DOI: 10.1091/mbc.e08-12-1252. The First Propeller Domain of LRP6 Regulates Sensitivity to DKK1

The First Propeller Domain of LRP6 Regulates Sensitivity to DKK1

10.1091/mbc.e08-12-1252

Crossref journal-article

American Society for Cell Biology (ASCB)

Molecular Biology of the Cell (1076)

Abstract

The Wnt coreceptor LRP6 is required for canonical Wnt signaling. To understand the molecular regulation of LRP6 function, we generated a series of monoclonal antibodies against the extra cellular domain (ECD) of LRP6 and selected a high-affinity mAb (mAb135) that recognizes cell surface expression of endogenous LRP6. mAb135 enhanced Wnt dependent TCF reporter activation and antagonized DKK1 dependent inhibition of Wnt3A signaling, suggesting a role in modulation of LRP6 function. Detailed analysis of LRP6 domain mutants identified Ser 243 in the first propeller domain of LRP6 as a critical residue for mAb135 binding, implicating this domain in regulating the sensitivity of LRP6 to DKK1. In agreement with this notion, mAb135 directly disrupted the interaction of DKK1 with recombinant ECD LRP6 and a truncated form of the LRP6 ECD containing only repeats 1 and 2. Finally, we found that mAb135 completely protected LRP6 from DKK1 dependent internalization. Together, these results identify the first propeller domain as a novel regulatory domain for DKK1 binding to LRP6 and show that mAb against the first propeller domain of LRP6 can be used to modulate this interaction.

Bibliography

Binnerts, M. E., Tomasevic, N., Bright, J. M., Leung, J., Ahn, V. E., Kim, K.-A., Zhan, X., Liu, S., Yonkovich, S., Williams, J., Zhou, M., Gros, D., Dixon, M., Korver, W., Weis, W. I., & Abo, A. (2009). The First Propeller Domain of LRP6 Regulates Sensitivity to DKK1. Molecular Biology of the Cell, 20(15), 3552â3560.

Authors 16

Minke E. Binnerts (first)
Nenad Tomasevic (additional)
Jessica M. Bright (additional)
John Leung (additional)
Victoria E. Ahn (additional)
Kyung-Ah Kim (additional)
Xiaoming Zhan (additional)
Shouchun Liu (additional)
Shirlee Yonkovich (additional)
Jason Williams (additional)
Mei Zhou (additional)
Delphine Gros (additional)
Melissa Dixon (additional)
Wouter Korver (additional)
William I. Weis (additional)
Arie Abo (additional)

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Dates

Type	When
Created	16 years, 3 months ago (May 28, 2009, 8:44 p.m.)
Deposited	3 years, 10 months ago (Oct. 6, 2021, 6:13 a.m.)
Indexed	4 months, 3 weeks ago (April 11, 2025, 8:05 a.m.)
Issued	16 years, 1 month ago (Aug. 1, 2009)
Published	16 years, 1 month ago (Aug. 1, 2009)
Published Print	16 years, 1 month ago (Aug. 1, 2009)

Funders 0

None

BibTeX

@article{Binnerts_2009, title={The First Propeller Domain of LRP6 Regulates Sensitivity to DKK1}, volume={20}, ISSN={1939-4586}, url={http://dx.doi.org/10.1091/mbc.e08-12-1252}, DOI={10.1091/mbc.e08-12-1252}, number={15}, journal={Molecular Biology of the Cell}, publisher={American Society for Cell Biology (ASCB)}, author={Binnerts, Minke E. and Tomasevic, Nenad and Bright, Jessica M. and Leung, John and Ahn, Victoria E. and Kim, Kyung-Ah and Zhan, Xiaoming and Liu, Shouchun and Yonkovich, Shirlee and Williams, Jason and Zhou, Mei and Gros, Delphine and Dixon, Melissa and Korver, Wouter and Weis, William I. and Abo, Arie}, editor={Chernoff, Jonathan}, year={2009}, month=aug, pages={3552–3560} }

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