Department of Molecular Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA.
J Biol Chem. 2011 Oct 28;286(43):37389-98. doi: 10.1074/jbc.M111.287433. Epub 2011 Sep 9.
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 (also known as IKKε and IKKi) activates Akt through a PI3K-independent pathway. IKBKE directly phosphorylates Akt-Thr308 and Ser473 independent of the pleckstrin 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 the 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 as well as PH domain. Our data also suggest that Akt inhibitors targeting the PH domain have no effect on the tumors in which hyperactive Akt resulted from elevated IKBKE.
丝氨酸/苏氨酸激酶 Akt 调节细胞生长、增殖和存活等关键细胞过程。有丝分裂原因子对 Akt 的激活依赖于磷脂酰肌醇 3-激酶（PI3K）。在这里，我们报告 IKBKE（也称为 IKKε 和 IKKi）通过一种非 PI3K 依赖的途径激活 Akt。IKBKE 独立于 PH 结构域直接磷酸化 Akt-Thr308 和 Ser473。PI3K 抑制、PDK1 或 mTORC2 复合物的敲低均不影响 IKBKE 对 Akt 的激活。此外，这种激活可以被 Akt 抑制剂 MK-2206 和 GSK690693 抑制，但不能被 Akt PH 结构域的靶向化合物（perifosine 和 triciribine）抑制。IKBKE 的表达与乳腺癌中 Akt 的激活密切相关。此外，抑制 Akt 可抑制 IKBKE 的致癌转化。这些发现表明，IKBKE 是 Akt-Thr308 和 -Ser473 激酶，可独立于 PI3K、PDK1 和 mTORC2 以及 PH 结构域直接激活 Akt。我们的数据还表明，针对 PH 结构域的 Akt 抑制剂对 Akt 活性过高是由于 IKBKE 升高而导致的肿瘤没有影响。
