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Signalling by neurotrophins and hepatocyte growth factor regulates axon morphogenesis by differential beta-catenin

Monica D David1, Andrée Yeramian, Mireia Duñach

  • 1Laboratori d'Investigació, Hospital Universitari Arnau de Vilanova, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Spain.

Journal of Cell Science
|July 31, 2008
PubMed

Insights

Beta-catenin is crucial for axon growth, acting downstream of neurotrophin (NT) and hepatocyte growth factor (HGF) signaling. Different receptor tyrosine kinases (RTKs) phosphorylate beta-catenin at distinct sites, regulating its function in axon development.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Beta-catenin is a key protein involved in cell adhesion and the Wnt signaling pathway.
  • Its tyrosine phosphorylation influences cell adhesion, migration, and gene transcription.
  • The role of beta-catenin in axon growth downstream of growth factor signaling requires further elucidation.

Purpose of the Study:

  • To investigate the role of beta-catenin in axon growth mediated by brain-derived neurotrophic factor (BDNF) and hepatocyte growth factor (HGF) signaling.
  • To determine how receptor tyrosine kinases (RTKs) like Trk and Met interact with and phosphorylate beta-catenin.
  • To understand the differential mechanisms by which NT and HGF signaling regulate axon morphogenesis via beta-catenin.

Main Methods:

  • shRNA-mediated gene silencing to reduce beta-catenin availability.
  • Expression of intracellular N-cadherin to modulate beta-catenin levels.
  • Stimulation of Trk and Met receptors with neurotrophins (NTs) and hepatocyte growth factor (HGF).
  • Analysis of beta-catenin phosphorylation at specific residues (Y654, Y142) and its subcellular localization.
  • Use of dominant-negative DeltaN-TCF4 to assess TCF4-dependent mechanisms.

Main Results:

  • Beta-catenin is essential for axon growth downstream of BDNF and HGF signaling.
  • Receptor tyrosine kinases (RTKs) Trk and Met interact with and phosphorylate beta-catenin.
  • NT stimulation leads to Y654 phosphorylation of beta-catenin, promoting axon growth and cytoskeletal localization.
  • HGF stimulation induces Y142 phosphorylation and nuclear localization of beta-catenin, impacting axon growth.
  • TCF4 activity is required for HGF-mediated axon growth but not for NT-mediated effects.

Conclusions:

  • Neurotrophin (NT) and HGF signaling differentially phosphorylate beta-catenin, directing it to specific cellular compartments.
  • Phosphorylated beta-catenin regulates axon morphogenesis through both TCF4-dependent and -independent mechanisms.
  • Beta-catenin functions downstream of growth factor-RTK signaling in the process of axon differentiation.

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