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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

Authors

  • Tamai K
  • Zeng X
  • Liu C
  • Zhang X
  • Harada Y
  • Chang Z
  • He X

Journal

Molecular cell

Publication Data

January 16, 2004

Associated Grants

None

Mesh Terms

  • 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