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

doi:10.1073/pnas.0702305104

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 journal › Article › peer-review

233 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 language	English (US)
Pages (from-to)	14700-14705
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	104
Issue number	37
DOIs	https://doi.org/10.1073/pnas.0702305104
State	Published - Sep 11 2007

Keywords

Beta-catenin
DKK1
Kremen

ASJC Scopus subject areas

General

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10.1073/pnas.0702305104

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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

Binnerts, ME, Kim, KA, Bright, JM, Patel, SM, Tran, K, Zhou, M, Leung, JM, Liu, Y, Lomas, WE, Dixon, M, Hazell, SA, Wagle, M, Nie, WS, Tomasevic, N, Williams, J, Zhan, X, Levy, MD, Funk, WD & 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, vol. 104, no. 37, pp. 14700-14705. https://doi.org/10.1073/pnas.0702305104

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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.",

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AU - Binnerts, Minke E.

AU - Kim, Kyung Ah

AU - Bright, Jessica M.

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AU - Tran, Karolyn

AU - Zhou, Mei

AU - Leung, John M.

AU - Liu, Yi

AU - Lomas, Woodrow E.

AU - Dixon, Melissa

AU - Hazell, Sophie A.

AU - Wagle, Marie

AU - Nie, Wen Sheng

AU - Tomasevic, Nenad

AU - Williams, Jason

AU - Zhan, Xiaoming

AU - Levy, Michael D.

AU - Funk, Walter D.

AU - Abo, Arie

PY - 2007/9/11

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AB - 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.

KW - Beta-catenin

KW - DKK1

KW - Kremen

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R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6

Abstract

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