Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of beta-catenin signaling

Hideki Yamamoto; Hiroshi Sakane; Hideki Yamamoto; Tatsuo Michiue; Akira Kikuchi

doi:10.1016/j.devcel.2008.04.015

Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of beta-catenin signaling

Dev Cell. 2008 Jul;15(1):37-48. doi: 10.1016/j.devcel.2008.04.015.

Authors

Hideki Yamamoto¹, Hiroshi Sakane, Hideki Yamamoto, Tatsuo Michiue, Akira Kikuchi

Affiliation

¹ Department of Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.

PMID: 18606139
DOI: 10.1016/j.devcel.2008.04.015

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Caveolins / metabolism
Cell Line
Embryo, Nonmammalian / metabolism
Endocytosis / physiology
HeLa Cells
Humans
Immunohistochemistry
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism*
Kidney / cytology
Low Density Lipoprotein Receptor-Related Protein-6
Membrane Microdomains / chemistry
Membrane Microdomains / physiology
Microinjections
Phosphorylation
Receptors, LDL / genetics
Receptors, LDL / metabolism*
Signal Transduction*
Transcription, Genetic
Wnt Proteins / genetics
Wnt Proteins / metabolism*
Wnt3 Protein
Wnt3A Protein
Xenopus / embryology
Xenopus / metabolism
Xenopus Proteins
beta Catenin / antagonists & inhibitors
beta Catenin / metabolism*

Substances

Caveolins
DKK1 protein, human
Intercellular Signaling Peptides and Proteins
LRP6 protein, human
Low Density Lipoprotein Receptor-Related Protein-6
Receptors, LDL
WNT3A protein, Xenopus
WNT3A protein, human
Wnt Proteins
Wnt3 Protein
Wnt3A Protein
Xenopus Proteins
beta Catenin