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Low-Density Lipoprotein Receptor-Related Protein-5 Binds to Axin and Regulates the Canonical Wnt Signaling Pathway
Open accessAbstract
To understand how the Wnt coreceptor LRP-5 is involved in transducing the canonical Wnt signals, we identified Axin as a protein that interacts with the intracellular domain of LRP-5. LRP-5, when expressed in fibroblast cells, showed no effect on the canonical Wnt signaling pathway by itself, but acted synergistically with Wnt. In contrast, LRP-5 mutants lacking the extracellular domain functioned as constitutively active forms that bind Axin and that induce LEF-1 activation by destabilizing Axin and stabilizing beta-catenin. Addition of Wnt caused the translocation of Axin to the membrane and enhanced the interaction between Axin and LRP-5. In addition, the LRP-5 sequences involved in interactions with Axin are required for LEF-1 activation. Thus, we conclude that the binding of Axin to LRP-5 is an important part of the Wnt signal transduction pathway.
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“The canonical Wnt signalling pathway is mainly involved in cell proliferation and survival in vital biological processes, including organogenesis and embryogenesis.1,2”
From Canonical Wnt pathway and the LDL receptor superfamily in neuronal cholesterol homeostasis and function (2024) · cites this paper as [1]
In the citing paper
“The binding of Wnt to the Fz/LRP5/6 complex induces the membrane translocation of a key negative regulator of signaling Axin, which binds to a conserved sequence in the cytoplasmic tail of LRP5/6.27,28”
From Wnt signal transduction pathways (2008) · cites this paper as [27]
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Why Is Wnt/β-Catenin Not Yet Targeted in Routine Cancer Care?
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Axin and the Axin/Arrow-binding protein DCAP mediate glucose–glycogen metabolism
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The S-G2 phase enriched β-catenin/TCF complex ensures cell survival and cell cycle progression
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“…of Dishevelled and Axin through the Frizzled–LRP5 or Frizzled–LRP6 receptor complex reduces the availability of the cytoplasmic destruction complex and results in the accumulation of cytosolic b-catenin (Mao et al., 2001; Zeng et al., 2005; Bilic et al., 2007; Li et al., 2012; Kim et al., 2013).”
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“Binding of a Wnt ligand to a Frizzled and LRP5/6 co-receptor (Mao et al., 2001; Tamai et al., 2000) leads to inactivation of the cytoplasmic Axin/APC/GSK-3h complex and stabilization of hcatenin.”
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“Thus axin is no longer available as scaffold protein, resulting in inactivation of the destruction complex [13, 14].”
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Parveen, N., Hussain, M. U., Pandith, A. A., & Mudassar, S. (2010) · Medical Oncology · doi:10.1007/s12032-010-9722-x · Cited by 20
“In Wnt signaling, axin binds to many components in the pathway, including the Wnt coreceptor LRP (low-density lipoprotein-related protein receptor) [40–42], Dishevelled or Dvl [22, 23], tumor suppressor adenomatous polyposis coli (APC), GSK-3b, b-catenin [43–45], casein kinases [46], protein phosphatase 2A (PP2A) [20]…”
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Dual Roles for Membrane Association of Drosophila Axin in Wnt Signaling
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“%) rs14128489 Wnt3A 0.0204 8.65 NA NA NA NA rs14524076 CHP 0.0075 3.62 NA NA NA NA TW (g) rs14552691 DAAM1 0.0286 2.35 −11.36 (5.04) 0.0244 −15.60 (5.86) 0.0079 TW (”
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“Ligation induces a conformational change in the receptors and by a currently unclear mechanism, recruits, and activates GSK-3 β and CK1 γ [80 – 82].”
Phosphorylation of β-catenin results in lack of β-catenin signaling in melanoma
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“Certain Wnt molecules, mainly Wnt1, Wnt2, Wnt3, Wnt3a and Wnt8 bind to Frizzled/LRP (low-density lipoprotein receptor-related protein) receptors which results in the inhibition of the APC-Axin-GSK-3β complex by activation of Dishevelled (4) and by recruitment of Axin to the plasma membrane (5).”
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“βTrcp transfers the ubiquitin chain to the β-catenin and ubiquitinated β-catenin degrades via the ubiquitin proteasome-mediated pathway [18, 21].”
