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dc.contributor.authorPeng, Jinghua
dc.contributor.authorRamatchandirin, Balamurugan
dc.contributor.authorWang, Yu
dc.contributor.authorPearah, Alexia
dc.contributor.authorNamachivayam, Kopperuncholan
dc.contributor.authorWolf, Risa M
dc.contributor.authorSteele, Kimberley
dc.contributor.authorMohanKumar, Krishnan
dc.contributor.authorYu, Liqing
dc.contributor.authorGuo, Shaodong
dc.contributor.authorWhite, Morris F
dc.contributor.authorMaheshwari, Akhil
dc.contributor.authorHe, Ling
dc.date.accessioned2022-01-28T15:31:20Z
dc.date.available2022-01-28T15:31:20Z
dc.date.issued2022-01-21
dc.identifier.urihttp://hdl.handle.net/10713/17799
dc.description.abstractInhibition of P300 acetyltransferase activity by specific inhibitor C646 has been shown to improve insulin signaling. However, the underlying molecular mechanism of this improvement remains unclear. In this study, we analyzed P300 levels of obese patients and found that they were significantly increased in liver hepatocytes. In addition, large amounts of P300 appeared in the cytoplasm. Inhibition of P300 acetyltransferase activity by C646 drastically increased tyrosine phosphorylation of the insulin receptor protein substrates (IRS1/2) without affecting the tyrosine phosphorylation of the beta subunit of the insulin receptor (IRβ) in hepatocytes in the absence of insulin. Since IRS1/2 requires membrane translocation and binding to inositol compounds for normal functions, we also examined the role of acetylation on binding to phosphatidylinositol(4,5)P2, and found that IRS1/2 acetylation by P300 reduced this binding. In contrast, we show that inhibition of IRS1/2 acetylation by C646 facilitates IRS1/2 membrane translocation. Intriguingly, we demonstrate that C646 activates IRβ's tyrosine kinase activity and directly promotes IRβ interaction with IRS1/2, leading to the tyrosine phosphorylation of IRS1/2 and subsequent activation of insulin signaling even in the absence of insulin. In conclusion, these data reveal the unique effects of C646 in activating insulin signaling in patients with obesity and diabetes.en_US
dc.description.urihttps://doi.org/10.1016/j.jbc.2022.101621en_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.rightsCopyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.en_US
dc.subjectInhibitor C646en_US
dc.subjectInsulin receptoren_US
dc.subjectinsulin receptor substrateen_US
dc.subjecttyrosine phosphorylationen_US
dc.titleThe P300 acetyltransferase inhibitor C646 promotes membrane translocation of insulin receptor protein substrate and interaction with the insulin receptor.en_US
dc.typeArticleen_US
dc.identifier.doi10.1016/j.jbc.2022.101621
dc.identifier.pmid35074429
dc.source.journaltitleThe Journal of biological chemistry
dc.source.beginpage101621
dc.source.endpage
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States


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