R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6

Minke E. Binnerts, Kyung Ah Kim, Jessica M. Bright, Sejal M. Patel, Karolyn Tran, Mei Zhou, John M. Leung, Yi Liu, Woodrow E. Lomas, Melissa Dixon, Sophie A. Hazell, Marie Wagle, Wen Sheng Nie, Nenad Tomasevic, Jason Williams, Xiaoming Zhan, Michael D. Levy, Walter D. Funk, Arie Abo

Research output: Contribution to journalArticle

193 Scopus citations

Abstract

The R-Spondin (RSpo) family of secreted proteins act as potent activators of the Wnt/β-catenin signaling pathway. We have previously shown that RSpo proteins can induce proliferative effects on the gastrointestinal epithelium in mice. Here we provide a mechanism whereby RSpo1 regulates cellular responsiveness to Wnt ligands by modulating the cell-surface levels of the coreceptor LRP6. We show that RSpo1 activity critically depends on the presence of canonical Wnt ligands and LRP6. Although RSpo1 does not directly activate LRP6, it interferes with DKK1/Kremen-mediated internalization of LRP6 through an interaction with Kremen, resulting in increased LRP6 levels on the cell surface. Our results support a model in which RSpo1 relieves the inhibition DKK1 imposes on the Wnt pathway.

Original languageEnglish (US)
Pages (from-to)14700-14705
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number37
DOIs
StatePublished - Sep 11 2007

Keywords

  • Beta-catenin
  • DKK1
  • Kremen

ASJC Scopus subject areas

  • General

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    Binnerts, M. E., Kim, K. A., Bright, J. M., Patel, S. M., Tran, K., Zhou, M., Leung, J. M., Liu, Y., Lomas, W. E., Dixon, M., Hazell, S. A., Wagle, M., Nie, W. S., Tomasevic, N., Williams, J., Zhan, X., Levy, M. D., Funk, W. D., & Abo, A. (2007). R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. Proceedings of the National Academy of Sciences of the United States of America, 104(37), 14700-14705. https://doi.org/10.1073/pnas.0702305104