LRP6 is internalized by Dkk1 to suppress its phosphorylation in the lipid raft and is recycled for reuse.
Beta-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-beta-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 1gamma (CK1gamma) by removing LRP6 from the lipid raft. Dkk1 internalized LRP6 in a Rab5-dependent mechanism to prevent phosphorylation mediated by CK1gamma. 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.
Sakane
Hiroshi
H
Department of Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
Yamamoto
Hideki
H
Kikuchi
Akira
A
D019921:Biotinylation; D002460:Cell Line; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D034741:RNA, Small Interfering; D051153:Wnt Proteins / Q000494:pharmacology; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins
D049452:Green Fluorescent Proteins; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C501126:DKK1 protein, human; C555475:LRP6 protein, human; C555510:WNT3A protein, human; C000716463:rab7 GTP-binding proteins, human