Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes
- PMID: 21183076
- PMCID: PMC3022472
- DOI: 10.1016/j.cell.2010.11.034
Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes
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.
Copyright © 2010 Elsevier Inc. All rights reserved.
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Comment in
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Wnt signaling: multivesicular bodies hold GSK3 captive.Cell. 2010 Dec 23;143(7):1044-6. doi: 10.1016/j.cell.2010.12.003. Cell. 2010. PMID: 21183070
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Membrane trafficking: a GSK3 lockdown.Nat Rev Mol Cell Biol. 2011 Feb;12(2):72. doi: 10.1038/nrm3052. Nat Rev Mol Cell Biol. 2011. PMID: 21252990 No abstract available.
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References
-
- Angers S, Moon RT. Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol. 2009;10:468–477. - PubMed
-
- Bilic J, Huang YL, Davidson G, Zimmermann T, Cruciat CM, Bienz M, Niehrs C. Wnt induces LRP6 Signalosomes and promotes Dishevelled-dependent LRP6 phosphorylation. Science. 2007;316:1619–1622. - PubMed
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