title: TBK1 directly engages Akt/PKB survival signaling to support oncogenic transformation.
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.
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Yi-Hung
authors.initials: YH
authors.lastname: Ou
authors.forename: Michael
authors.initials: M
authors.lastname: Torres
authors.forename: Rosalyn
authors.initials: R
authors.lastname: Ram
authors.forename: Etienne
authors.initials: E
authors.lastname: Formstecher
authors.forename: Christina
authors.initials: C
authors.lastname: Roland
authors.forename: Tzuling
authors.initials: T
authors.lastname: Cheng
authors.forename: Rolf
authors.initials: R
authors.lastname: Brekken
authors.forename: Ryan
authors.initials: R
authors.lastname: Wurz
authors.forename: Andrew
authors.initials: A
authors.lastname: Tasker
authors.forename: Tony
authors.initials: T
authors.lastname: Polverino
authors.forename: Seng-Lai
authors.initials: SL
authors.lastname: Tan
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
mesh_terms: D000818:Animals; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D045325:HCT116 Cells; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D009369:Neoplasms / Q000201:enzymology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt