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-...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Public Library of Science
2010
|
| _version_ | 1826274287488598016 |
|---|---|
| author | Sei, Y Li, Z Song, J Ren-Patterson, R Tunbridge, E Iizuka, Y Inoue, M Alfonso, B Beltaifa, S Nakai, Y Kolachana, B Chen, J Weinberger, DR |
| author_facet | Sei, Y Li, Z Song, J Ren-Patterson, R Tunbridge, E Iizuka, Y Inoue, M Alfonso, B Beltaifa, S Nakai, Y Kolachana, B Chen, J Weinberger, DR |
| author_sort | Sei, Y |
| collection | OXFORD |
| description | 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. 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. |
| first_indexed | 2024-03-06T22:41:10Z |
| format | Journal article |
| id | oxford-uuid:5b9a3404-10f3-419c-bf86-30b34c408c98 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:41:10Z |
| publishDate | 2010 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:5b9a3404-10f3-419c-bf86-30b34c408c982022-03-26T17:23:06ZEpistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5b9a3404-10f3-419c-bf86-30b34c408c98EnglishSymplectic Elements at OxfordPublic Library of Science2010Sei, YLi, ZSong, JRen-Patterson, RTunbridge, EIizuka, YInoue, MAlfonso, BBeltaifa, SNakai, YKolachana, BChen, JWeinberger, DR 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. 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. |
| spellingShingle | Sei, Y Li, Z Song, J Ren-Patterson, R Tunbridge, E Iizuka, Y Inoue, M Alfonso, B Beltaifa, S Nakai, Y Kolachana, B Chen, J Weinberger, DR Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models. |
| title | Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models. |
| title_full | Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models. |
| title_fullStr | Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models. |
| title_full_unstemmed | Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models. |
| title_short | Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models. |
| title_sort | epistatic and functional interactions of catechol o methyltransferase comt and akt1 on neuregulin1 erbb signaling in cell models |
| work_keys_str_mv | AT seiy epistaticandfunctionalinteractionsofcatecholomethyltransferasecomtandakt1onneuregulin1erbbsignalingincellmodels AT liz epistaticandfunctionalinteractionsofcatecholomethyltransferasecomtandakt1onneuregulin1erbbsignalingincellmodels AT songj epistaticandfunctionalinteractionsofcatecholomethyltransferasecomtandakt1onneuregulin1erbbsignalingincellmodels AT renpattersonr epistaticandfunctionalinteractionsofcatecholomethyltransferasecomtandakt1onneuregulin1erbbsignalingincellmodels AT tunbridgee epistaticandfunctionalinteractionsofcatecholomethyltransferasecomtandakt1onneuregulin1erbbsignalingincellmodels AT iizukay epistaticandfunctionalinteractionsofcatecholomethyltransferasecomtandakt1onneuregulin1erbbsignalingincellmodels AT inouem epistaticandfunctionalinteractionsofcatecholomethyltransferasecomtandakt1onneuregulin1erbbsignalingincellmodels AT alfonsob epistaticandfunctionalinteractionsofcatecholomethyltransferasecomtandakt1onneuregulin1erbbsignalingincellmodels AT beltaifas epistaticandfunctionalinteractionsofcatecholomethyltransferasecomtandakt1onneuregulin1erbbsignalingincellmodels AT nakaiy epistaticandfunctionalinteractionsofcatecholomethyltransferasecomtandakt1onneuregulin1erbbsignalingincellmodels AT kolachanab epistaticandfunctionalinteractionsofcatecholomethyltransferasecomtandakt1onneuregulin1erbbsignalingincellmodels AT chenj epistaticandfunctionalinteractionsofcatecholomethyltransferasecomtandakt1onneuregulin1erbbsignalingincellmodels AT weinbergerdr epistaticandfunctionalinteractionsofcatecholomethyltransferasecomtandakt1onneuregulin1erbbsignalingincellmodels |