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First published online 29 July 2008
doi: 10.1242/jcs.029660

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

Monica D. David^1,*, Andrée Yeramian^1,*, Mireia Duñach², Marta Llovera¹, Carles Cantí¹, Antonio García de Herreros³, Joan X. Comella^1, and Judit Herreros^1,

¹ Laboratori d'Investigació, Hospital Universitari Arnau de Vilanova, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Spain
² Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Spain
³ Programa de Recerca en Càncer, IMIM-Hospital del Mar, Parc de Recerca Biomèdica de Barcelona, Spain

Author for correspondence (e-mail: j.herreros{at}cmb.udl.cat)

Accepted 26 May 2008

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 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 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.

Key words: β-catenin, Neurotrophins, Hepatocyte growth factor, Axon growth, Trk, Met

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				Signalling by neurotrophins and hepatocyte growth factor regulates axon morphogenesis by differential {beta}-catenin phosphorylation Development, September 1, 2008; 135(17): e1 - e1. [Full Text]