| Literature DB >> 25168244 |
M Salazar1, M Lorente1, E García-Taboada2, E Pérez Gómez3, D Dávila1, P Zúñiga-García4, J María Flores5, A Rodríguez5, Z Hegedus6, D Mosén-Ansorena4, A M Aransay7, S Hernández-Tiedra1, I López-Valero1, M Quintanilla8, C Sánchez3, J L Iovanna9, N Dusetti9, M Guzmán10, S E Francis11, A Carracedo12, E Kiss-Toth11, G Velasco1.
Abstract
Tribbles pseudokinase-3 (TRIB3) has been proposed to act as an inhibitor of AKT although the precise molecular basis of this activity and whether the loss of TRIB3 contributes to cancer initiation and progression remain to be clarified. In this study, by using a wide array of in vitro and in vivo approaches, including a Trib3 knockout mouse, we demonstrate that TRIB3 has a tumor-suppressing role. We also find that the mechanism by which TRIB3 loss enhances tumorigenesis relies on the dysregulation of the phosphorylation of AKT by the mTORC2 complex, which leads to an enhanced phosphorylation of AKT on Ser473 and the subsequent hyperphosphorylation and inactivation of the transcription factor FOXO3. These observations support the notion that loss of TRIB3 is associated with a more aggressive phenotype in various types of tumors by enhancing the activity of the mTORC2/AKT/FOXO axis.Entities:
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Year: 2014 PMID： 25168244 PMCID： PMC4262779 DOI： 10.1038/cdd.2014.133
Source DB: PubMed Journal: Cell Death Differ ISSN： 1350-9047 Impact factor: 15.828