TY - JOUR
T1 - TBK1 Directly Engages Akt/PKB Survival Signaling to Support Oncogenic Transformation
AU - Ou, Yi Hung
AU - Torres, Michael
AU - Ram, Rosalyn
AU - Formstecher, Etienne
AU - Roland, Christina
AU - Cheng, Tzuling
AU - Brekken, Rolf
AU - Wurz, Ryan
AU - Tasker, Andrew
AU - Polverino, Tony
AU - Tan, Seng Lai
AU - White, Michael A.
N1 - Funding Information:
We are grateful to Zhijian James Chen, Xuetao Cao, Philip N. Tsichlis, Charles Yeaman, William Hahn, Keqiang Ye, Shu-Chan Hsu, Bing Su, Dos Sarbassov, Mark Magnuson, David Sabatini, and Bert Vogelstein for many of the reagents used in these studies. We thank Melanie H. Cobb, Philip N. Tsichlis, Lawrence Lum, and members of our laboratory for invaluable advice and discussion. This work was supported by the National Institutes of Health (CA71443 and CA129451) and the Robert Welch Foundation (I-1414).
PY - 2011/2/18
Y1 - 2011/2/18
N2 - 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.
AB - 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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U2 - 10.1016/j.molcel.2011.01.019
DO - 10.1016/j.molcel.2011.01.019
M3 - Article
C2 - 21329883
AN - SCOPUS:79951494608
SN - 1097-2765
VL - 41
SP - 458
EP - 470
JO - Molecular cell
JF - Molecular cell
IS - 4
ER -