IκB kinase ε and TANK-binding kinase 1 activate AKT by direct phosphorylation
IκB kinase ε and TANK-binding kinase 1 activate AKT by direct phosphorylation
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DOI：
10.1073/pnas.1016132108
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发表时间：
2011-04-19
影响因子：
11.1
通讯作者：
Guan, Kun-Liang
中科院分区：
文献类型：
--
作者：
Xie, Xiaoduo;Zhang, Denghong;Guan, Kun-Liang
AKT活化需要通过3-磷酸肌醇依赖性蛋白激酶1（PDK 1）磷酸化活化环（T308）和通过雷帕霉素复合物2（mTORC 2）的哺乳动物靶标磷酸化疏水基序（S473）。我们最近观察到，在mTOR敲除的心脏组织中，AKT疏水基序的磷酸化显著升高，而不是降低，这表明存在有助于AKT磷酸化的其他激酶。在这里，我们表明，非典型I κ B激酶e和TANK结合激酶1（IKK β/TBK 1）磷酸化AKT的疏水基序和激活环的方式依赖于PI 3 K信号。这种双重磷酸化导致体外稳健的AKT活化。因此，我们发现生长因子可以诱导Rictor（-/-）细胞中AKT（S473）磷酸化，并且这种作用对mTOR抑制剂Torin 1不敏感。在IKK β/TBK 1双敲除细胞中，生长因子对AKT的激活受到损害。我们还观察到TBK 1在mTOR敲除心脏组织中的表达升高，并且TBK 1是Ras诱导的小鼠胚胎成纤维细胞转化所需的。我们的观察结果表明IKK β/TBK 1在AKT调节中的生理功能和IKK β/TBK 1通过激活AKT在肿瘤发生中的可能机制。
AKT activation requires phosphorylation of the activation loop (T308) by 3-phosphoinositide-dependent protein kinase 1 (PDK1) and the hydrophobic motif (S473) by the mammalian target of rapamycin complex 2 (mTORC2). We recently observed that phosphorylation of the AKT hydrophobic motif was dramatically elevated, rather than decreased, in mTOR knockout heart tissues, indicating the existence of other kinase(s) contributing to AKT phosphorylation. Here we show that the atypical I kappa B kinase e and TANK-binding kinase 1 (IKK epsilon/TBK1) phosphorylate AKT on both the hydrophobic motif and the activation loop in a manner dependent on PI3K signaling. This dual phosphorylation results in a robust AKT activation in vitro. Consistently, we found that growth factors can induce AKT (S473) phosphorylation in Rictor(-/-) cells, and this effect is insensitive to mTOR inhibitor Torin1. In IKK epsilon/TBK1 double-knockout cells, AKT activation by growth factors is compromised. We also observed that TBK1 expression is elevated in the mTOR knockout heart tissues, and that TBK1 is required for Ras-induced mouse embryonic fibroblast transformation. Our observations suggest a physiological function of IKK epsilon/TBK1 in AKT regulation and a possible mechanism of IKK epsilon/TBK1 in oncogenesis by activating AKT.