BackgroundWingless Signaling: An Axin to Grind
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“[12] have shown that mouse Axin interacts with mouse LRP5, an LDL receptor-related protein which, together with a transmembrane protein of the Frizzled (Fz) class, forms the receptor for Wnt ligand.”
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“Two kinases activate the Wnt co-receptor LRP Within canonical Wnt/b-catenin signaling, LRP6 serves as docking station for Axin molecules upon Wnt stimulation((13)) and thereby prevents Axin from participating in b-catenin degradation.”
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“This co‐cluster of proteins (LRP5/6, frizzled and Disheveled (Dsh/Dvl)) recruit Axin and GSK3 complex to form the destruction complex, which is key in regulating the stability of β‐ catenin (Dajani et al., 2003; He et al., 2004; Mao et al., 2001).”
BackgroundSerpinB3: A Multifaceted Player in Health and Disease—Review and Future Perspectives
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“When phosphorylated, axin is recruited to the cytoplasmic tail of LRP-6 and prevents β -catenin phosphorylation and proteasomal degradation, leading to its accumulation in the cytoplasm and subsequent translocation to the nucleus [38].”
BackgroundModulation of β-Catenin Signaling by Glucagon Receptor Activation
Ke, J., Zhang, C., Harikumar, K. G., Diegel, C. R., Wang, L., Mowry, L. E., Miller, L. J., Williams, B. O., & Xu, H. E. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033676 · Cited by 16
“Lrp5 extracellular domain (ECD) [21,22].”
Nucleo-cytoplasmic shuttling of APC can maximize β‐catenin/TCF concentration
Schmitz, Y., Olaf Wolkenhauer, A., & Rateitschak, K. (2011) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2011.03.018 · Cited by 16
“Upon binding of Wnt ligands to their receptors Frizzled (Bhanot et al., 1996) and LRP5/6 (Mao et al., 2001), the pathway is activated (Fig.”
BackgroundBaldwin, A. T., Clemons, A. M., & Phillips, B. T. (2016) · Journal of Cell Science · doi:10.1242/jcs.175802 · Cited by 16
“…inactivation of β-catenin phosphorylation mediating destruction complex inactivation or dissociation, whereas a recent model proposes that the complex remains intact, although inactivated, during signal transduction (Lee et al., 2003; Li et al., 2012;Mao et al., 2001; Taelman et al., 2010).”
BackgroundScope of Wnt signaling in the precise diagnosis and treatment of breast cancer
Patel, D. K., Kesharwani, R., Verma, A., Al-Abbasi, F. A., Anwar, F., & Kumar, V. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103597 · Cited by 15
Natraj, P., Rajan, P., Jeon, Y.-A., Kim, S. S., & Lee, Y. J. (2023) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c03559 · Cited by 15
Beagle, B. R., Mi, K., & Johnson, G. V. W. (2009) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22318 · Cited by 15
“Phosphorylation creates a binding site for axin thereby promoting recruitment of axin to the plasma membrane [Mao et al., 2001; Tamai et al., 2004; Zeng et al., 2005].”
Backgroundβ-catenin relieves I-mfa-mediated suppression of LEF-1 in mammalian cells
Pan, W., Jia, Y., Huang, T., Wang, J., Tao, D.-L., Gan, X., & Li, L. (2006) · Journal of Cell Science · doi:10.1242/jcs.03257 · Cited by 15
“Wnt3a-containing conditioned medium was prepared as previously described (Mao et al., 2001).”
MethodSelf-citationSchneider, P. N., Slusarski, D. C., & Houston, D. W. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044096 · Cited by 15
“Although Axin degradation is a long-term result of membrane localization [10,39], a subset of Axin must dissociate from this membrane complex to rapidly reassemble cytoplasmic b-catenin degradation complexes.”
BackgroundAntagonists of LRP6 regulate PTH‐induced cAMP generation
Shi, C., Li, J., Wang, W., Cao, W., Cao, X., & Wan, M. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2011.06226.x · Cited by 15
Menon, N. A., Kumar, C. D., Ramachandran, P., Blaize, B., Gautam, M., Cordani, M., & Kumar, L. D. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.177137 · Cited by 14
YI, N., Liao, Q.-P., LI, Z.-H., Xie, B.-J., HU, Y.-H., Yi, W., & Liu, M. (2013) · Oncology Letters · doi:10.3892/ol.2013.1439 · Cited by 14
“The dephosphorylated form of β ‑catenin has been shown to have significant effects on the Wnt signaling pathway (18,19).”
