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dc.contributor.authorJo, Hakryul
dc.contributor.authorLo, Pang-Kuo
dc.contributor.authorLi, Yitang
dc.contributor.authorLoison, Fabien
dc.contributor.authorGreen, Sarah
dc.contributor.authorWang, Jake
dc.contributor.authorSilberstein, Leslie E.
dc.contributor.authorYe, Keqiang
dc.contributor.authorChen, Hexin
dc.contributor.authorLuo, Hongbo
dc.date.accessioned2014-10-30T14:15:51Z
dc.date.issued2011
dc.identifier.citationJo, Hakryul, Pang-Kuo Lo, Yitang Li, Fabien Loison, Sarah Green, Jake Wang, Leslie E. Silberstein, Keqiang Ye, Hexin Chen, and Hongbo R. Luo. 2011. “Deactivation of Akt by a Small Molecule Inhibitor Targeting Pleckstrin Homology Domain and Facilitating Akt Ubiquitination.” Proceedings of the National Academy of Sciences 108 (16) (April 4): 6486–6491. doi:10.1073/pnas.1019062108. http://dx.doi.org/10.1073/pnas.1019062108.en_US
dc.identifier.issn1091-6490en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:13320255
dc.description.abstractThe phosphatidylinositol-3,4,5-triphosphate (PIP3) binding function of pleckstrin homology (PH) domain is essential for the activation of oncogenic Akt/PKB kinase. Following the PIP3-mediated activation at the membrane, the activated Akt is subjected to other regulatory events, including ubiquitination-mediated deactivation. Here, by identifying and characterizing an allosteric inhibitor, SC66, we show that the facilitated ubiquitination effectively terminates Akt signaling. Mechanistically, SC66 manifests a dual inhibitory activity that directly interferes with the PH domain binding to PIP3 and facilitates Akt ubiquitination. A known PH domain-dependent allosteric inhibitor, which stabilizes Akt, prevents the SC66-induced Akt ubiquitination. A cancer-relevant Akt1 (e17k) mutant is unstable, making it intrinsically sensitive to functional inhibition by SC66 in cellular contexts in which the PI3K inhibition has little inhibitory effect. As a result of its dual inhibitory activity, SC66 manifests a more effective growth suppression of transformed cells that contain a high level of Akt signaling, compared with other inhibitors of PIP3/Akt pathway. Finally, we show the anticancer activity of SC66 by using a soft agar assay as well as a mouse xenograft tumor model. In conclusion, in this study, we not only identify a dual-function Akt inhibitor, but also demonstrate that Akt ubiquitination could be chemically exploited to effectively facilitate its deactivation, thus identifying an avenue for pharmacological intervention in Akt signaling.en_US
dc.language.isoen_USen_US
dc.publisherProceedings of the National Academy of Sciencesen_US
dc.relation.isversionofdoi:10.1073/pnas.1019062108en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pubmed/21464312en_US
dash.licenseLAA
dc.subjectchemical screeningen_US
dc.subjectcell deathen_US
dc.titleDeactivation of Akt by a Small Molecule Inhibitor Targeting Pleckstrin Homology Domain and Facilitating Akt Ubiquitinationen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dash.depositing.authorLuo, Hongbo
dc.date.available2014-10-30T14:15:51Z
dc.identifier.doi10.1073/pnas.1019062108*
dash.contributor.affiliatedLoison, Fabien
dash.contributor.affiliatedSilberstein, Leslie
dash.contributor.affiliatedJo, Hakryul
dash.contributor.affiliatedLuo, Hongbo


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