title: IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation.
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. We also 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.
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Xiaoduo
authors.initials: X
authors.lastname: Xie
authors.forename: Denghong
authors.initials: D
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.forename: Min-Kan
authors.initials: MK
authors.lastname: Lu
authors.forename: Ming
authors.initials: M
authors.lastname: You
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.forename: Cun-Yu
authors.initials: CY
authors.lastname: Wang
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005347:Fibroblasts / Q000201:enzymology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D009206:Myocardium / Q000201:enzymology; D009287:Naphthyridines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; C493245:CRTC2 protein, human; D002352:Carrier Proteins; C504923:Crtc2 protein, mouse; D009287:Naphthyridines; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015534:Trans-Activators; D014157:Transcription Factors; C525637:rictor protein, mouse; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C403191:TBK1 protein, human; D051550:I-kappa B Kinase; C496565:IKBKE protein, human; C496566:Ikbke protein, mouse