Effect of Klotho protein during porcine oocyte maturation via Wnt signaling
Kim, E. H., Taweechaipaisankul, A., Ridlo, M. R., Kim, G. A., & Lee, B. C. (2020) · Aging · doi:10.18632/aging.104002 · Cited by 14
Zhao, G., Kim, K., Zheng, Z., Oh, Y., Yoo, D., Lee, M., Chung, K. Y., Roh, M. R., & Jin, Z. (2020) · Oncology Letters · doi:10.3892/ol.2020.11324 · Cited by 14
“β-catenin is subsequently protected from the degradation process and further involved in the transcription of Wnt target genes (23,24).”
BackgroundFeng, S., Liu, J., Hailiang, L., Wen, J., Zhao, Y., Li, X., Lu, G., Gao, P., & Zeng, X. (2021) · Translational Oncology · doi:10.1016/j.tranon.2021.101124 · Cited by 14
Yamaguchi, Y., Ogura, S., Ishida, M., Karasawa, M., & Takada, S. (2005) · Developmental Dynamics · doi:10.1002/dvdy.20348 · Cited by 14
Self-citationReducing Oxidative Stress and Enhancing Neurovascular Longevity During Diabetes Mellitus
Maiese, K., Chong, Z. Z., & Li, F. (2009) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780195326697.003.0022 · Cited by 14
Smargiassi, A., Bertacchini, J., Checchi, M., Potì, F., Tenedini, E., Montosi, G., Magarò, M. S., Amore, E., Cavani, F., Ferretti, M., et al. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.110817 · Cited by 13
Ciliary membrane, localised lipid modification and cilia function
Dutta, P., & Ray, K. (2022) · Journal of Cellular Physiology · doi:10.1002/jcp.30787 · Cited by 12
Trybek, G., Jaroń, A., Trybek, G., Rutkowska, M., Markowska, A., Chmielowiec, K., Chmielowiec, J., & Grzywacz, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241813889 · Cited by 13
“The protein produced in individuals with the C1966T mutation lacks the C-terminal domain responsible for oligomerization and interaction with other proteins [42,82,83].”
BackgroundThe Role of Sclerostin in Rheumatic Diseases: A Review
Jaśkiewicz, Ł., Chmielewski, G., Kuna, J., Stompór, T. P., & Krajewska–Włodarczyk, M. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12196248 · Cited by 13
“Additionally, Dishevelled (Dvl) protein [34] and axin [35] bind to the cytoplasmic parts of the Frizzled receptor and LRP co-receptor, respectively.”
It takes more than two to tango: Dishevelled polymerization and Wnt signaling
Roberts, D. M., Slep, K. C., & Peifer, M. A. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb0607-463 · Cited by 13
Puca, A., Russo, G. M., & Giordano, A. (2012) · Oncotarget · doi:10.18632/oncotarget.472 · Cited by 13
“com/oncotarget megakaryocytopoiesis and thrombopoiesis (GM-CSF), (G-CSF) granulocyte-CSF sustains and induces the proliferation of myeloid lineages, and (EPO) erythropoietin primarily affects expansion and differentiation of the erythroid lineage, however, the identity of cytokines promoting the self-renewal of hemato…”
BackgroundThe WNT signaling pathway and its role in human solid tumors
Thorstensen, L., & Lothe, R. A. (2011) · Atlas of Genetics and Cytogenetics in Oncology and Haematology · doi:10.4267/2042/37975 · Cited by 14
“As outlined above, GSK-3β phosphorylates primed β-catenin prior to proteasome degradation, and it phosphorylates Axin and APC and enhances their interaction with β-catenin.”
