TBK1 Directly Engages Akt/PKB Survival Signaling to Support Oncogenic Transformation

Yi Hung Ou, Michael Torres, Rosalyn Ram, Etienne Formstecher, Christina Roland, Tzuling Cheng, Rolf Brekken, Ryan Wurz, Andrew Tasker, Tony Polverino, Seng Lai Tan, Michael A. White

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

The innate immune-signaling kinase, TBK1, couples pathogen surveillance to induction of host defense mechanisms. Pathological activation of TBK1 in cancer can overcome programmed cell death cues, enabling cells to survive oncogenic stress. The mechanistic basis of TBK1 prosurvival signaling, however, has been enigmatic. Here, we show that TBK1 directly activates AKT by phosphorylation of the canonical activation loop and hydrophobic motif sites independently of PDK1 and mTORC2. Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, TBK1 is recruited to the exocyst, where it activates AKT. In cells lacking TBK1, insulin activates AKT normally, but AKT activation by exocyst-dependent mechanisms is impaired. Discovery and characterization of a 6-aminopyrazolopyrimidine derivative, as a selective low-nanomolar TBK1 inhibitor, indicates that this regulatory arm can be pharmacologically perturbed independently of canonical PI3K/PDK1 signaling. Thus, AKT is a direct TBK1 substrate that connects TBK1 to prosurvival signaling.

Original languageEnglish (US)
Pages (from-to)458-470
Number of pages13
JournalMolecular Cell
Volume41
Issue number4
DOIs
StatePublished - Feb 18 2011

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Defense Mechanisms
Phosphatidylinositol 3-Kinases
Mitogens
Oncogenes
Innate Immunity
Cues
Cell Death
Phosphotransferases
Phosphorylation
Insulin
Glucose
Neoplasms
TOR complex 2

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

TBK1 Directly Engages Akt/PKB Survival Signaling to Support Oncogenic Transformation. / Ou, Yi Hung; Torres, Michael; Ram, Rosalyn; Formstecher, Etienne; Roland, Christina; Cheng, Tzuling; Brekken, Rolf; Wurz, Ryan; Tasker, Andrew; Polverino, Tony; Tan, Seng Lai; White, Michael A.

In: Molecular Cell, Vol. 41, No. 4, 18.02.2011, p. 458-470.

Research output: Contribution to journalArticle

Ou, YH, Torres, M, Ram, R, Formstecher, E, Roland, C, Cheng, T, Brekken, R, Wurz, R, Tasker, A, Polverino, T, Tan, SL & White, MA 2011, 'TBK1 Directly Engages Akt/PKB Survival Signaling to Support Oncogenic Transformation', Molecular Cell, vol. 41, no. 4, pp. 458-470. https://doi.org/10.1016/j.molcel.2011.01.019
Ou YH, Torres M, Ram R, Formstecher E, Roland C, Cheng T et al. TBK1 Directly Engages Akt/PKB Survival Signaling to Support Oncogenic Transformation. Molecular Cell. 2011 Feb 18;41(4):458-470. https://doi.org/10.1016/j.molcel.2011.01.019
Ou, Yi Hung ; Torres, Michael ; Ram, Rosalyn ; Formstecher, Etienne ; Roland, Christina ; Cheng, Tzuling ; Brekken, Rolf ; Wurz, Ryan ; Tasker, Andrew ; Polverino, Tony ; Tan, Seng Lai ; White, Michael A. / TBK1 Directly Engages Akt/PKB Survival Signaling to Support Oncogenic Transformation. In: Molecular Cell. 2011 ; Vol. 41, No. 4. pp. 458-470.
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