Analysis of endogenous LRP6 function reveals a novel feedback mechanism by which Wnt negatively regulates its receptor
Open accessAbstract
The canonical Wnt pathway plays a crucial role in embryonic development, and its deregulation is involved in human diseases. The LRP6 single-span transmembrane coreceptor is essential for transmission of canonical Wnt signaling. However, due to the lack of immunological reagents, our understanding of LRP6 structure and function has relied on studies involving its overexpression, and regulation of the endogenous receptor by the Wnt ligand has remained unexplored. Using a highly sensitive and specific antibody to LRP6, we demonstrate that the endogenous receptor is modified by N-glycosylation and is phosphorylated in response to Wnt stimulation in a sustained yet ligand-dependent manner. Moreover, following triggering by Wnt, endogenous LRP6 is internalized and recycled back to the cellular membrane within hours of the initial stimulus. Finally, we have identified a novel feedback mechanism by which Wnt, acting through beta-catenin, negatively regulates LRP6 at the mRNA level. Together, these findings contribute significantly to our understanding of LRP6 function and uncover a new level of regulation of Wnt signaling. In light of the direct role that the Wnt pathway plays in human bone diseases and malignancies, our findings may support the development of novel therapeutic approaches that target Wnt signaling through LRP6.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Some studies reported pathway activation without detection of nuclear β-catenin, while others described negative feedback loops that activate pathway repressors or suppress pathway activators in Wnt-signaling.
“While some studies reported pathway activation without detection of nuclear β-catenin, others described negative feedback loops that activate pathway repressors or suppress pathway activators in Wnt-signaling (33).”
From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [33]
The Discussion (page not provided) identifies a Wnt-driven negative feedback mechanism that reduces expression of LRP6, a pathway-activating receptor. The paper does not report pathway activation without detection of nuclear β-catenin; it describes β-catenin translocation to the nucleus during canonical signaling. It also does not show activation of a pathway repressor. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Wnt Signaling: Multiple Pathways, Multiple Receptors, and Multiple Transcription Factors
Gordon, M. D., & Nusse, R. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.r600015200 · Cited by 1,333 · see citing works
Mao, J., Wang, J., Liu, B., Pan, W., Farr, G. H., Flynn, C., Yuan, H., Takada, S., Kimelman, D., Li, L., et al. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00224-6 · Cited by 839 · cited 2× · see citing works
“Evidence for LRP6-axin interaction has been provided by studies involving their cotransfection in model cells (20, 22).”
BackgroundMethodNovel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow
Bafico, A., Liu, G., Yaniv, A., Gazit, A., & Aaronson, S. A. (2001) · Nature Cell Biology · doi:10.1038/35083081 · Cited by 772 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 2
- [30]30. Russell, D. W., T. Yamamoto, W. J. Schneider, C. J. Slaughter, M. S. Brown, and J. L. Goldstein. 1983. cDNA cloning of the bovine low density lipoprotein receptor: feedback regulation of a receptor mRNA. Proc. Natl. Acad. Sci. USA 80: 7501-7505.
- [37]37. Wiley, H. S. 2003. Trafficking of the ErbB receptors and its influence on signaling. Exp. Cell Res. 284: 78-88.
Cited by
Sorted by citations
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 · see citing works
Lachenmayer, A., Alsinet, C., Savic, R., Cabellos, L., Toffanin, S., Hoshida, Y., Villanueva, A., Minguez, B., Newell, P., Tsai, H.-W., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2322 · Cited by 306 · see citing works
Kogan, Y., Halevi-Tobias, K. E., Hochman, G., Baczmanska, A. K., Leyns, L., & Agur, Z. (2012) · Biochemical Journal · doi:10.1042/bj20111887 · Cited by 39 · see citing works
Exploring the mechanistic and temporal regulation of LRP6 endocytosis in canonical WNT signaling
Haack, F., Budde, K., & Uhrmacher, A. M. (2020) · Journal of Cell Science · doi:10.1242/jcs.243675 · Cited by 18 · see citing works
- Authors
- Khan, Z., Vijayakumar, S., de la Torre, T. V., Rotolo, S., & Bafico, A.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029
- Corresponding author
- Bafico, Anna
- ORCID
- Khan, Zahid
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2007-10-01
- Volume
- 27
- Issue
- 20
- Pages
- 7291-7301
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2168903
- OpenAlex
- W2106281886
- Cited by
- 73
- References
- 3
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 1 · 2022: 2 · 2021: 5 · 2020: 4 · 2019: 3 · 2018: 2 · 2017: 7 · 2016: 2 · 2015: 2 · 2014: 2 · 2013: 1 · 2012: 7
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- Breast Cancer Research Foundation
- National Institutes of Health (1r01ca121119-01a1)
- National Cancer Institute (R01 CA121119, 1 R01 CA121119-01A1)
- 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 › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- LRP6, Wnt/β-catenin signaling, N-glycosylation, receptor phosphorylation, β-catenin, feedback mechanisms
- MeSH terms
- Animals, Antibodies, Monoclonal, Cell Line, Humans, Ligands, Protein Processing, Post-Translational, Receptors, LDL, Repressor Proteins, Transcription, Genetic, Signal Transduction, Dimerization, Feedback, Physiological, Wnt Proteins, beta Catenin, Mice, Axin Protein, Low Density Lipoprotein Receptor-Related Protein-6, Wnt3 Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
