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

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