title: Wnt stabilization of β-catenin reveals principles for morphogen receptor-scaffold assemblies.
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.
authors.affiliation: F. M. Kirby Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Xinjun
authors.initials: X
authors.lastname: Zhang
authors.forename: Aili
authors.initials: A
authors.lastname: Zhang
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Semonov
authors.forename: Bryan T
authors.initials: BT
authors.lastname: MacDonald
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Zhang
authors.forename: Jose
authors.initials: J
authors.lastname: Garcia Abreu
authors.forename: Leilei
authors.initials: L
authors.lastname: Peng
authors.forename: Xi
authors.initials: X
authors.lastname: He
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D060466:Axin Protein / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D055550:Protein Stability; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D014981:Xenopus; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D060466:Axin Protein; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051153:Wnt Proteins; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3