p85α SH2 Domain Phosphorylation by IKK Promotes Feedback Inhibition of PI3K and Akt in Response to Cellular Starvation
p85α SH2 Domain Phosphorylation by IKK Promotes Feedback Inhibition of PI3K and Akt in Response to Cellular Starvation
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DOI：
10.1016/j.molcel.2012.01.010
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发表时间：
2012-03-30
期刊：
影响因子：
16
通讯作者：
Baldwin, Albert S.
中科院分区：
文献类型：
--
作者：
Comb, William C.;Hutti, Jessica E.;Baldwin, Albert S.
I κ B激酶（IKK）途径是炎症、致癌和细胞应激途径的重要介质。最近，IKK被证明对于哺乳动物细胞中的自噬诱导是必需的，而不依赖于其调节NF-κ B的能力，但其发生的机制尚不清楚。在这里，我们证明了P13 K的p85调节亚基是IKK底物，在体外和体内响应于细胞饥饿在S690磷酸化。表达p85 S690 A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PI 3 K反馈抑制所必需的。S690位于p85 cSH 2结构域的保守区域，IKK介导的该位点的磷酸化导致对酪氨酸磷酸化蛋白的亲和力降低和PI 3 K膜定位降低。最后，亮氨酸剥夺被证明是必要的和足够的饥饿诱导，IKK介导的p85磷酸化和PI 3 K反馈抑制。
The I kappa B 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 independenl: of its ability to regulate NF-kappa B, but the mechanism by which this occurs is unclear. Here we demonstrate that the p85 regulatory subunit of P13K 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.