Deactivation of Akt by a Small Molecule Inhibitor Targeting Pleckstrin Homology Domain and Facilitating Akt Ubiquitination
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Lo, Pang-Kuo
Li, Yitang
Green, Sarah
Wang, Jake
Ye, Keqiang
Chen, Hexin
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https://doi.org/10.1073/pnas.1019062108Metadata
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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.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.Other Sources
http://www.ncbi.nlm.nih.gov/pubmed/21464312Terms of Use
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