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J Cell Sci September 15, 2014; 127 (Pt 18): 3970-82.
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In vivo analysis of formation and endocytosis of the Wnt/β-catenin signaling complex in zebrafish embryos.

Hagemann AI , Kurz J , Kauffeld S , Chen Q , Reeves PM , Weber S , Schindler S , Davidson G , Kirchhausen T , Scholpp S .

After activation by Wnt/β-Catenin ligands, a multi-protein complex assembles at the plasma membrane as membrane-bound receptors and intracellular signal transducers are clustered into the so-called Lrp6-signalosome [Corrected]. However, the mechanism of signalosome formation and dissolution is yet not clear. Our imaging studies of live zebrafish embryos show that the signalosome is a highly dynamic structure. It is continuously assembled by Dvl2-mediated recruitment of the transducer complex to the activated receptors and partially disassembled by endocytosis. We find that, after internalization, the ligand-receptor complex and the transducer complex take separate routes. The Wnt-Fz-Lrp6 complex follows a Rab-positive endocytic path. However, when still bound to the transducer complex, Dvl2 forms intracellular aggregates. We show that this endocytic process is not only essential for ligand-receptor internalization but also for signaling. The μ2-subunit of the endocytic Clathrin adaptor Ap2 interacts with Dvl2 to maintain its stability during endocytosis. Blockage of Ap2μ2 function leads to Dvl2 degradation, inhibiton of signalosome formation at the plasma membrane and, consequently, reduction of signaling. We conclude that Ap2μ2-mediated endocytosis is important to maintain Wnt/β-catenin signaling in vertebrates.

PubMed ID: 25074807
PMC ID: PMC4163645
Article link: J Cell Sci
Grant support: [+]

Species referenced: Xenopus
Genes referenced: axin1 axin2 cfp cltc ctnnb1 dvl2 gnpda1 h2bc21 lef1 lrp6 pcna rab5a rab7a tfap2a wnt8a

Article Images: [+] show captions
References [+] :
Angers, Proximal events in Wnt signal transduction. 2009, Pubmed