Wnt signaling requires sequestration of Glycogen Synthase Kinase 3 inside multivesicular endosomes

Vincent F. Taelman, Radoslaw Dobrowolski, Jean Louis Plouhinec, Luis C. Fuentealba, Peggy P. Vorwald, Iwona Gumper, David D. Sabatini, Edward M. De Robertis

Research output: Contribution to journalArticlepeer-review

460 Scopus citations

Abstract

Canonical Wnt signaling requires inhibition of Glycogen Synthase Kinase 3 (GSK3) activity, but the molecular mechanism by which this is achieved remains unclear. Here, we report that Wnt signaling triggers the sequestration of GSK3 from the cytosol into multivesicular bodies (MVBs), so that this enzyme becomes separated from its many cytosolic substrates. Endocytosed Wnt colocalized with GSK3 in acidic vesicles positive for endosomal markers. After Wnt addition, endogenous GSK3 activity decreased in the cytosol, and GSK3 became protected from protease treatment inside membrane-bounded organelles. Cryoimmunoelectron microscopy showed that these corresponded to MVBs. Two proteins essential for MVB formation, HRS/Vps27 and Vps4, were required for Wnt signaling. The sequestration of GSK3 extended the half-life of many other proteins in addition to β-Catenin, including an artificial Wnt-regulated reporter protein containing GSK3 phosphorylation sites. We conclude that multivesicular endosomes are essential components of the Wnt signal-transduction pathway.

Original languageEnglish (US)
Pages (from-to)1136-1148
Number of pages13
JournalCell
Volume143
Issue number7
DOIs
StatePublished - Dec 23 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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