InfluentialWnt/β‐catenin‐mediated transcriptional regulation
Parker, D. S., Blauwkamp, T. A., & Cadigan, K. M. (2007) · Advances in developmental biology · doi:10.1016/s1574-3349(06)17001-5 · Cited by 14
The role of Wnt signaling in the development of the epiblast and axial progenitors
Schnirman, R. E., Kuo, S., Kelly, R. C., & Yamaguchi, T. P. (2023) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2023.01.010 · Cited by 12
Wnt signalosomes: What we know that we do not know
Hartmann, H. A., Siddiqui, G. S., Bryant, J. M., Robbins, D. J., Weiss, V. L., Ahmed, Y. F., & Lee, E. N. (2024) · BioEssays · doi:10.1002/bies.202400110 · Cited by 12
“Subsequently, LRP6 interacts with Axin [22,23] via its phosphorylated PPPSPxS motifs, [24] resulting in a positive feedback loop.”
Gammons, M. V. R., Franco-Echevarría, E., Li, T., Rutherford, T. J., Renko, M., Batters, C., & Bienz, M. (2025) · Nature Communications · doi:10.1038/s41467-025-59984-9 · Cited by 13
“Western blots for IP experiments need to be quantified.”
Targeting Wnt-Frizzled signaling in cardiovascular diseases
Pandey, S., & Chandravati, C. (2013) · Molecular Biology Reports · doi:10.1007/s11033-013-2710-4 · Cited by 12
Lin, I., Wei, A., Awamleh, Z., Singh, M., Ning, A., Herrera, A., REACH Biobank and Registry, Russell, B. E., Weksberg, R., & Arboleda, V. A. (2023) · JCI Insight · doi:10.1172/jci.insight.167744 · Cited by 14
Membrane Bound GSK-3 Activates Wnt Signaling through Disheveled and Arrow
Mannava, A. G., & Tolwinski, N. S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0121879 · Cited by 12
Dickkopf1 - A New Player in Modelling the Wnt Pathway
Pedersen, L., Jensen, M. H., & Krishna, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0025550 · Cited by 12
“At the cell membrane Axin is phosphorylated by GSK3b and then degraded [26,27].”
BackgroundHeterozygote loss‐of‐function variants in the LRP5 gene cause familial exudative vitreoretinopathy
Zhao, R., Wang, S., Zhao, P., Dai, E., Zhang, X., Li, P., He, Y., Yang, M., Li, S., & Yang, Z. (2022) · Clinical and Experimental Ophthalmology · doi:10.1111/ceo.14037 · Cited by 12
Metadata
- Authors
- Mao, J., Wang, J., Liu, B., Pan, W., Farr, G. H., Flynn, C., Yuan, H., Takada, S., Kimelman, D., Li, L., & Wu, D.
- Affiliations
- University of Connecticut (US)
- Chinese Academy of Sciences (CN)
- University of Washington (US)
- University of Rochester Medicine (US)
- Setsunan University (JP)
- Corresponding author
- Wu, Dianqing
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2001-04
- Volume
- 7
- Issue
- 4
- Pages
- 801-809
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2152769008
- Cited by
- 839
- References
- 32
- Citations by year
- 2026: 1 · 2025: 15 · 2024: 20 · 2023: 23 · 2022: 25 · 2021: 21 · 2020: 25 · 2019: 25 · 2018: 25 · 2017: 27 · 2016: 23 · 2015: 30 · 2014: 37 · 2013: 46 · 2012: 40
- FWCI
- 17.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r29gm053162-04)
- National Cancer Institute (R01CA085420, CA85420)
- National Institute of General Medical Sciences (GM53162, GM54167)
- 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 › Hedgehog Signaling Pathway Studies
- Keywords
- low-density lipoprotein receptor-related protein 5, Axin, Wnt/β-catenin signaling, β-catenin stabilization, protein-protein interaction
- MeSH terms
- Amino Acid Sequence, Animals, Mammals, Molecular Sequence Data, Protein Binding, Proteins, Proto-Oncogene Proteins, Receptors, LDL, Repressor Proteins, Signal Transduction, Gene Expression, Mutagenesis, 3T3 Cells, Protein Structure, Tertiary, Calcium-Calmodulin-Dependent Protein Kinases, COS Cells, LDL-Receptor Related Proteins, Zebrafish Proteins, Glycogen Synthase Kinase 3, Wnt Proteins, Mice, Axin Protein, Low Density Lipoprotein Receptor-Related Protein-5
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