/000076563 · Cited by 154
The role of the Wnt signalling pathway in colorectal tumorigenesis
Behrens, J. (2005) · Biochemical Society Transactions · doi:10.1042/bst0330672 · Cited by 160
Winding through the WNT pathway during cellular development and demise.
Li, F., Chong, Z. Z., & Maiese, K. (2006) · PubMed · doi:10.14670/hh-21.103 · Cited by 154
Ettenberg, S. A., Charlat, O., Daley, M., Liu, S., Vincent, K. J., Stuart, D. D., Schuller, A. G., Yuan, J., Ospina, B., Green, J., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1007428107 · Cited by 155
Tolwinski, N. S., & Wieschaus, E. (2004) · Trends in Genetics · doi:10.1016/j.tig.2004.02.003 · Cited by 151
Self-citationDKK1 Antagonizes Wnt Signaling without Promotion of LRP6 Internalization and Degradation
Semënov, M. V., Zhang, X., & He, X. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800014200 · Cited by 133
Haÿ, E., Laplantine, E., Geoffroy, V., Frain, M., Kohler, T., Müller, R., & Marie, P. J. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00349-08 · Cited by 147
“Moreover, Wnt signaling induces LRP5-axin interaction, and LRP5 transduces Wnt signals in part by binding and recruiting axin to the membrane (17, 38, 51, 55).”
BackgroundWnt 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
“Although cytosolic b-catenin levels most often positively correlate with transcriptional activity in the nucleus, there is also evidence that this increase in cytosolic b-catenin is not the only factor controlling Wnt output (Guger and Gumbiner, 2000; Staal et al., 2002; Tolwinski et al., 2003).”
BackgroundWeitzel, H. E., Illies, M. R., Byrum, C. A., Xu, R., Wikramanayake, A. H., & Ettensohn, C. A. (2004) · Development · doi:10.1242/dev.01152 · Cited by 141
“For example, X nopus and sea urchin forms of cadherins, GSK3β and LEF/TCF have been tested in overexpression studies, and in each case the homologs have similar effects (Emily-Fenouil et al., 1998; Wikramanayake et al., 1998: Logan et al., 1999; Vonica et al., 2000).”
Adamska, M., Larroux, C., Adamski, M., Green, K., Lovas, E., Koop, D., Richards, G. S., Zwafink, C., & Degnan, B. M. (2010) · Evolution & Development · doi:10.1111/j.1525-142x.2010.00435.x · Cited by 139
“The single Tcf gene of Amphimedon queenslandica encodes both the N-terminal b-catenin-binding motif (Behrens et al. 1996; Graham et al. 2000) and the HMG domain (Travis et al. 1991) (Fig.”
BackgroundPTK7/Otk interacts with Wnts and inhibits canonical Wnt signalling
Peradziryi, H., Kaplan, N., Podleschny, M., Liu, X., Wehner, P., Borchers, A., & Tolwinski, N. S. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.236 · Cited by 135
“In the canonical pathway, Axin is brought to the membrane by Arr/LRP5/6 and this step is required to inactivate the destruction complex (Tolwinski et al, 2003; Tolwinski and Wieschaus, 2001, 2004).”
BackgroundSelf-citationKinetic Responses of β-Catenin Specify the Sites of Wnt Control
Hernandez, A., Klein, A. M., & Kirschner, M. W. (2012) · Science · doi:10.1126/science.1228734 · Cited by 134
Protein phosphatase 1 regulates assembly and function of the β‐catenin degradation complex
Luo, W., Peterson, A. G., Garcia, B. A., Coombs, G. S., Kofahl, B., Heinrich, R., Shabanowitz, J., Hunt, D. F., Yost, H. J., & Virshup, D. M. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601607 · Cited by 132
“Alternatively, it has been proposed that Wnt signals lead to axin degradation, thereby removing the b-catenin degradation complex (Lee et al, 2003; Tolwinski et al, 2003).”
