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A mechanism for Wnt coreceptor activation.

Keiko Tamai1, Xin Zeng, Chunming Liu

  • 1Division of Neuroscience, Children's Hospital, Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.

Molecular Cell
|January 21, 2004
PubMed
Summary
This summary is machine-generated.

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The Wnt/beta-catenin signaling pathway is activated by a specific PPPSP motif in LRP5/6/Arrow proteins. Phosphorylation of this motif creates a docking site for Axin, crucial for beta-catenin stability and Wnt signaling.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Developmental Biology

Background:

  • Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are crucial transmembrane Wnt coreceptors.
  • The precise mechanism of Wnt activation of LRP5/6/Arrow remains incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanism by which Wnt activates LRP5/6/Arrow to initiate signal transduction.
  • To identify the critical signaling module and activation steps within the Wnt receptor complex.

Main Methods:

  • Mutational analysis of the LRP5/6/Arrow intracellular domain, focusing on the PPPSP motif.
  • Functional assays including axis duplication in Xenopus and TCF/beta-catenin-responsive transcription in human cells.
  • Phosphorylation studies of the PPPSP motif and its interaction with Axin.

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Main Results:

  • A reiterated PPPSP motif in LRP5/6/Arrow is necessary and sufficient for Wnt/beta-catenin signaling.
  • A single PPPSP motif, when transferred to the LDL receptor, fully activates the Wnt pathway.
  • Wnt signaling stimulates and requires PPPSP motif phosphorylation, creating an Axin docking site.

Conclusions:

  • The PPPSP motif is a critical signaling module for Wnt/beta-catenin pathway activation.
  • Phosphorylation of the PPPSP motif is a key, inducible activation step for the Wnt receptor complex.
  • This study reveals a unifying mechanism for transmembrane signaling by Wnts, growth factors, and cytokines.