Report

Wnt Stabilization of β-Catenin Reveals Principles for Morphogen Receptor-Scaffold Assemblies

+ See all authors and affiliations

Science  17 May 2013:
Vol. 340, Issue 6134, pp. 867-870
DOI: 10.1126/science.1232389

You are currently viewing the abstract.

View Full Text

Signal Scaffolds

Scaffolds in cellular signaling pathways are turning out to do way more than just hold proteins together in a complex. Kim et al. (p. 867, published online 11 April) showed the importance of the scaffold protein Axin as an active participant controlling the kinetics of activation of signaling through the pathways. Axin is part of two protein complexes that have opposing actions that may regulate the timing of signaling—either activating Wnt signaling, thus protecting β-catenin from destruction, or causing proteolytic destruction of β-catenin. Rock et al. (p. 871, published online 11 April) characterized the role of the scaffold protein Nud1 in the mitotic exit network and found that the kinase that produces the output from the signaling complex only interacts with a scaffold that is primed by its activator protein kinase, already bound to the scaffold and creating a docking site.

Abstract

Wnt signaling stabilizes β-catenin through the LRP6 receptor signaling complex, which antagonizes the β-catenin destruction complex. The Axin scaffold and associated glycogen synthase kinase-3 (GSK3) have central roles in both assemblies, but the transduction mechanism from the receptor to the destruction complex is contentious. We report that Wnt signaling is governed by phosphorylation regulation of the Axin scaffolding function. Phosphorylation by GSK3 kept Axin activated ("open") for β-catenin interaction and poised for engagement of LRP6. Formation of the Wnt-induced LRP6-Axin signaling complex promoted Axin dephosphorylation by protein phosphatase-1 and inactivated ("closed") Axin through an intramolecular interaction. Inactivation of Axin diminished its association with β-catenin and LRP6, thereby inhibiting β-catenin phosphorylation and enabling activated LRP6 to selectively recruit active Axin for inactivation reiteratively. Our findings reveal mechanisms for scaffold regulation and morphogen signaling.

View Full Text