BackgroundThe canonical Wnt pathway in early mammalian embryogenesis and stem cell maintenance/differentiation
Wang, J., & Wynshaw-Boris, A. J. (2004) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2004.07.013 · Cited by 125
Mouse Axin and Axin2/Conductin Proteins Are Functionally Equivalent In Vivo
Chia, I. V., & Costantini, F. D. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.11.4371-4376.2005 · Cited by 121
Faunes, F., Hayward, P. C., Muñoz‐Descalzo, S., Chatterjee, S. S., Balayo, T., Trott, J., Christoforou, A., Ferrer‐Vaquer, A., Hadjantonakis, A., DasGupta, R., et al. (2013) · Development · doi:10.1242/dev.085654 · Cited by 125
“However, the levels of β-catenin might not be diagnostic of its transcriptional activity (Fagotto et al., 1997; Guger and Gumbiner, 2000; Lawrence et al., 2000; Staal et al., 2002; Tolwinski et al., 2003; Fodde and Brabletz, 2007; Hendriksen et al., 2008) and this has led to the suggestion that there is a transcriptio…”
BackgroundMolecular Pathogenesis of Hepatocellular Carcinoma
Ho, D. W., Lo, R. C., Chan, L., & Ng, I. O. (2016) · Liver Cancer · doi:10.1159/000449340 · Cited by 122
The Dawn of Developmental Signaling in the MetazoaPreprint
Richards, G. S., & Degnan, B. M. (2009) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2009.74.028 · Cited by 117
Wnt signalling and cancer stem cells
Espada, J., Blanco, M., Díaz‐Prado, S., & Médina, V. (2009) · Clinical & Translational Oncology · doi:10.1007/s12094-009-0380-4 · Cited by 116
“binding of extracellular domain of Lrp5/6 to Axin, a key component in the Gsk3b complex, indicating that the Lrp5/6 receptor is an important part of the Wnt-Fzd signalling pathway [32, 33].”
BackgroundPhosphorylation-Dependent Regulation of WNT/Beta-Catenin Signaling
Shah, K., & Kazi, J. U. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.858782 · Cited by 126
“Thus, the scaffolding member of the destruction complex, AXIN, is no longer present to form the destruction complex (45).”
BackgroundHematopoietic Stem Cell Development, Niches, and Signaling Pathways
Chotinantakul, K., & Leeanansaksiri, W. (2012) · Bone Marrow Research · doi:10.1155/2012/270425 · Cited by 114
“Specifically, Dishevelled (DVL) is phosphorylated by casein kinase Iε (CKIε), which then binds typically to FRAT and confers the assembly between Fz to DVL (Fz-DVL complex) and LRP5/6 to AXIN and FRAT (LRP5/6-AXIN-FRAT complex) [155, 156].”
BackgroundThe many roles of PTK7: A versatile regulator of cell–cell communication
Peradziryi, H., Tolwinski, N. S., & Borchers, A. (2012) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2011.12.019 · Cited by 117
Self-citationMetcalfe, C., Mendoza-Topaz, C., Mieszczanek, J., & Bienz, M. (2010) · Journal of Cell Science · doi:10.1242/jcs.067546 · Cited by 111
“This is consistent with the results from a membrane-tethered Arrow ctail, which also proved to be inactive in the embryo (Tolwinski et al., 2003).”
BackgroundResultInfluentialBrennan, K. R., González‐Sancho, J. M., Castelo‐Soccio, L. A., Howe, L. R., & Brown, A. M. C. (2004) · Oncogene · doi:10.1038/sj.onc.1207642 · Cited by 106
“The result appears to contrast with a report that a myristoylated form of the Arrow intracellular domain was unable to activate Wnt/b-catenin signaling in Drosophila (Tolwinski et al., 2003).”
ResultMizumoto, K., & Sawa, H. (2007) · Developmental Cell · doi:10.1016/j.devcel.2007.01.004 · Cited by 99
Mechanisms of Wnt signaling and control
Grainger, S. J., & Willert, K. (2018) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1422 · Cited by 103
“Aside from this central Fzd-Lrp5/6 complex, which stimulates Wnt/β-catenin signaling, several other Wnt receptors have been identified (Figure 2), including Ror1 and 2 (Receptor tyrosine kinase-like orphan receptors) and Ryk (Receptor-like tyrosine kinase), which promote alternate signaling cascades.”
BackgroundInfluentialWnt Signaling in Polycystic Kidney Disease
Benzing, T. R., Simons, M., & Walz, G. (2007) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006121355 · Cited by 100
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
“Wnt-mediated receptor activation leads to the recruitment of axin (Mao et al., 2001; Cliffe et al., 2003; Tolwinski et al., 2003; Tamai et al., 2004; Zeng et al., 2005; Bilic et al., 2007; SchwarzRomond et al., 2007b; MacDonald et al., 2008; Fiedler et al., 2011) and subsequent inhibition of GSK3 via pseudosubstrate i…”
Valvezan, A. J., Zhang, F., Diehl, J. A., & Klein, P. S. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.323337 · Cited by 100
“Several mechanisms have been proposed to explain Wnt-induced inhibition of GSK-3, including Axin degradation (19, 20) and sequestration of GSK-3 within multivesicular endosomes (21).”
