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Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling

Yoshitatsu Sei1, Zhen Li, Jian Song

  • 1Clinical Brain Disorder Branch, Genes, Cognition, and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA. seiy@mail.nih.gov

Plos One
|June 4, 2010
PubMed
Abstract

Insights

Catechol-O-methyltransferase (COMT) enzyme activity influences AKT1 activation and cell migration in response to Neuregulin1 (NRG1) signaling. This interaction, mediated by phosphatidylserine synthesis, offers new insights into schizophrenia and cancer pathogenesis.

Area of Science:

  • Molecular biology
  • Neuroscience
  • Genetics

Background:

  • Neuregulin1 (NRG1)-ErbB signaling is implicated in cancer and schizophrenia.
  • NRG1-stimulated B lymphoblast migration is PI3K-AKT1 dependent and impaired in schizophrenia patients.
  • This impairment is linked to the catechol-O-methyltransferase (COMT) Val108/158Met polymorphism.

Purpose of the Study:

  • To examine AKT1 activation in NRG1-stimulated cells.
  • To explore the functional relationship between COMT and AKT1.
  • To investigate the impact of COMT genotype on NRG1-mediated signaling.

Main Methods:

  • Assessed AKT1 phosphorylation and translocation in response to NRG1.
  • Investigated genetic interactions between AKT1 and COMT.
  • Measured phosphatidylserine (PS) levels and COMT enzyme activity.
  • Utilized cell transfection and S-adenosylmethionine (SAM) administration.

Main Results:

  • NRG1-induced AKT1 phosphorylation was diminished in COMT Val carriers.
  • AKT1 translocation to the plasma membrane was impaired in Val carriers.
  • COMT activity inversely correlated with PS levels, affecting AKT1 activation and migration.
  • SAM administration rescued NRG1-induced signaling deficits.

Conclusions:

  • Genetic and functional interactions between COMT and AKT1 influence cellular responses to NRG1.
  • COMT enzyme activity impacts AKT1 function via competition for SAM in PS synthesis.
  • Findings provide novel insights into the pathogenesis of schizophrenia and ErbB-associated cancers.

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