A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation

Xin Zeng, Keiko Tamai, Brad Doble, Shitao Li, He Huang, Raymond Habas, Heidi Okamura, Jim Woodgett and Xi He ()
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Xin Zeng: Neurobiology Program, Children's Hospital Boston, Department of Neurology
Keiko Tamai: Neurobiology Program, Children's Hospital Boston, Department of Neurology
Brad Doble: Ontario Cancer Institute/Princess Margaret Hospital
Shitao Li: Neurobiology Program, Children's Hospital Boston, Department of Neurology
He Huang: Neurobiology Program, Children's Hospital Boston, Department of Neurology
Raymond Habas: Neurobiology Program, Children's Hospital Boston, Department of Neurology
Heidi Okamura: Harvard Medical School
Jim Woodgett: Ontario Cancer Institute/Princess Margaret Hospital
Xi He: Neurobiology Program, Children's Hospital Boston, Department of Neurology

Nature, 2005, vol. 438, issue 7069, 873-877

Abstract: Abstract Signalling by the Wnt family of secreted lipoproteins has essential functions in development and disease1. The canonical Wnt/β-catenin pathway requires a single-span transmembrane receptor, low-density lipoprotein (LDL)-receptor-related protein 6 (LRP6)2,3,4, whose phosphorylation at multiple PPPSP motifs is induced upon stimulation by Wnt and is critical for signal transduction5. The kinase responsible for LRP6 phosphorylation has not been identified. Here we provide biochemical and genetic evidence for a ‘dual-kinase’ mechanism for LRP6 phosphorylation and activation. Glycogen synthase kinase 3 (GSK3), which is known for its inhibitory role in Wnt signalling through the promotion of β-catenin phosphorylation and degradation, mediates the phosphorylation and activation of LRP6. We show that Wnt induces sequential phosphorylation of LRP6 by GSK3 and casein kinase 1, and this dual phosphorylation promotes the engagement of LRP6 with the scaffolding protein Axin. We show further that a membrane-associated form of GSK3, in contrast with cytosolic GSK3, stimulates Wnt signalling and Xenopus axis duplication. Our results identify two key kinases mediating Wnt co-receptor activation, reveal an unexpected and intricate logic of Wnt/β-catenin signalling, and illustrate GSK3 as a genuine switch that dictates both on and off states of a pivotal regulatory pathway.

Date: 2005
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DOI: 10.1038/nature04185

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