title: Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of beta-catenin signaling.
abstract: Wnt and Dickkopf (Dkk) regulate the stabilization of beta-catenin antagonistically in the Wnt signaling pathway; however, the molecular mechanism is not clear. In this study, we found that Wnt3a acts in parallel to induce the caveolin-dependent internalization of low-density-lipoprotein receptor-related protein 6 (LRP6), as well as the phosphorylation of LRP6 and the recruitment of Axin to LRP6 on the cell surface membrane. The phosphorylation and internalization of LRP6 occurred independently of one another, and both were necessary for the accumulation of beta-catenin. In contrast, Dkk1, which inhibits Wnt3a-dependent stabilization of beta-catenin, induced the internalization of LRP6 with clathrin. Knockdown of clathrin suppressed the Dkk1-dependent inhibition of the Wnt3a response. Furthermore, Dkk1 reduced the distribution of LRP6 in the lipid raft fraction where caveolin is associated. These results indicate that Wnt3a and Dkk1 shunt LRP6 to distinct internalization pathways in order to activate and inhibit the beta-catenin signaling, respectively.
authors.affiliation: Department of Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakane
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Michiue
authors.forename: Akira
authors.initials: A
authors.lastname: Kikuchi
mesh_terms: D000818:Animals; D022461:Caveolins / Q000378:metabolism; D002460:Cell Line; D004625:Embryo, Nonmammalian / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D021962:Membrane Microdomains / Q000737:chemistry / Q000502:physiology; D008845:Microinjections; D010766:Phosphorylation; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D014981:Xenopus / Q000196:embryology / Q000378:metabolism; D029867:Xenopus Proteins; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D022461:Caveolins; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011973:Receptors, LDL; C555506:WNT3A protein, Xenopus; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D029867:Xenopus Proteins; D051176:beta Catenin