title: RAB8B is required for activity and caveolar endocytosis of LRP6.
abstract: Wnt/β-catenin signaling plays an important role in embryonic development and adult tissue homeostasis. When Wnt ligands bind to the receptor complex, LRP5/6 coreceptors are activated by phosphorylation and concomitantly endocytosed. In vertebrates, Wnt ligands induce caveolin-dependent endocytosis of LRP6 to relay signal downstream, whereas antagonists such as Dickkopf promote clathrin-dependent endocytosis, leading to inhibition. However, little is known about how LRP6 is directed to different internalization mechanisms, and how caveolin-dependent endocytosis is mediated. In an RNAi screen, we identified the Rab GTPase RAB8B as being required for Wnt/β-catenin signaling. RAB8B depletion reduces LRP6 activity, β-catenin accumulation, and induction of Wnt target genes, whereas RAB8B overexpression promotes LRP6 activity and internalization and rescues inhibition of caveolar endocytosis. In Xenopus laevis and Danio rerio, RAB8B morphants show lower Wnt activity during embryonic development. Our results implicate RAB8B as an essential evolutionary conserved component of Wnt/β-catenin signaling through regulation of LRP6 activity and endocytosis.
authors.affiliation: German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, Heidelberg University, Department of Cell and Molecular Biology, Medical Faculty Mannheim, 69120 Heidelberg, Germany.
authors.forename: Kubilay
authors.initials: K
authors.lastname: Demir
authors.forename: Nadine
authors.initials: N
authors.lastname: Kirsch
authors.forename: Carlo A
authors.initials: CA
authors.lastname: Beretta
authors.forename: Gerrit
authors.initials: G
authors.lastname: Erdmann
authors.forename: Dierk
authors.initials: D
authors.lastname: Ingelfinger
authors.forename: Enrico
authors.initials: E
authors.lastname: Moro
authors.forename: Francesco
authors.initials: F
authors.lastname: Argenton
authors.forename: Matthias
authors.initials: M
authors.lastname: Carl
authors.forename: Christof
authors.initials: C
authors.lastname: Niehrs
authors.forename: Michael
authors.initials: M
authors.lastname: Boutros
mesh_terms: D000818:Animals; D004705:Endocytosis / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D014162:Transfection; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D014981:Xenopus; D015027:Zebrafish; D020691:rab GTP-Binding Proteins
chemical_list: D060488:Low Density Lipoprotein Receptor-Related Protein-6; D015513:Oncogene Proteins; C529761:Rab8b protein, human; D051153:Wnt Proteins; D020691:rab GTP-Binding Proteins