Akt-dependent Activation of mTORC1 Complex Involves Phosphorylation of mTOR (Mammalian Target of Rapamycin) by IκB Kinase α (IKKα)

被引:120
作者
Dan, Han C. [1 ,4 ]
Ebbs, Aaron [1 ]
Pasparakis, Manolis [2 ]
Van Dyke, Terry [3 ]
Basseres, Daniela S. [1 ]
Baldwin, Albert S. [1 ]
机构
[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA
[2] Univ Cologne, Inst Genet, Cologne, Germany
[3] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA
[4] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA
基金
美国国家卫生研究院;
关键词
CELL-GROWTH; DOMAIN PHOSPHORYLATION; FEEDBACK INHIBITION; GENETIC-ANALYSIS; CANCER; PTEN; RHEB; TUMORIGENESIS; SUPPRESSION; BETA;
D O I
10.1074/jbc.M114.554881
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 serine/threonine protein kinase Akt promotes cell survival, growth, and proliferation through phosphorylation of different downstream substrates. A key effector of Akt is the mammalian target of rapamycin (mTOR). Akt is known to stimulate mTORC1 activity through phosphorylation of tuberous sclerosis complex 2 (TSC2) and PRAS40, both negative regulators of mTOR activity. We previously reported that I kappa B kinase alpha (IKK alpha), a component of the kinase complex that leads to NF-kappa B activation, plays an important role in promoting mTORC1 activity downstream of activated Akt. Here, we demonstrate IKK alpha-dependent regulation of mTORC1 using multiple PTEN null cancer cell lines and an animal model with deletion of IKK alpha. Importantly, IKK alpha is shown to phosphorylate mTOR at serine 1415 in a manner dependent on Akt to promote mTORC1 activity. These results demonstrate that IKK alpha is an effector of Akt in promoting mTORC1 activity.
引用
收藏
页码:25227 / 25240
页数:14
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