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

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Issue date
2008
Author
David, Mónica Delia
Yeramian Hakim, Andree
Duñach, Mireia
Llovera i Tomàs, Marta
Cantí Nicolás, Carles
Garcia de Herreros, Antonio
Comella i Carnicé, Joan Xavier
Herreros Danés, Judit
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David, Mónica Delia; Yeramian Hakim, Andree; Duñach, Mireia; Llovera i Tomàs, Marta; Cantí Nicolás, Carles; Garcia de Herreros, Antonio; ... Herreros Danés, Judit. (2008) . Signalling by neurotrophins and hepatocyte growth factor regulates axon morphogenesis by differential β-catenin phosphorylation. Journal of Cell Science, 2008, vol. 121, núm. 16, p. 2718-2730. https://doi.org/10.1242/jcs.029660.
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Abstract
Tyrosine phosphorylation of ß-catenin, a component of adhesion complexes and the Wnt pathway, affects cell adhesion, migration and gene transcription. By reducing ßcatenin availability using shRNA-mediated gene silencing or expression of intracellular N-cadherin, we show that ß-catenin is required for axon growth downstream of Brain Derived Neurotrophic Factor (BDNF) and Hepatocyte Growth Factor (HGF) signalling. We demonstrate that receptor tyrosine kinases (RTK) Trk and Met interact with and phosphorylate ß-catenin. Neurotrophins (NT) stimulation of Trk receptors results in phosphorylation of ß-catenin at residue Y654 and increased axon growth and branching. Conversely, pharmacological inhibition of Trk or a Y654F mutant blocks these effects. ß-catenin phospho(P)-Y654 colocalizes with the cytoskeleton at growth cones. However, HGF that also increases axon growth and branching, induces ß-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 of NT. We conclude that NT and HGF signalling differentially phosphorylate ß-catenin, targeting ß-catenin to distinct compartments to regulate axon morphogenesis by TCF4-transcription-dependent and independent mechanisms. These results place ß-catenin downstream of growth factor/RTK signalling in axon differentiation.
URI
http://hdl.handle.net/10459.1/47340
DOI
https://doi.org/10.1242/jcs.029660
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Journal of Cell Science, 2008, vol. 121, núm. 16, p. 2718-2730
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