ArticlePloS one2010
Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models.
Article in PloS one, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 22 citations in OpenAlex.
- Peering into the mind: unraveling schizophrenia's secrets using models.Molecular psychiatry · 2025Review
- Integrated multiplexed assays of variant effect reveal determinants of catechol-O-methyltransferase gene expression.Molecular systems biology · 2024Article
- Mechanisms Underlying the Comorbidity of Schizophrenia and Type 2 Diabetes Mellitus.The international journal of neuropsychopharmacology · 2021Review
- Article
- Neuregulin 1-induced AKT and ERK phosphorylation in patients with fragile X syndrome (FXS) and intellectual disability associated with obstetric complications.Journal of molecular neuroscience : MN · 2014Article
- Animal Models of Psychosis: Current State and Future Directions.Current behavioral neuroscience reports · 2014Article
- Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia.Frontiers in behavioral neuroscience · 2014Article
- Genetic variation in GAD1 is associated with cortical thickness in the parahippocampal gyrus.Journal of psychiatric research · 2013Article
- Structural synaptic elements are differentially regulated in superior temporal cortex of schizophrenia patients.European archives of psychiatry and clinical neuroscience · 2012Article
- Neuroglialpharmacology: myelination as a shared mechanism of action of psychotropic treatments.Neuropharmacology · 2012Review
- A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health.Journal of psychiatry & neuroscience : JPN · 2012Review
- AKT/GSK3 signaling pathway and schizophrenia.Frontiers in molecular neuroscience · 2012Article
- ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2.PloS one · 2012Article
- Orientation and cellular distribution of membrane-bound catechol-O-methyltransferase in cortical neurons: implications for drug development.The Journal of biological chemistry · 2011Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 3 countries.
Funding
Abstract
backgroundNeuregulin1 (NRG1)-ErbB signaling has been implicated in the pathogenesis of cancer and schizophrenia. We have previously reported that NRG1-stimulated migration of B lymphoblasts is PI3K-AKT1dependent and impaired in patients with schizophrenia and significantly linked to the catechol-o-methyltransferase (COMT) Val108/158Met functional polymorphism. METHODOLOGY/PRINCIPAL
findingsWe have now examined AKT1 activation in NRG1-stimulated B lymphoblasts and other cell models and explored a functional relationship between COMT and AKT1. NRG1-induced AKT1 phosphorylation was significantly diminished in Val carriers compared to Met carriers in both normal subjects and in patients. Further, there was a significant epistatic interaction between a putatively functional coding SNP in AKT1 (rs1130233) and COMT Val108/158Met genotype on AKT1 phosphorylation. NRG1 induced translocation of AKT1 to the plasma membrane also was impaired in Val carriers, while PIP(3) levels were not decreased. Interestingly, the level of COMT enzyme activity was inversely correlated with the cells' ability to synthesize phosphatidylserine (PS), a factor that attracts the pleckstrin homology domain (PHD) of AKT1 to the cell membrane. Transfection of SH-SY5Y cells with a COMT Val construct increased COMT activity and significantly decreased PS levels as well as NRG1-induced AKT1 phosphorylation and migration. Administration of S-adenosylmethionine (SAM) rescued all of these deficits. These data suggest that AKT1 function is influenced by COMT enzyme activity through competition with PS synthesis for SAM, which in turn dictates AKT1-dependent cellular responses to NRG1-mediated signaling. CONCLUSION/SIGNIFICANCE: Our findings implicate genetic and functional interactions between COMT and AKT1 and may provide novel insights into pathogenesis of schizophrenia and other ErbB-associated human diseases such as cancer.
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