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 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.
“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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Three decades of Wnts: a personal perspective on how a scientific field developed
Nusse, R., & VARMUS, H. E. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.146 · Cited by 412 · see citing works
“Arrow/LRP is also the target of several Wnt antagonists including the protein Dickkopf, isolated by Christof Niehrs (Glinka et al , 1998; Bafico et al , 2001; Mao et al , 2001a; Semenov et al , 2001).”
InfluentialCaught up in a Wnt storm: Wnt signaling in cancer
Giles, R. H., van Es, J. H., & Clevers, H. (2003) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(03)00005-2 · Cited by 1,482 · see citing works
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Self-citationLipoprotein receptors in the nervous system
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Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and disease
Hu, L., Chen, W., Qian, A., & Li, Y.-P. (2024) · Bone Research · doi:10.1038/s41413-024-00342-8 · Cited by 359 · see citing works
“48 LRP6 is the best-studied LRP.”
Wnts as ligands: processing, secretion and reception
Mikels, A. J., & Nusse, R. (2006) · Oncogene · doi:10.1038/sj.onc.1210053 · Cited by 353 · see citing works
“Interestingly, the Axin protein, a negative regulator of Wnt signaling, can bind to the cytoplasmic tail of LRP6, providing a mechanism by which Axin is released from beta-catenin (Mao et al., 2001).”
BackgroundActivation of AXIN2 Expression by β-Catenin-T Cell Factor
Leung, J. Y., Kolligs, F. T., WU, R. T., Zhai, Y., Kuick, R. D., Hanash, S., Cho, K. R., & Fearon, E. R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200139200 · Cited by 352 · see citing works
Growth factor regulation of lens development
Lovicu, F. J., & McAvoy, J. W. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.01.020 · Cited by 350 · see citing works
“Recent studies indicate that LRP5/6, when part of the Wnt ligand– receptor complex, removes axin from the h-catenin destruction complex, resulting in stabilization of h-catenin, its translocation to the nucleus, and subsequent association with the TCF/Lef family of transcription factors (Mao et al., 2001; Zorn, 2001).”
BackgroundDkk2 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 341 · see citing works
“Through mechanisms that are not well characterized but may involve interactions between LRP5/6 and axi”
BackgroundSelf-citationNusse, R. (2003) · Development · doi:10.1242/dev.00821 · Cited by 337 · see citing works
The new bone biology: Pathologic, molecular, and clinical correlates
Cohen, M. M. (2006) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.31368 · Cited by 332 · see citing works
WNT signalling and haematopoiesis: a WNT–WNT situation
Staal, F. J. T., & Clevers, H. C. (2005) · Nature reviews. Immunology · doi:10.1038/nri1529 · Cited by 330 · see citing works
“fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4040">LRP6”
Wharton, K. A. (2003) · Developmental Biology · doi:10.1006/dbio.2002.0869 · Cited by 315 · see citing works
Wnt/β-catenin signalling: from plasma membrane to nucleus
Kim, W., Kim, M., & Jho, E. (2013) · Biochemical Journal · doi:10.1042/bj20121284 · Cited by 310 · see citing works
Noncanonical Wnt Signaling through G Protein-Linked PKCδ Activation Promotes Bone Formation
Tu, X., Joeng, K. S., Nakayama, K., Nakayama, K., Rajagopal, J., Carroll, T. J., McMahon, A. P., & Long, F. (2007) · Developmental Cell · doi:10.1016/j.devcel.2006.11.003 · Cited by 314 · see citing works
“…Nusse, 1998), Wnt Developm binding to Frizzled receptors and the low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) in vertebrates (Mao et al., 2001b; Pinson et al., 2000; Tamai et al., 2000) stabilizes b-catenin and thereby activates transcription of downstream target genes via…”
BackgroundMethodHuman placental trophoblast invasion and differentiation: a particular focus on Wnt signaling
Knöfler, M., & Pollheimer, J. (2013) · Frontiers in Genetics · doi:10.3389/fgene.2013.00190 · Cited by 303 · see citing works
Regulation of Transmembrane Signaling by Phase Separation
Case, L. B., Ditlev, J. A., & Rosen, M. K. (2019) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-052118-115534 · Cited by 304 · see citing works
“Canonical Wnt signaling Wnts are secreted proteins that bind to the extracellular domain of Frizzled (Fz) and LRP5/6 transmembrane receptors to regulate many aspects of development and adult homeostasis (137).”
BackgroundInfluentialWnt 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 302 · see citing works
“Wnt stimulation or LRP overexpression decrease Axin protein levels in several systems (Kofron et al. 2007; Mao et al. 2001; Tolwinski et al. 2003), which should compromise the destruction complex.”
