R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-09, Vol.104 (37), p.14700-14705
• Main Authors: Binnerts, Minke E, Kim, Kyung-Ah, Bright, Jessica M, Patel, Sejal M, Tran, Karolyn, Zhou, Mei, Leung, John M, Liu, Yi, Lomas, Woodrow E. III, Dixon, Melissa, Hazell, Sophie A, Wagle, Marie, Nie, Wen-Sheng, Tomasevic, Nenad, Williams, Jason, Zhan, Xiaoming, Levy, Michael D, Funk, Walter D, Abo, Arie
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - genetics; beta Catenin - metabolism; Biochemistry; Biological Sciences; Cell Line; Cells; Digestive system; Drosophila - cytology; Drosophila - metabolism; Gene Expression Regulation; Genes, Reporter; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Internalization; Journalism; Kidney - cytology; L cells; LDL-Receptor Related Proteins - antagonists & inhibitors; LDL-Receptor Related Proteins - metabolism; Ligands; Low Density Lipoprotein Receptor-Related Protein-6; Luciferases - metabolism; Membrane Proteins - metabolism; Models, Biological; Phosphorylation; Physiological regulation; Plasmids; Precipitin Tests; Protein Binding; Proteins; Receptors; Recombinant Proteins - metabolism; RNA, Small Interfering - metabolism; Rodents; Signal Transduction; Small interfering RNA; Thrombospondins - genetics; Thrombospondins - metabolism; Transfection; Wnt Proteins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0702305104

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.