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J. Biol. Chem. 282 (21): 15903-15911

© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

R-spondin1 Is a High Affinity Ligand for LRP6 and Induces LRP6 Phosphorylation and beta-Catenin Signaling*

Qiou Wei{ddagger}1, Chika Yokota{ddagger}, Mikhail V. Semenov{ddagger}, Brad Doble§, Jim Woodgett§, , and Xi He{ddagger}2

{ddagger}Program of Neurobiology, Children's Hospital Boston, Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115 and the §Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada

Abstract: R-spondin proteins are newly identified secreted molecules that activate beta-catenin signaling. However, the mechanism of R-spondin action and its relationship with Wnt signaling remain unclear. Here we show that human R-spondin1 (hRspo1) is a high affinity ligand for the Wnt co-receptor LRP6 (Kd = 1.2 nM). hRspo1 induces glycogen synthase kinase 3-dependent phosphorylation and activation of LRP6. DKK1, an LRP6 antagonist, inhibits hRspo1-induced LRP6 phosphorylation. We further demonstrate that hRspo1 synergizes with Frizzled5 in Xenopus axis induction assays and induces the phosphorylation of Dishevelled, a cytoplasmic component downstream of Frizzled function. Our study reveals interesting similarity and distinction between Wnt and R-spondin signaling.

Received for publication October 10, 2006. Revision received March 30, 2007.

* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Postdoctoral Fellow of the Leukemia and Lymphoma Society.

2 Supported by grants from the National Institutes of Health. W. M. Keck Foundation Distinguished Young Scholar and Leukemia and Lymphoma Society Scholar. To whom correspondence should be addressed: Program of Neurobiology, Children's Hospital Boston, Dept. of Neurology, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115. Tel.: 617-919-2257; Fax: 617-730-1953; E-mail: Xi.He{at}childrens.harvard.edu.

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