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

J Cell Sci. 2008 Aug 15;121(Pt 16):2718-30. doi: 10.1242/jcs.029660. Epub 2008 Jul 29.

Abstract

Tyrosine phosphorylation of beta-catenin, a component of adhesion complexes and of the Wnt pathway, affects cell adhesion, migration and gene transcription. By reducing beta-catenin availability using shRNA-mediated gene silencing or expression of intracellular N-cadherin, we show that beta-catenin is required for axon growth downstream of brain-derived neurotrophic factor (BDNF) signalling and hepatocyte growth factor (HGF) signalling. We demonstrate that the receptor tyrosine kinases (RTKs) Trk and Met interact with and phosphorylate beta-catenin. Stimulation of Trk receptors by neurotrophins (NTs) results in phosphorylation of beta-catenin at residue Y654, and increased axon growth and branching. Conversely, pharmacological inhibition of Trk or expression of a Y654F mutant blocks these effects. beta-catenin phosphorylated at Y654 colocalizes with the cytoskeleton at growth cones. However, HGF, which also increases axon growth and branching, induces beta-catenin phosphorylation at Y142 and a nuclear localization. Interestingly, dominant-negative DeltaN-TCF4 abolishes the effects of HGF in axon growth and branching, but not that of NTs. We conclude that NT- and HGF-signalling differentially phosphorylate beta-catenin, targeting this protein to distinct compartments to regulate axon morphogenesis by TCF4-transcription-dependent and -independent mechanisms. These results place beta-catenin downstream of growth-factor-RTK signalling in axon differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / drug effects*
  • Axons / metabolism
  • Axons / physiology
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Embryo, Mammalian
  • Hepatocyte Growth Factor / metabolism
  • Hepatocyte Growth Factor / pharmacology*
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / embryology
  • Hippocampus / metabolism
  • Humans
  • Models, Biological
  • Morphogenesis / drug effects*
  • Nerve Growth Factors / metabolism
  • Nerve Growth Factors / pharmacology*
  • Phosphorylation / drug effects
  • Protein Binding
  • Rats
  • Receptor, trkA / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Tyrosine / metabolism
  • beta Catenin / metabolism*

Substances

  • Nerve Growth Factors
  • beta Catenin
  • Tyrosine
  • Hepatocyte Growth Factor
  • Receptor, trkA