Signalling by neurotrophins and hepatocyte growth factor regulates axon morphogenesis by differential beta-catenin phosphorylation.
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.
David
Monica D
MD
Laboratori d'Investigació, Hospital Universitari Arnau de Vilanova, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Spain.
Yeramian
Andrée
A
Duñach
Mireia
M
Llovera
Marta
M
Cantí
Carles
C
de Herreros
Antonio García
AG
Comella
Joan X
JX
Herreros
Judit
J
D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009024:Morphogenesis / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
D009414:Nerve Growth Factors; D051176:beta Catenin; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; D020917:Receptor, trkA