A mechanism for Wnt coreceptor activation.
LDL receptor related proteins 5 and 6 (LRP5/6) and their Drosophila homolog Arrow are single-span transmembrane proteins essential for Wnt/beta-catenin signaling, likely via acting as Wnt coreceptors. How Wnt activates LRP5/6/Arrow to initiate signal transduction is not well defined. Here we show that a PPPSP motif, which is reiterated five times in the LRP5/6/Arrow intracellular domain, is necessary and sufficient to trigger Wnt/beta-catenin signaling. A single PPPSP motif, upon transfer to the LDL receptor, fully activates the Wnt pathway, inducing complete axis duplication in Xenopus and TCF/beta-catenin-responsive transcription in human cells. We further show that Wnt signal-ing stimulates, and requires, phosphorylation of the PPPSP motif, which creates an inducible docking site for Axin, a scaffolding protein controlling beta-catenin stability. Our study identifies a critical signaling module and a key phosphorylation-dependent activation step of the Wnt receptor complex and reveals a unifying logic for transmembrane signaling by Wnts, growth factors, and cytokines.
Pubmed ID: 14731402 RIS Download
Alanine | Amino Acid Motifs | Amino Acid Sequence | Animals | Axin Protein | Cytoskeletal Proteins | Embryo, Nonmammalian | Models, Biological | Phosphorylation | Point Mutation | Protein Structure, Tertiary | Proto-Oncogene Proteins | Receptors, LDL | Repressor Proteins | Sequence Homology, Amino Acid | Signal Transduction | Trans-Activators | Transcriptional Activation | Wnt Proteins | Xenopus Proteins | Xenopus laevis | Zebrafish Proteins | beta Catenin