BackgroundMonga, S. P., Mars, W. M., Pediaditakis, P., Bell, A. W., Mulé, K., Bowen, W. C., Wang, X., Zarnegar, R., & Michalopoulos, G. K. (2002) · PubMed · Cited by 298 · see citing works
PTH and PTHrP signaling in osteoblasts
Datta, N. S., & Abou‐Samra, A. (2009) · Cellular Signalling · doi:10.1016/j.cellsig.2009.02.012 · Cited by 296 · see citing works
Caveolin Is Necessary for Wnt-3a-Dependent Internalization of LRP6 and Accumulation of β-Catenin
Yamamoto, H., Komekado, H., & Kikuchi, A. (2006) · Developmental Cell · doi:10.1016/j.devcel.2006.07.003 · Cited by 296 · see citing works
Wg/Wnt Signal Can Be Transmitted through Arrow/LRP5,6 and Axin Independently of Zw3/Gsk3β Activity
Tolwinski, N. S., Wehrli, M., Rives, A., Erdeniz, N., DiNardo, S., & Wieschaus, E. (2003) · Developmental Cell · doi:10.1016/s1534-5807(03)00063-7 · Cited by 286 · see citing works
The 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 291 · see citing works
“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).”
BackgroundHarwood, A. J. (2001) · Cell · doi:10.1016/s0092-8674(01)00412-3 · Cited by 291 · see citing works
A 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 · see citing works
Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights
Patel, S., Alam, A., Pant, R., & Chattopadhyay, S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02872 · Cited by 284 · see citing works
“Research studies have identified Axin as a protein that interacts with the intracellular domain of LRP5/6 through five phosphorylated PPPSP motifs in the cytoplasmic tail of LRP (18, 19).”
BackgroundInfluentialMultiplicity 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 285 · see citing works
Gregory, C. A., Singh, H., Perry, A. S., & Prockop, D. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300373200 · Cited by 283 · see citing works
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 · see citing works
“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 ].”
BackgroundR-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6
Binnerts, M. E., Kim, K.-A., Bright, J. M., Patel, S. M., Tran, K., Zhou, M., Leung, J., Liu, Y., Lomas, W. E., Dixon, M., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702305104 · Cited by 282 · see citing works
Wnt10b Increases Postnatal Bone Formation by Enhancing Osteoblast Differentiation
Bennett, C. N., Ouyang, H., Li, Y., Zeng, Q., Gerin, I., Sousa, K. M., Lane, T. F., Krishnan, V., Hankenson, K. D., & MacDougald, O. A. (2007) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.070810 · Cited by 282 · see citing works
Heads or tails: Wnts and anterior–posterior patterning
Yamaguchi, T. P. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00417-1 · Cited by 276 · see citing works
“Recent data indicate that the intracellular domain of LRP5 can bind Axin [44] providing a potential mechanism for how the ligand–receptor membrane complex interacts with the cytoplasmic β-catenin-containing multiprotein complex.”
Miller, J. R. (2001) · Genome biology · doi:10.1186/gb-2001-3-1-reviews3001 · Cited by 275 · see citing works
May, P., Woldt, E., Matz, R. L., & Boucher, P. (2007) · Annals of Medicine · doi:10.1080/07853890701214881 · Cited by 267 · see citing works
“The structural organization of the extracellular domain of MEGF7/LRP4 resembles that of Lrp5 and Lrp6, two more distantly related members of the LDL receptor superfamily that are likely to function as coreceptors for the Wnt proteins (72,73).”
BackgroundWnt Signalling in Implantation, Decidualisation and Placental Differentiation – Review
Sonderegger, S., Pollheimer, J., & Knöfler, M. (2010) · Placenta · doi:10.1016/j.placenta.2010.07.011 · Cited by 265 · see citing works
“Moreover Axin, a key negative regulator ofbcateninstability, translocates to thecytoplasmatic tailof LRPcatalysed by CK1g- and GSK-3b-dependent phosphorylation of the FZD coreceptor [19,20].”
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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 259 · see citing works
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Self-citationTumor formation by genetic mutations in the components of the Wnt signaling pathway
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Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28
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“AXIN also interacts with the plasma membrane, possibly by binding the cytoplasmic tail of LRP5/6 (Mao et al., 2001).”
BackgroundInfluentialAi, M., Holmen, S. L., Hul, W. V., Williams, B. O., & Warman, M. L. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.12.4946-4955.2005 · Cited by 253 · see citing works
“Additionally, yeast two-hybrid experiments identified Axin, a cytoplasmic component of the canonical signaling cascade, as being an LRP5-interacting partner (24).”
BackgroundWnt and the Wnt signaling pathway in bone development and disease
Wang, Y. (2014) · Frontiers in bioscience · doi:10.2741/4214 · Cited by 250 · see citing works
“The intracellular domain of LRP5 can interact with Axin, stabilize β-catenin, and induce LEF activation (78).”
BackgroundInfluentialThe links between axin and carcinogenesis
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A Wnt- and β-catenin-dependent pathway for mammalian cardiac myogenesis
Nakamura, T., Sano, M., Songyang, Z., & Schneider, M. D. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0935626100 · Cited by 248 · see citing works
The subcellular destinations of apc proteins
Bienz, M. (2002) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm806 · Cited by 243 · see citing works
“The second possibility was proposed by fluorescence resonance energy transfer ( FRET ) experiment”
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“Ligand-binding results in inhibition of the destruction complex composed out of Adenomatosis polyposis coli, Axin, Casein kinase 1 α (CK1 α ) and the Glycogen synthase kinase 3 β (GSK3 β ) 13, 14 .”
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Self-citationWnt signalling: Antagonistic Dickkopfs
Zorn, A. M. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00360-8 · Cited by 238 · see citing works
- 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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