IκB kinase ε and TANK-binding kinase 1 activate AKT by direct phosphorylation

Xiaoduo Xie, Denghong Zhang, Bin Zhao, Min Kan Lu, Ming You, Gianluigi Condorelli, Cun Yu Wang, Kun Liang Guan

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

AKT activation requires phosphorylation of the activation loop (T308) by 3-phosphoinositide-dependent protein kinase 1 (PDK1) and the hydrophobic motif (S473) by the mammalian target of rapamycin complex 2 (mTORC2). We recently observed that phosphorylation of the AKT hydrophobic motif was dramatically elevated, rather than decreased, in mTOR knockout heart tissues, indicating the existence of other kinase(s) contributing to AKT phosphorylation. Here we show that the atypical IκB kinase ε and TANK-binding kinase 1 (IKKε/TBK1) phosphorylate AKT on both the hydrophobic motif and the activation loop in a manner dependent on PI3K signaling. This dual phosphorylation results in a robust AKT activation in vitro. Consistently, we found that growth factors can induce AKT (S473) phosphorylation in Rictor -/- cells, and this effect is insensitive to mTOR inhibitor Torin1. In IKKε/TBK1 double-knockout cells, AKT activation by growth factors is compromised. Wealso observed that TBK1 expression is elevated in the mTOR knockout heart tissues, and that TBK1 is required for Ras-induced mouse embryonic fibroblast transformation. Our observations suggest a physiological function of IKKε/TBK1 in AKT regulation and a possible mechanism of IKKε/TBK1 in oncogenesis by activating AKT.

Original languageEnglish
Pages (from-to)6474-6479
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number16
DOIs
Publication statusPublished - Apr 19 2011

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Phosphotransferases
Phosphorylation
Intercellular Signaling Peptides and Proteins
3-Phosphoinositide-Dependent Protein Kinases
I-kappa B Kinase
Phosphatidylinositol 3-Kinases
Carcinogenesis
Fibroblasts

Keywords

  • Cancer
  • IKK-related protein kinase
  • Protein kinase B

ASJC Scopus subject areas

  • General

Cite this

IκB kinase ε and TANK-binding kinase 1 activate AKT by direct phosphorylation. / Xie, Xiaoduo; Zhang, Denghong; Zhao, Bin; Lu, Min Kan; You, Ming; Condorelli, Gianluigi; Wang, Cun Yu; Guan, Kun Liang.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 16, 19.04.2011, p. 6474-6479.

Research output: Contribution to journalArticle

Xie, Xiaoduo ; Zhang, Denghong ; Zhao, Bin ; Lu, Min Kan ; You, Ming ; Condorelli, Gianluigi ; Wang, Cun Yu ; Guan, Kun Liang. / IκB kinase ε and TANK-binding kinase 1 activate AKT by direct phosphorylation. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 16. pp. 6474-6479.
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AU - Condorelli, Gianluigi

AU - Wang, Cun Yu

AU - Guan, Kun Liang

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