BackgroundKofron, M. J., Birsoy, B., Houston, D. W., Tao, Q., Wylie, C. C., & Heasman, J. (2007) · Development · doi:10.1242/dev.02739 · Cited by 95
“LRP may bind to axin and sequester it from the -catenin-destruction complex (Nusse, 2005), or may promote its degradation, thus inactivating the -catenin-degradation complex (Mao et al., 2001; Tolwinski et al., 2003; Willert et al., 1999b).”
BackgroundLevina, E. M., Oren, M., & Ben‐Ze'ev, A. (2004) · Oncogene · doi:10.1038/sj.onc.1207587 · Cited by 94
“This process is suggested to Oncogene involve, in Drosophila, the Dsh/Dvl phosphoprotein, a crucial modulator of Wg/Wnt signaling (Cliffe et al., 2003), and is apparently independent of GSK-3b (Tolwinski et al., 2003).”
BackgroundLladó, V., Nakanishi, Y., Durán, Á., Reina‐Campos, M., Shelton, P. M., Linares, J. F., Yajima, T., Campos, A. R., Aza‐Blanc, P., Leitges, M., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.01.007 · Cited by 102
“It is well established that cell activation by Wnt results in the degradation of Axin1, which correlates with b-catenin stabilization (Li et al., 2012; Mao et al., 2001; Tolwinski et al., 2003).”
BackgroundThe various roles of ubiquitin in Wnt pathway regulation
Tauriello, D. V. F., & Maurice, M. M. (2010) · Cell Cycle · doi:10.4161/cc.9.18.13204 · Cited by 100
Role of Wnt5a in the Pathogenesis of Inflammatory Diseases
Pashirzad, M., Shafiee, M., Rahmani, F., Behnam‐Rassouli, R., Hoseinkhani, F., Ryzhikov, M., Binabaj, M. M., Parizadeh, M. R., Avan, A., & Hassanian, S. M. (2016) · Journal of Cellular Physiology · doi:10.1002/jcp.25687 · Cited by 94
“In support of the inhibitory function ofWnt5a onWnt canonical pathway, Topol et al. (2003) showed that following the activation of Ror-2 receptor,Wnt/b-catenin signaling is increased in the distal limb of Wnt5a knockout mice, suggesting that Wnt5a antagonizes the Wnt canonical pathway by promoting…”
BackgroundVital Elements of the Wnt-Frizzled Signaling Pathway in the Nervous System
Li, F., Chong, Z. Z., & Maiese, K. (2005) · Current Neurovascular Research · doi:10.2174/156720205774322557 · Cited by 93
A Nuclear Function for Armadillo/β-Catenin
Tolwinski, N. S., & Wieschaus, E. F. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020095 · Cited by 92
“Further work has pointed to the importance of controlling Axin stability in pathway activation (Salic et al. 2000; Mao et al. 2001; Lee et al. 2003; Tolwinski et al. 2003).”
Self-citationBryja, V., Schulte, G., & Arenas, E. (2006) · Cellular Signalling · doi:10.1016/j.cellsig.2006.08.011 · Cited by 91
Metadata
- Authors
- Tolwinski, N. S., Wehrli, M., Rives, A., Erdeniz, N., DiNardo, S., & Wieschaus, E.
- Affiliations
- Howard Hughes Medical Institute (US)
- Oregon Health & Science University (US)
- University of Pennsylvania (US)
- Corresponding author
- Wieschaus, Eric
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2003-03
- Volume
- 4
- Issue
- 3
- Pages
- 407-418
- ISSN
- 1534-5807 (ISSN-L)
- OpenAlex
- W2037128138
- Cited by
- 286
- References
- 45
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 7 · 2018: 7 · 2017: 14 · 2016: 10 · 2015: 8 · 2014: 9 · 2013: 11 · 2012: 18
- FWCI
- 9.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 3791 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (GM45747, PO1CA41086, F32GM20342)
- Howard Hughes Medical Institute
- National Science Foundation
- 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 › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Keywords
- Wnt signaling, Axin, GSK3β, Frizzled-2, ligand-independent signaling, Wnt receptors
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Carrier Proteins, Drosophila melanogaster, Embryo, Nonmammalian, Female, Membrane Proteins, Mutation, Proto-Oncogene Proteins, Receptors, Cell Surface, Receptors, LDL, Recombinant Fusion Proteins, Transcription Factors, Signal Transduction, Trans-Activators, Gene Expression Regulation, Developmental, Active Transport, Cell Nucleus, LDL-Receptor Related Proteins, Drosophila Proteins, Glycogen Synthase Kinase 3, Receptors, G-Protein-Coupled, Adaptor Proteins, Signal Transducing, Wnt1 Protein, Frizzled Receptors, Armadillo Domain Proteins, Low Density Lipoprotein Receptor-Related Protein-5
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