Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

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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.
This 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 IT2009-0053 to GV), Comunidad de Madrid (S2011/BMD-2308 to MG), Fundación Mutua Madrileña (AP101042012 to GV) and Breast Cancer Campaign (2012NovSP033 to EKT and GV). Purchase of the TRIB3-deficient mice (LEXKO-1947) line was funded by the Wellcome Trust. MS was recipient of a fellowship from Spanish Ministry of Education and Science (MEC), a research formation contract from Comunidad de Madrid and a Postdoctoral Research Contract from Fundación Científica Asociación Española Contra el Cáncer (AECC); ML was sequentially the recipient of a ‘Juan de la Cierva’ contract, a postdoctoral contract from Spanish Ministry of Education and Science (MEC) and a postdoctoral contract from Comunidad de Madrid. AC is supported by an ERC StG (336343), the Ramón y Cajal award (Spanish Ministry of Education), the Basque Department of Industry, Tourism and Trade (Etortek), Marie Curie Reintegration grant (277043), Movember Global Action Plan, ISCIII (PI10/01484) and the Basque Government of health (2012111086) and education (PI2012-03). EPG was the recipient of a Postdoctoral Research Contract from AECC.