RAB8B Is Required for Activity and Caveolar Endocytosis of LRP6

Cell Reports. 2013;4(6):1224-1234 DOI 10.1016/j.celrep.2013.08.008

 

Journal Homepage

Journal Title: Cell Reports

ISSN: 2211-1247 (Online)

Publisher: Elsevier

LCC Subject Category: Science: Biology (General)

Country of publisher: Netherlands

Language of fulltext: English

Full-text formats available: PDF, HTML

 

AUTHORS

Kubilay Demir (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)
Nadine Kirsch (German Cancer Research Center (DKFZ), Division of Molecular Embryology, 69120 Heidelberg, Germany)
Carlo A. Beretta (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)
Gerrit Erdmann (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)
Dierk Ingelfinger (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)
Enrico Moro (Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy)
Francesco Argenton (Department of Biology, University of Padova, 35131 Padova, Italy)
Matthias Carl (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)
Christof Niehrs (German Cancer Research Center (DKFZ), Division of Molecular Embryology, 69120 Heidelberg, Germany)
Michael Boutros (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)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 31 weeks

 

Abstract | Full Text

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.