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IKK interacts with rictor and regulates mTORC2

机译：IKK与rictor相互作用并调节mTORC2

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摘要

mTORC2, the mammalian target of rapamycin complex 2 is activated by upstream growth factors, and performs two major functions, phosphorylation of AKT at the serine of 473 and cell cycle-dependent organization of actin cytoskeleton. However, the mechanisms through which mTORC2 is triggered by these signals remain unclear. We demonstrated, for the first time, that inhibitor of nuclear factor κ-B kinase (IKK) interacted with rictor and regulated mTORC2 activity. Not only endogenously, but ectopically expressed IKK α and IKK β physically interacted with rictor. An in vitro binding assay revealed that rictor interacted with IKKα and IKKβ from amino acids 999 to 1397. Moreover, chemical inhibition of IKK, knockdown of IKK by small interference RNA (siRNA), or ectopic expression of kinase-dead IKK (IKK KD) repressed phosphorylation of AKT (S473) in a variety of cell lines and decreased the kinase activity of mTORC2. In NIH 3. T3 cells, inhibition of IKK also reduced phosphorylation of protein kinase α (PKCα) (S657) and resulted in disorganization of actin cytoskeleton. Interestingly, the interaction between IKKα/β and rictor was increased, while the mTOR-rictor association was attenuated by inhibition of IKK. We identified a novel signaling mechanism for the regulation of mTORC2 by IKK: IKK interacted with rictor and regulated the function of mTORC2 including phosphorylation of AKT (S473) and organization of actin cytoskeleton. Inactivated IKK interacted with rictor and competed against mTOR, which resulted in a reduced mTORC2 level and a decrease in mTORC2 activity.
机译：雷帕霉素复合物2的哺乳动物靶标mTORC2被上游生长因子激活，并执行两个主要功能，即473丝氨酸上的AKT磷酸化和肌动蛋白细胞骨架的细胞周期依赖性组织。但是，由这些信号触发mTORC2的机制仍不清楚。我们首次证明了核因子κB激酶（IKK）抑制剂与rictor相互作用并调节了mTORC2的活性。不仅内源性，而且异位表达的IKKα和IKKβ与rictor物理相互作用。体外结合试验显示rictor与IKKα和IKKβ从999至1397位氨基酸发生相互作用。此外，IKK的化学抑制，小干扰RNA（siRNA）抑制IKK或激酶死亡的IKK的异位表达（IKK KD）抑制多种细胞系中AKT（S473）的磷酸化，并降低mTORC2的激酶活性。在NIH 3. T3细胞中，对IKK的抑制作用还减少了蛋白激酶α（PKCα）的磷酸化（S657），并导致肌动蛋白细胞骨架解体。有趣的是，IKKα/β和rictor之间的相互作用增加了，而mTOR-rictor的缔合则由于抑制了IKK而减弱。我们确定了由IKK调节mTORC2的新型信号传导机制：IKK与rictor相互作用并调节了mTORC2的功能，包括AKT（S473）的磷酸化和肌动蛋白细胞骨架的组织。灭活的IKK与rictor相互作用并与mTOR竞争，这导致mTORC2水平降低和mTORC2活性降低。

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