PI3K/Akt promotes feedforward mTORC2 activation through IKKα.
PI3K/Akt promotes feedforward mTORC2 activation through IKKα.
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DOI：
10.18632/oncotarget.8383
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发表时间：
2016-04-19
期刊：
影响因子：
--
通讯作者：
Baldwin AS
中科院分区：
文献类型：
--
作者：
Dan HC;Antonia RJ;Baldwin AS
Ser-Thr Akt在细胞存活、细胞生长和增殖以及能量代谢的调节中起关键作用，并且在许多癌症中失调。Akt活性的调节取决于两个位点的磷酸化：（i）磷酸肌醇依赖性激酶-1（PDK 1）激活环中的Thr 308和（ii）称为PDK 2的第二活性的羧基末端Ser 473疏水基序，PDK 2是由mTOR、rictor和Sin 1组成的mTORC 2复合物。以前我们证明了IKKα（IKK复合物中控制NF-κB活化的组分）参与了mTORC 1的Akt依赖性调节。在这里，我们探讨了IKKα在控制Akt活性中的潜在参与，以及这是否可能涉及mTORC 2。实验表明，在几种癌细胞中，IKKα以依赖于PI 3 K/Akt活性的方式与mTORC 2结合，并且IKKα积极促进Akt在Ser 473和Thr 308的磷酸化。此外，IKKα增强了针对Ser 473上Akt的mTORC 2激酶活性以及Akt介导的FOXO 3a和GSK 3 β磷酸化，但不增强其他Akt相关靶点（如TSC 2和PRAS 40）的活性，表明细胞中存在多种Akt激活机制。此外，IKKα的缺失抑制了与mTORC 1抑制相关的生长因子诱导的Akt活化。这些结果表明，IKKα可作为mTORC 2的前馈调节因子，并且IKKα可作为阻断某些癌症中mTORC 2和Akt活化的关键治疗靶点。
The ser-thr Akt plays a critical role in the regulation of cell survival, cell growth and proliferation, as well as energy metabolism and is dysregulated in many cancers. The regulation of Akt activity depends on the phosphorylation at two sites: (i) Thr308 in the activation loop by phosphoinositide-dependent kinase-1 (PDK1) and (ii) Ser473 hydrophobic motif at the carboxyl terminus by a second activity termed PDK2, which is the mTORC2 complex composed of mTOR, rictor, and Sin1. Previously we demonstrated that IKKα, a component of the IKK complex that controls NF-κB activation, participates in the Akt-dependent regulation of mTORC1. Here we have explored a potential involvement of IKKα in controlling Akt activity and whether this may involve mTORC2. The experiments show that IKKα associates with mTORC2 in several cancer cells in a manner dependent on PI3K/Akt activity and that IKKα positively promotes Akt phosphorylation at Ser473 and at Thr308. Moreover, IKKα enhances mTORC2 kinase activity directed to Akt on Ser473 and Akt-mediated phosphorylation of FOXO3a and GSK3β, but not other Akt-associated targets such as TSC2 and PRAS40, indicating the existence of multiple mechanisms of Akt activation in cells. In addition, loss of IKKα suppresses growth factor-induced Akt activation associated with mTORC1 inhibition. These results indicate that IKKα serves as a feedforward regulator of mTORC2 and that IKKα could serve as a key therapeutic target to block mTORC2 and Akt activation in some cancers.
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DOI：
10.1083/jcb.200408161
发表时间：
2004-11-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Manning BD
通讯作者：
Manning BD
MTORC2激酶复合物的PTDINS（3,4,5）P3依赖性激活。
影响因子：
28.2
作者：
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通讯作者：
Wei W
影响因子：
64.5
作者：
Jacinto, Estela;Facchinetti, Valeria;Su, Bing
通讯作者：
Su, Bing
影响因子：
11.2
作者：
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通讯作者：
Baldwin, Albert S.
DOI：
10.1073/pnas.1016132108
发表时间：
2011-04-19
影响因子：
11.1
作者：
Xie, Xiaoduo;Zhang, Denghong;Guan, Kun-Liang
通讯作者：
Guan, Kun-Liang