dc.contributor.author | Jo, Hakryul | |
dc.contributor.author | Lo, Pang-Kuo | |
dc.contributor.author | Li, Yitang | |
dc.contributor.author | Loison, Fabien | |
dc.contributor.author | Green, Sarah | |
dc.contributor.author | Wang, Jake | |
dc.contributor.author | Silberstein, Leslie E. | |
dc.contributor.author | Ye, Keqiang | |
dc.contributor.author | Chen, Hexin | |
dc.contributor.author | Luo, Hongbo | |
dc.date.accessioned | 2014-10-30T14:15:51Z | |
dc.date.issued | 2011 | |
dc.identifier.citation | Jo, 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.issn | 1091-6490 | en_US |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:13320255 | |
dc.description.abstract | The 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.iso | en_US | en_US |
dc.publisher | Proceedings of the National Academy of Sciences | en_US |
dc.relation.isversionof | doi:10.1073/pnas.1019062108 | en_US |
dc.relation.hasversion | http://www.ncbi.nlm.nih.gov/pubmed/21464312 | en_US |
dash.license | LAA | |
dc.subject | chemical screening | en_US |
dc.subject | cell death | en_US |
dc.title | Deactivation of Akt by a Small Molecule Inhibitor Targeting Pleckstrin Homology Domain and Facilitating Akt Ubiquitination | en_US |
dc.type | Journal Article | en_US |
dc.description.version | Version of Record | en_US |
dc.relation.journal | Proceedings of the National Academy of Sciences | en_US |
dash.depositing.author | Luo, Hongbo | |
dc.date.available | 2014-10-30T14:15:51Z | |
dc.identifier.doi | 10.1073/pnas.1019062108 | * |
dash.contributor.affiliated | Loison, Fabien | |
dash.contributor.affiliated | Silberstein, Leslie | |
dash.contributor.affiliated | Jo, Hakryul | |
dash.contributor.affiliated | Luo, Hongbo | |