http://www.ncbi.nlm.nih.gov/pubmed/?term=tbk1+directly+engages
Mol Cell. 2011 Feb 18;41(4):458-70. doi: 10.1016/j.molcel.2011.01.019.
TBK1 directly engages Akt/PKB survival signaling to support oncogenic transformation.
Ou YH,
Torres M,
Ram R,
Formstecher E,
Roland C,
Cheng T,
Brekken R,
Wurz R,
Tasker A,
Polverino T,
Tan SL,
White MA.
Source
Department of Cell Biology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
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.
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