title: Receptor Tyrosine Kinase MET Interactome and Neurodevelopmental Disorder Partners at the Developing Synapse.
abstract: Atypical synapse development and plasticity are implicated in many neurodevelopmental disorders (NDDs). NDD-associated, high-confidence risk genes have been identified, yet little is known about functional relationships at the level of protein-protein interactions, which are the dominant molecular bases responsible for mediating circuit development.
  
  
  
  Proteomics in three independent developing neocortical synaptosomal preparations identified putative interacting proteins of the ligand-activated MET receptor tyrosine kinase, an autism risk gene that mediates synapse development. The candidates were translated into interactome networks and analyzed bioinformatically. Additionally, three independent quantitative proximity ligation assays in cultured neurons and four independent immunoprecipitation analyses of synaptosomes validated protein interactions.
  
  
  
  Approximately 11% (8/72) of MET-interacting proteins, including SHANK3, SYNGAP1, and GRIN2B, are associated with NDDs. Proteins in the MET interactome were translated into a novel MET interactome network based on human protein-protein interaction databases. High-confidence genes from different NDD datasets that encode synaptosomal proteins were analyzed for being enriched in MET interactome proteins. This was found for autism but not schizophrenia, bipolar disorder, major depressive disorder, or attention-deficit/hyperactivity disorder. There is correlated gene expression between MET and its interactive partners in developing human temporal and visual neocortices but not with highly expressed genes that are not in the interactome. Proximity ligation assays and biochemical analyses demonstrate that MET-protein partner interactions are dynamically regulated by receptor activation.
  
  
  
  The results provide a novel molecular framework for deciphering the functional relations of key regulators of synaptogenesis that contribute to both typical cortical development and to NDDs.
authors.affiliation: Department of Pediatrics and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: College of Science, University of Notre Dame, South Bend, Indiana.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baker
authors.affiliation: Department of Pediatrics, Children's Hospital Los Angeles and the Keck School of Medicine of the University of Southern California; Los Angeles, California.
authors.forename: Kathie L
authors.initials: KL
authors.lastname: Eagleson
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California.
authors.forename: Marcelo P
authors.initials: MP
authors.lastname: Coba
authors.affiliation: Department of Pediatrics, Children's Hospital Los Angeles and the Keck School of Medicine of the University of Southern California; Los Angeles, California; Program in Developmental Neurogenetics, Institute for the Developing Mind and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California. Electronic address: plevitt@med.usc.edu.
authors.forename: Pat
authors.initials: P
authors.lastname: Levitt
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D019579:Neocortex / Q000254:growth & development* / Q000378:metabolism*; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons; D060066:Protein Interaction Maps / Q000235:genetics*; D040901:Proteomics / Q000379:methods*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D013569:Synapses / Q000502:physiology*
chemical_list: C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: Autism; Interactome; Mental illnesses; Neocortex; Proteomics; Synaptogenesis