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Cell. December 23, 2010; 143 (7): 1136-48.

Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes.

Taelman VF , Dobrowolski R , Plouhinec JL , Fuentealba LC , Vorwald PP , Gumper I , Sabatini DD , De Robertis EM .

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.

PubMed ID: 21183076
PMC ID: PMC3022472
Article link: Cell.
Grant support: HD21502-24 NICHD NIH HHSHoward Hughes Medical Institute , R01 HD021502-24 NICHD NIH HHS , R01 HD021502-25 NICHD NIH HHS , HHMI_DE ROBERTIS_E Howard Hughes Medical Institute , R01 HD021502 NICHD NIH HHS , R37 HD021502 NICHD NIH HHS

Genes referenced: ctnnb1 gsk3b gys1 hgs rab5a

Morpholinos referenced: hgs MO1

Article Images: [+] show captions

Angers, 2009, Pubmed[+]

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