Caveolin is necessary for Wnt-3a-dependent internalization of LRP6 and accumulation of beta-catenin.
beta-catenin-mediated Wnt signaling is critical in animal development and tumor progression. The single-span transmembrane Wnt receptor, low-density lipoprotein receptor-related protein 6 (LRP6), interacts with Axin to promote the Wnt-dependent accumulation of beta-catenin. However, the molecular mechanism of receptor internalization and its impact on signaling are unclear. Here, we present evidence that LRP6 is internalized with caveolin and that the components of this endocytic pathway are required not only for Wnt-3a-induced internalization of LRP6 but also for accumulation of beta-catenin. Overall, our data suggest that Wnt-3a triggers the interaction of LRP6 with caveolin and promotes recruitment of Axin to LRP6 phosphorylated by glycogen synthase kinase-3beta and that caveolin thereby inhibits the binding of beta-catenin to Axin. Thus, caveolin plays critical roles in inducing the internalization of LRP6 and activating the Wnt/beta-catenin pathway. We also discuss the idea that distinct endocytic pathways correlate with the specificity of Wnt signaling events.
Yamamoto
Hideki
H
Department of Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
Komekado
Hideyuki
H
Kikuchi
Akira
A
D060466:Axin Protein; D022461:Caveolins / Q000378:metabolism*; D002460:Cell Line; D004705:Endocytosis / Q000502:physiology; D051157:Frizzled Receptors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D021962:Membrane Microdomains / Q000737:chemistry / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000378:metabolism*
D060466:Axin Protein; D022461:Caveolins; C498589:FZD5 protein, human; D051157:Frizzled Receptors; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D043562:Receptors, G-Protein-Coupled; D011973:Receptors, LDL; D012097:Repressor Proteins; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin