Serine/threonine kinase Akt regulates key cellular processes such as cell growth, proliferation, and survival. Activation of Akt by mitogenic factor depends on phosphatidylinositol 3-kinase (PI3K). Here, we report that IKBKE activates Akt in response to inflammatory agent but not growth factor stimuli through a PI3K-independent pathway. Depletion of IKBKE inhibits basal and inflammatory factor-stimulated Akt activation. IKBKE directly phosphorylates Akt-Thr308 and -Ser473 independent of plecstrin-homology (PH) domain. IKBKE activation of Akt was not affected by inhibition of PI3K, knockdown of PDK1 or mTORC2 complex. Further, this activation could be inhibited by Akt inhibitors MK-2206 and GSK690693 but not the compounds (perifosine and triciribine) targeting PH domain of Akt. Expression of IKBKE largely correlates with activation of Akt in breast cancer. Moreover, inhibition of Akt suppresses IKBKE oncogenic transformation. These findings indicate that IKBKE is an Akt-Thr308 and -Ser473 kinase and directly activates Akt independent of PI3K, PDK1 and mTORC2. Our data also suggest that Akt inhibitors targeting the PH domain have no effect on the tumours in which hyperactive Akt is resulted from elevated IKBKE.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2233. doi:1538-7445.AM2012-2233

©2012 American Association for Cancer Research
2012