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

Nature (2005-12-13)
Xin Zeng, Keiko Tamai, Brad Doble, Shitao Li, He Huang, Raymond Habas, Heidi Okamura, Jim Woodgett, Xi He
ABSTRACT

Signalling by the Wnt family of secreted lipoproteins has essential functions in development and disease. The canonical Wnt/beta-catenin pathway requires a single-span transmembrane receptor, low-density lipoprotein (LDL)-receptor-related protein 6 (LRP6), whose phosphorylation at multiple PPPSP motifs is induced upon stimulation by Wnt and is critical for signal transduction. 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 beta-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/beta-catenin signalling, and illustrate GSK3 as a genuine switch that dictates both on and off states of a pivotal regulatory pathway.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-β-Catenin antibody produced in rabbit, whole antiserum
Sigma-Aldrich
Anti-VSV-G antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-LRP6 antibody produced in rabbit, ~1.5 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-LRP6 (C-terminal) antibody produced in rabbit, ~1.5 mg/mL, affinity isolated antibody, buffered aqueous solution

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