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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 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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“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]
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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 302
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 302
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
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 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).”
BackgroundHarwood, A. J. (2001) · Cell · doi:10.1016/s0092-8674(01)00412-3 · Cited by 291
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
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 293
“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 289
Gregory, C. A., Singh, H., Perry, A. S., & Prockop, D. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300373200 · Cited by 284
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 ].”
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 289
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 285
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
“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
May, P., Woldt, E., Matz, R. L., & Boucher, P. (2007) · Annals of Medicine · doi:10.1080/07853890701214881 · Cited by 276
“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 271
“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].”
BackgroundHoang, B. H., Kubo, T., Healey, J. H., Yang, R., Nathan, S. S., Kolb, E. A., Mazza, B., Meyers, P. A., & Gorlick, R. G. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-1952 · Cited by 261
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
Mohammed, M. K., Shao, C. C., Wang, J., Wei, Q., Wang, X. W., Collier, Z. J., Tang, S., Liu, H., Zhang, F., Huang, J., et al. (2016) · Genes & Diseases · doi:10.1016/j.gendis.2015.12.004 · Cited by 266
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
Le, P. N., McDermott, J. D., & Jimeno, A. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.08.005 · Cited by 257
“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 252
“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 255
“The intracellular domain of LRP5 can interact with Axin, stabilize β-catenin, and induce LEF activation (78).”
BackgroundInfluentialThe links between axin and carcinogenesis
Salahshor, S., & Woodgett, J. R. (2005) · Journal of Clinical Pathology · doi:10.1136/jcp.2003.009506 · Cited by 256
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 252
The subcellular destinations of apc proteins
Bienz, M. (2002) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm806 · Cited by 243
“The second possibility was proposed by fluorescence resonance energy transfer ( FRET ) experiment”
BackgroundLyashenko, N., Winter, M., Migliorini, D., Biechele, T. L., Moon, R. T., & Hartmann, C. (2011) · Nature Cell Biology · doi:10.1038/ncb2260 · Cited by 244
“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 .”
Gan, X., Wang, J., Xi, Y., Wu, Z., Li, Y.-P., & Li, L. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200710050 · Cited by 240
Self-citationWnt signalling: Antagonistic Dickkopfs
Zorn, A. M. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00360-8 · Cited by 238
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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