Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Mol Cell. 2012 Mar 30;45(6):719-30. doi: 10.1016/j.molcel.2012.01.010. Epub 2012 Feb 16.
The IκB kinase (IKK) pathway is an essential mediator of inflammatory, oncogenic, and cell stress pathways. Recently IKK was shown to be essential for autophagy induction in mammalian cells independent of its ability to regulate NF-κB, but the mechanism by which this occurs is unclear. Here we demonstrate that the p85 regulatory subunit of PI3K is an IKK substrate, phosphorylated at S690 in vitro and in vivo in response to cellular starvation. Cells expressing p85 S690A or inhibited for IKK activity exhibit increased Akt activity following cell starvation, demonstrating that p85 phosphorylation is required for starvation-induced PI3K feedback inhibition. S690 is in a conserved region of the p85 cSH2 domain, and IKK-mediated phosphorylation of this site results in decreased affinity for tyrosine-phosphorylated proteins and decreased PI3K membrane localization. Finally, leucine deprivation is shown to be necessary and sufficient for starvation-induced, IKK-mediated p85 phosphorylation and PI3K feedback inhibition.
IKK 激酶(IKK)途径是炎症、致癌和细胞应激途径的重要介质。最近,研究表明 IKK 在不调节 NF-κB 的情况下对哺乳动物细胞自噬的诱导是必需的,但发生这种情况的机制尚不清楚。在这里,我们证明 PI3K 的 p85 调节亚基是 IKK 的底物,可在体外和体内响应细胞饥饿而在 S690 处被磷酸化。表达 p85 S690A 或抑制 IKK 活性的细胞在细胞饥饿后表现出 Akt 活性增加,表明 p85 磷酸化是饥饿诱导的 PI3K 反馈抑制所必需的。S690 位于 p85 cSH2 结构域的保守区域内,IKK 介导的该位点磷酸化导致对酪氨酸磷酸化蛋白的亲和力降低和 PI3K 膜定位减少。最后,亮氨酸剥夺被证明是饥饿诱导的、IKK 介导的 p85 磷酸化和 PI3K 反馈抑制所必需和充分的。