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Science
2013 May 17;3406134:867-70. doi: 10.1126/science.1232389.
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Wnt stabilization of β-catenin reveals principles for morphogen receptor-scaffold assemblies.
Kim SE, Huang H, Zhao M, Zhang X, Zhang A, Semonov MV, MacDonald BT, Zhang X, Garcia Abreu J, Peng L, He X.
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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.
Behrens,
Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta.
1998, Pubmed,
Xenbase
Behrens,
Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta.
1998,
Pubmed
,
Xenbase Bilic,
Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation.
2007,
Pubmed Clevers,
Wnt/β-catenin signaling and disease.
2012,
Pubmed Cselenyi,
LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3's phosphorylation of beta-catenin.
2008,
Pubmed
,
Xenbase Davidson,
Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction.
2005,
Pubmed
,
Xenbase Doble,
Functional redundancy of GSK-3alpha and GSK-3beta in Wnt/beta-catenin signaling shown by using an allelic series of embryonic stem cell lines.
2007,
Pubmed Hernández,
Kinetic responses of β-catenin specify the sites of Wnt control.
2012,
Pubmed Ikeda,
Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin.
1998,
Pubmed Jho,
A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression.
1999,
Pubmed Kimelman,
beta-catenin destruction complex: insights and questions from a structural perspective.
2006,
Pubmed Li,
Wnt signaling through inhibition of β-catenin degradation in an intact Axin1 complex.
2012,
Pubmed Liu,
Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism.
2002,
Pubmed
,
Xenbase Luo,
Protein phosphatase 1 regulates assembly and function of the beta-catenin degradation complex.
2007,
Pubmed
,
Xenbase MacDonald,
Wnt/beta-catenin signaling: components, mechanisms, and diseases.
2009,
Pubmed
,
Xenbase Mao,
Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway.
2001,
Pubmed Metcalfe,
Inhibition of GSK3 by Wnt signalling--two contrasting models.
2011,
Pubmed Niehrs,
Regionally specific induction by the Spemann-Mangold organizer.
2004,
Pubmed Piao,
Direct inhibition of GSK3beta by the phosphorylated cytoplasmic domain of LRP6 in Wnt/beta-catenin signaling.
2008,
Pubmed
,
Xenbase Schwarz-Romond,
Dynamic recruitment of axin by Dishevelled protein assemblies.
2007,
Pubmed Smith,
Scaffolding proteins: not such innocent bystanders.
2013,
Pubmed Stamos,
The β-catenin destruction complex.
2013,
Pubmed Taelman,
Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes.
2010,
Pubmed
,
Xenbase Tamai,
A mechanism for Wnt coreceptor activation.
2004,
Pubmed
,
Xenbase Valvezan,
Adenomatous polyposis coli (APC) regulates multiple signaling pathways by enhancing glycogen synthase kinase-3 (GSK-3) activity.
2012,
Pubmed Virshup,
From promiscuity to precision: protein phosphatases get a makeover.
2009,
Pubmed Willert,
Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex.
1999,
Pubmed Wu,
Inhibition of GSK3 phosphorylation of beta-catenin via phosphorylated PPPSPXS motifs of Wnt coreceptor LRP6.
2009,
Pubmed
,
Xenbase Yamamoto,
Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability.
1999,
Pubmed Zalatan,
Conformational control of the Ste5 scaffold protein insulates against MAP kinase misactivation.
2012,
Pubmed Zeng,
A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation.
2005,
Pubmed
,
Xenbase Zeng,
Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions.
2008,
Pubmed
,
Xenbase
