Salazar Roa, MaríaLorente Pérez, María Del MarGarcia-Taboada, ElenaPérez Gómez, EduardoDavila, DavilaZuñiga, PatriciaFlores Landeira, Juana MaríaRodriguez, AntonioHegedus, ZoltánMosen-Ansorena, DavidAransay, Ana MaríaHernandez-Tiedra, SoniaLopez-Valero, IsraëlQuintanilla, MiguelSánchez García, María CristinaIovanna, JuanDusetti, NelsonGuzmán Pastor, ManuelFrancis, SheilaCarracedo, ArkaitzKiss-Toth, EndreVelasco Díez, Guillermo2024-01-292024-01-292014Salazar, M., Lorente, M., García-Taboada, E. et al. Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation. Cell Death Differ 22, 131–144 (2015). https://doi.org/10.1038/cdd.2014.1331350-904710.1038/cdd.2014.133https://hdl.handle.net/20.500.14352/96199This work was supported by grants from Spanish Ministry of Economy and Competitiveness (MINECO) and Fondo Europeo de Desarrollo Regional (FEDER) (PS09/01401; PI12/02248, FR2009-0052 and IT2009-0053toGV), Comunidad de Madrid (S2011/BMD-2308toMG), Fundacion Mutua Madrilena (AP101042012 to GV) and Breast Cancer Campaign (2012NovSP033 to EKT and GV). Purchase of the TRIB3-deficient mice (LEXKO-1947) linewas fundedby theWellcomeTrust.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 axisengjournal articlehttps://doi.org/10.1038/cdd.2014.133restricted access577.1CancerTribblesAKT-mTOR axisBiología2403 Bioquímica2407 Biología Celular