Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models.
BACKGROUND
Neuregulin1 (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.


RESULTS
We 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.


CONCLUSIONS
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.
Sei
Yoshitatsu
Y
Clinical Brain Disorder Branch, Genes, Cognition, and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA. seiy@mail.nih.gov
Li
Zhen
Z
Song
Jian
J
Ren-Patterson
Renee
R
Tunbridge
Elizabeth M
EM
Iizuka
Yukihiko
Y
Inoue
Masahiro
M
Alfonso
Berenice T
BT
Beltaifa
Senda
S
Nakai
Yoko
Y
Kolachana
Bhaskar S
BS
Chen
Jingshan
J
Weinberger
Daniel R
DR
D019943:Amino Acid Substitution / Q000235:genetics; D001402:B-Lymphocytes / Q000201:enzymology; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D004843:Epistasis, Genetic; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D020890:Neuregulin-1 / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
D020890:Neuregulin-1; D018129:Phosphatidylinositol Phosphates; D010718:Phosphatidylserines; C060974:phosphatidylinositol 3,4,5-triphosphate; D002394:Catechol O-Methyltransferase; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt