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

Sung-Eun Kim1,*, He Huang1,*,†, Ming Zhao2,*, Xinjun Zhang1, Aili Zhang2,4, Mikhail V. Semonov1,‡, Bryan T. MacDonald1, Xiaowu Zhang5, Jose Garcia Abreu1,3, Leilei Peng2, Xi He1,§

1F. M. Kirby Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

2College of Optical Sciences, University of Arizona, Tucson, AZ 85721, USA.

3Instituto de Ciencias Biomedicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

4School of Biomedical Engineering, Jiaotong University, Shanghai, China.

5Cell Signaling Technology, Danvers, MA 01923, USA. ?§Corresponding author. E-mail: xi.he{at}childrens.harvard.edu?* These authors contributed equally to this work.

?† Present address: Department of Pathology, University of Buffalo, Buffalo, NY 14203, USA.

?‡ Present address: Veterans Administration Hospital and Department of Pathology, Boston University, Bedford, MA 01730, USA.

Wnt signaling stabilizes ß-catenin through the LRP6 receptor signaling complex, which antagonizes the ß-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 Axin scaffolding function. Phosphorylation by GSK3 kept Axin activated (“open”) for ß-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 ß-catenin and LRP6, thereby inhibiting ß-catenin phosphorylation and enabling activated LRP6 to selectively recruit active Axin for inactivation reiteratively. Our findings reveal mechanisms for scaffold regulation and morphogen signaling.

Received for publication 5 November 2012. Accepted for publication 19 March 2013.

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