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MET pathway PMID 19339766

Met is a receptor tyrosine kinase that is expressed during the mouse development in the areas of the brain involved in social behavior and emotional regulation. Previous studies suggest that when MET receptors are activated, the development and maturation of social behavior and emotional regulation are changed. In addition, changes in the transcription of the MET gene via the promoter variant rs1858830 C allele or of another marker on the MET gene, have been significantly associated with Autism Spectrum Disorders.1 However, in one study it was found that this allele was only associated with ASD in multiplex familes.3 MET transcript and MET protein are decreased 2 fold in postmortem brains of individuals with ASD as compared to typically developing individuals. MET receptor tyrosine kinase also has a role in Gastrointestinal repair, which could explain why gastrointestinal problems occur more frequently in those with ASD than in the typically developing population. It has been shown in the mouse forebrain that there is an enrichment of Met expression in projection neurons of the cerebral cortex, hippocampus, and amygdala especially during synapse formation and pruning. The circuits in these brain regions control the striatum, thalamus, subcortical limbic structures, and the integration of information across cortical areas, thus affecting the core social, communication, and behavioral flexibility domains.1

The MET biological pathway, which is composed of its is the only known ligand hepatocyte growth factor, the proteins that mediate receptor signaling, and the proteins that mediate receptor signaling can be influenced by all of these mechanism of heritable risk variants, de novo mutations and copy number variations, and genetic and environmental modifiers of core phenotypes and associated medical conditions.1 Two genes, PLAUR and SERPINE1 that are involved in the MET signaling pathway are associated with increased ASD risk, and each mRNA exhibits altered expression in the postmortem cerebral cortex of individuals with ASD compared to controls. 2 The activating ligand for the MET receptor is encoded by the hepatocyte growth factor gene. After translation, it must be cleaved by the enzyme plasminogen activator (PLAUR) in order to bind efficiently to the MET receptor. HGF cleavage can be suppressed by SERPINE1. There were increased levels of HGF, SERPINE1, and PLAUR found in the postmortem cerebral cortex as well as differences in MET.3 In both multigenic and syndromic ASD, Pl3K signal disruption occurs. However, the MET-regulating genes PLAUR and SERPINE1 are only found in multiplex families and thus linked to multigenic, idiopathic ASD. The broader autism phenotype is found to a far greater extent in parents from multiplex rather than simplex families, suggesting that heritable, rather than de novo mechanisms for ASD expression occur in multiplex families. 2

Furthermore, the MET/Pl3K pathway is highly vulnerable to environmental perturbations. The normal level of binding of the transcription factor SP1 in the ERK/Pl3K pathway is reduced by the ASD-associated rs188830 C allele. 2


HGF and MET are present in both developing and adult mammalian brains which suggests that they have a role development as a child and adult. HGF act as a neurotrophic factor for motor, sensory, and parasympathetic neurons and influences neuronal migration and dendritic development. The HGF/MET pathway also has a part in regulating dendritic morphology in the cerebral cortex and promoting neurite outgrowth. This pathway is also used by the immune system, since it was found that MET is expressed during the activation of monocytes. Monocytes that have been stimulated by HGF have increased expression of chemoattractant factors. Additionally, HGF has immunosuppressive effects without the need for an upregulation of IL-10 or TGF-β, suggesting that HGF/MET signalling is involved in the regulation of inflammatory responses. 4

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1. Campbell DB et. al. Association of MET with social and communication phenotypes in individuals with autism spectrum disorder.Am J Med Genet B Neuropsychiatr Genet. 2009 Jun 22. PMID 19548256

2. Levitt P. et. al. The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders.J Clin Invest. 2009 Apr;119(4):747-54 PMID 19339766

3. Campbell DB et. al. Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder.Autism Res. 2008 Jun;1(3):159-68. PMID 19360663

4. Pardo, CA et. al. The Neurobiology of Autism.Brain Pathol. 2007 Oct;17(4):434-47. PMID 17919129