R-Spondin1 Regulates Wnt Signaling by Inhibiting Internalization of LRP6

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 Sep 7

PMID 17804805

Citations 156

Authors

Minke E Binnerts

Kyung-Ah Kim

Jessica M Bright

Sejal M Patel

Karolyn Tran

Mei Zhou

John M Leung

Yi Liu

Woodrow E Lomas 3rd

Melissa Dixon

Sophie A Hazell

Marie Wagle

Wen-Sheng Nie

Nenad Tomasevic

Jason Williams

Xiaoming Zhan

Michael D Levy

Walter D Funk

Arie Abo

Affiliations

Soon will be listed here.

Abstract

The R-Spondin (RSpo) family of secreted proteins act as potent activators of the Wnt/beta-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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