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

Monica D. David, Andrée Yeramian, Mireia Duñach, Marta Llovera, Carles Cantí, Antonio García de Herreros, Joan X. Comella, Judit Herreros

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43 Citations (Scopus)

Abstract

Tyrosine phosphorylation of β-catenin, a component of adhesion complexes and of the Wnt pathway, affects cell adhesion, migration and gene transcription. By reducing β-catenin availability using shRNA-mediated gene silencing or expression of intracellular N-cadherin, we show that β-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 β-catenin. Stimulation of Trk receptors by neurotrophins (NTs) results in phosphorylation of β-catenin at residue Y654, and increased axon growth and branching. Conversely, pharmacological inhibition of TrK or expression of a Y654F mutant blocks these effects. β-catenin phosphorylated at Y654 colocalizes with the cytoskeleton at growth cones. However, HGF, which also increases axon growth and branching, induces β-catenin phosphorylation at Y142 and a nuclear localization. Interestingly, dominant-negative ΔN-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 β-catenin, targeting this protein to distinct compartments to regulate axon morphogenesis by TCF4- transcription-dependent and -independent mechanisms. These results place β-catenin downstream of growth-factor-RTK signalling in axon differentiation.
Original languageEnglish
Pages (from-to)2718-2730
JournalJournal of Cell Science
Volume121
DOIs
Publication statusPublished - 15 Aug 2008

Keywords

  • Axon growth
  • Hepatocyte growth factor
  • Met
  • Neurotrophins
  • Trk
  • β-catenin

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