Journal Article

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

Doble, Brad, He, Xi, Huang, He, Habas, Raymond, Okamura, Heidi, Zeng, Xin, Li, Shitao, Woodgett, Jim, Tamai, Keiko

2005

Overview

Signalling by the Wnt family of secreted lipoproteins has essential functions in development and disease 1 . 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 transduction 5 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Amino Acid Motifs / Amino Acid Sequence / Animals / Axin Protein / beta Catenin - metabolism / Biological and medical sciences / Body Patterning / Cell Line / Cell Membrane - metabolism / Cell physiology / Cellular biology / Freshwater / Fundamental and applied biological sciences. Psychology / Genetics / Glycogen Synthase Kinase 3 - genetics / Glycogen Synthase Kinase 3 - metabolism / Humanities and Social Sciences / Humans / letter / Low Density Lipoprotein Receptor-Related Protein-6 / Mice / Molecular and cellular biology / Molecular Sequence Data / multidisciplinary / Phosphorylation / Protein Binding / Proteins / Receptors, LDL - chemistry / Receptors, LDL - genetics / Receptors, LDL - metabolism / Repressor Proteins - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Substrate Specificity / TCF Transcription Factors - metabolism / Wnt Proteins - metabolism / Xenopus / Xenopus laevis - embryology / Xenopus laevis - genetics / Xenopus laevis - metabolism / Xenopus Proteins