p85α SH2 Domain Phosphorylation by IKK Promotes Feedback Inhibition of PI3K and Akt in Response to Cellular Starvation

被引：59

作者：

Comb, William C. ^{[1
,2
]}

Hutti, Jessica E. ^{[1
]}

Cogswell, Patricia ^{[1
]}

Cantley, Lewis C. ^{[4
,5
]}

Baldwin, Albert S. ^{[1
,2
,3
]}

机构：

[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA

[3] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA

[4] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA

来源：

MOLECULAR CELL | 2012年 / 45卷 / 06期

基金：

美国国家卫生研究院;

关键词：

NF-KAPPA-B; PHOSPHOINOSITIDE; 3-KINASE; REGULATORY SUBUNIT; PROTEIN-KINASE; INSULIN-RESISTANCE; WIDE PREDICTION; INFLAMMATION; ACTIVATION; GROWTH; P85;

D O I：

10.1016/j.molcel.2012.01.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：719 / 730

页数：12

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