Wnt Signaling Requires the Sequestration of Glycogen Synthase Kinase 3 inside Multivesicular Endosomes

By V. Taelman, Radoslaw Dobrowolski, J. Plouhinec, L. Fuentealba, P. Vorwald, I. Gumper, D. Sabatini, E. M. De Robertis. Cell, 2010

725 citations recorded by the source corpus.

SUMMARY 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 co-localized 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. Cryoimmuno electron microscopy showed that these corresponded to multivesicular bodies. 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.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/cb9cbaee906607c82c9f5de541c4b2e7c407912a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. S. Piccolo
2. T. Panciera
3. M. Cordenonsi
4. S. Dupont
5. R. Nusse
6. Hans Clevers
7. Eléonore Beurel
8. R. Jope

In Molecular Biology

1. Hans Clevers
2. R. Nusse
3. S. Piccolo
4. M. Cordenonsi
5. Eléonore Beurel
6. S. Grieco
7. S. Dupont
8. T. Panciera

Citations in the corpus

• R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/β-catenin signaling (2011, background): “Interestingly, it is well established that Wnt/β-catenin signaling requires internalization of the Wnt coreceptors and the sequestration of glycogen synthase kinase 3 inside multivesicular endosomes (30, 31).”
• YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. (2014, background): “Wnt causes functional inactivation of the destruction complex, with ensuing escape of b-catenin from degradation, resulting into b-catenin accumulation and nuclear entry (Clevers, 2006; Taelman et al., 2010).”
• Endocytosis, Signaling, and Beyond (2014, background): “…now suggest that GSK-3 might be sequestered into the intraluminal vesicles of MVBs, away from its substrates (including b-catenin), after it is internalized from the PM together with a multiprotein signalosome complex (the LPR6-signalosome) containing Frizzled and LPR6 (Taelman et al. 2010).”
• Wnt/β-catenin signaling and disease. (2012, positive): “Likewise, it has been proposed that the regulation of GSK3 by Wnt is stoichiometric, caused by sequestration of the enzyme inside multivesicular endosomes (Taelman et al., 2010).”
• Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases (2014, background): “Furthermore, sustained Wnt signaling leads to sequestration of GSK3 in multi-vesicular endosomes, which affects its functions in both Wnt-mediated and Wntindependent actions (Taelman et al., 2010).”