The first propeller domain of LRP6 regulates sensitivity to DKK1

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3552-3560
Number of pages9
JournalMolecular Biology of the Cell
Volume20
Issue number15
DOIs
StatePublished - Aug 1 2009

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Monoclonal Antibodies

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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Binnerts, M. E., Tomasevic, N., Bright, J. M., Leung, J., Ahn, V. E., Kim, K. A., ... Abo, A. (2009). The first propeller domain of LRP6 regulates sensitivity to DKK1. Molecular Biology of the Cell, 20(15), 3552-3560. https://doi.org/10.1091/mbc.E08-12-1252

The first propeller domain of LRP6 regulates sensitivity to DKK1. / Binnerts, Minke E.; Tomasevic, Nenad; Bright, Jessica M.; Leung, John; Ahn, Victoria E.; Kim, Kyung Ah; Zhan, Xiaoming; Liu, Shouchun; Yonkovich, Shirlee; Williams, Jason; Zhou, Mei; Gros, Delphine; Dixon, Melissa; Korver, Wouter; Weis, William I.; Abo, Arie.

In: Molecular Biology of the Cell, Vol. 20, No. 15, 01.08.2009, p. 3552-3560.

Research output: Contribution to journalArticle

Binnerts, ME, Tomasevic, N, Bright, JM, Leung, J, Ahn, VE, Kim, KA, Zhan, X, Liu, S, Yonkovich, S, Williams, J, Zhou, M, Gros, D, Dixon, M, Korver, W, Weis, WI & Abo, A 2009, 'The first propeller domain of LRP6 regulates sensitivity to DKK1', Molecular Biology of the Cell, vol. 20, no. 15, pp. 3552-3560. https://doi.org/10.1091/mbc.E08-12-1252
Binnerts ME, Tomasevic N, Bright JM, Leung J, Ahn VE, Kim KA et al. The first propeller domain of LRP6 regulates sensitivity to DKK1. Molecular Biology of the Cell. 2009 Aug 1;20(15):3552-3560. https://doi.org/10.1091/mbc.E08-12-1252
Binnerts, Minke E. ; Tomasevic, Nenad ; Bright, Jessica M. ; Leung, John ; Ahn, Victoria E. ; Kim, Kyung Ah ; Zhan, Xiaoming ; Liu, Shouchun ; Yonkovich, Shirlee ; Williams, Jason ; Zhou, Mei ; Gros, Delphine ; Dixon, Melissa ; Korver, Wouter ; Weis, William I. ; Abo, Arie. / The first propeller domain of LRP6 regulates sensitivity to DKK1. In: Molecular Biology of the Cell. 2009 ; Vol. 20, No. 15. pp. 3552-3560.
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