Hepatocyte Growth Factor Modulates MET Receptor Tyrosine Kinase and β-Catenin Functional Interactions to Enhance Synapse Formation.
MET, a pleiotropic receptor tyrosine kinase implicated in autism risk, influences multiple neurodevelopmental processes. There is a knowledge gap, however, in the molecular mechanism through which MET mediates developmental events related to disorder risk. In the neocortex, MET is expressed transiently during periods of peak dendritic outgrowth and synaptogenesis, with expression enriched at developing synapses, consistent with demonstrated roles in dendritic morphogenesis, modulation of spine volume, and excitatory synapse development. In a recent coimmunoprecipitation/mass spectrometry screen, β-catenin was identified as part of the MET interactome in developing neocortical synaptosomes. Here, we investigated the influence of the MET/β-catenin complex in mouse neocortical synaptogenesis. Western blot analysis confirms that MET and β-catenin coimmunoprecipitate, but N-cadherin is not associated with the MET complex. Following stimulation with hepatocyte growth factor (HGF), β-catenin is phosphorylated at tyrosine(142) (Y142) and dissociates from MET, accompanied by an increase in β-catenin/N-cadherin and MET/synapsin 1 protein complexes. In neocortical neurons in vitro, proximity ligation assays confirmed the close proximity of these proteins. Moreover, in neurons transfected with synaptophysin-GFP, HGF stimulation increases the density of synaptophysin/bassoon (a presynaptic marker) and synaptophysin/PSD-95 (a postsynaptic marker) clusters. Mutation of β-catenin at Y142 disrupts the dissociation of the MET/β-catenin complex and prevents the increase in clusters in response to HGF. The data demonstrate a new mechanism for the modulation of synapse formation, whereby MET activation induces an alignment of presynaptic and postsynaptic elements that are necessary for assembly and formation of functional synapses by subsets of neocortical neurons that express MET/β-catenin complex.
Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California , Los Angeles, California 90027.
Zhihui
Z
Xie
Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California , Los Angeles, California 90027.
Kathie L
KL
Eagleson
Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California , Los Angeles, California 90027.
Hsiao-Huei
0000-0002-9538-9017
HH
Wu
Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California 90027; Institute for the Developing Mind, The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California 90027.
Pat
0000-0002-9717-1695
P
Levitt
D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D051528:Guanylate Kinases / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D047468:Immunoprecipitation; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D019579:Neocortex / Q000166:cytology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
C498441:Bsn protein, mouse; C495267:CTNNB1 protein, mouse; D015820:Cadherins; C489083:Cdh2 protein, mouse; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016708:Synaptophysin; C569015:Syp protein, mouse; D051176:beta Catenin; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D051528:Guanylate Kinases
MET receptor tyrosine kinase; autism; synapse development; β-catenin