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J Biol Chem. 2014 Sep 5;289(36):25227-40. doi: 10.1074/jbc.M114.554881. Epub 2014 Jul 2.

Akt-dependent activation of mTORC1 complex involves phosphorylation of mTOR (mammalian target of rapamycin) by IκB kinase α (IKKα).

Author information

1
From the Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201.
2
From the Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
3
Institute for Genetics University of Cologne, Cologne, Germany.
4
Mouse Cancer Genetics Program, NCI, National Institutes of Health, Frederick, Maryland 21702, and.
5
From the Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, abaldwin@med.unc.edu.

Abstract

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 IκB kinase α (IKKα), a component of the kinase complex that leads to NF-κB activation, plays an important role in promoting mTORC1 activity downstream of activated Akt. Here, we demonstrate IKKα-dependent regulation of mTORC1 using multiple PTEN null cancer cell lines and an animal model with deletion of IKKα. Importantly, IKKα is shown to phosphorylate mTOR at serine 1415 in a manner dependent on Akt to promote mTORC1 activity. These results demonstrate that IKKα is an effector of Akt in promoting mTORC1 activity.

KEYWORDS:

Akt; Cell Proliferation; IKK; Mammalian Target of Rapamycin (mTOR); Phosphatase and Tensin Homolog (PTEN); Phosphorylation; Raptor

PMID:
24990947
PMCID:
PMC4155685
DOI:
10.1074/jbc.M114.554881
[Indexed for MEDLINE]
Free PMC Article

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