LRP6 is internalized by Dkk1 to suppress its phosphorylation in the lipid raft and is recycled for reuse

• Published in: Journal of cell science Vol. 123; no. 3; pp. 360 - 368
• Main Authors: Sakane, Hiroshi, Yamamoto, Hideki, Kikuchi, Akira
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Limited 01-02-2010
• Subjects: Biotinylation; Cell Line; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; HeLa Cells; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - pharmacology; LDL-Receptor Related Proteins - genetics; LDL-Receptor Related Proteins - metabolism; Low Density Lipoprotein Receptor-Related Protein-6; Membrane Microdomains - drug effects; Membrane Microdomains - metabolism; Phosphorylation - drug effects; Protein Binding; rab GTP-Binding Proteins - metabolism; rab5 GTP-Binding Proteins - metabolism; RNA, Small Interfering; Wnt Proteins - pharmacology; Wnt3 Protein; Wnt3A Protein
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.058008

β-catenin-mediated Wnt signaling is crucial in animal development and tumor progression. The phosphorylation of low-density lipoprotein receptor-related protein 6 (LRP6), a single-span transmembrane Wnt receptor, plays a vital role in this signaling. Dickkopf1 (Dkk1) has been shown to inhibit the Wnt-- β-catenin pathway, but the mechanism is not yet clear. Here, evidence is presented that Wnt3a-dependent phosphorylation of LRP6 occurs in the lipid raft and that Dkk1 inhibits the formation of a complex between LRP6 and casein kinase 1γ (CK1γ) by removing LRP6 from the lipid raft. Dkk1 internalized LRP6 in a Rab5-dependent mechanism to prevent phosphorylation mediated by CK1γ. The internalized LRP6 was recycled back in a Rab11-dependent mechanism to the cell-surface membrane, and the recycled LRP6 again responded to Wnt3a and Dkk1. Internalized Dkk1 was trafficked in a Rab7-mediated route and degraded in the lysosome. These results suggest that Dkk1 induces the internalization of LRP6 to suppress its phosphorylation in the lipid raft and allows subsequent recycling of LRP6 so that it can be reused for signaling.