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Springer Nature [academic journals on nature.com], Cell Death & Differentiation, 1(22), p. 131-144, 2014

DOI: 10.1038/cdd.2014.133

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

Journal article published in 2014 by M. Salazar, M. Lorente, E. García-Taboada, E. Pérez Gómez, D. Dávila, P. Zúñiga-García ORCID, J. María Flores, A. Rodríguez, Zoltán Hegedus, D. Mosén-Ansorena, A. M. Aransay, S. Hernández-Tiedra, I. López-Valero, M. Quintanilla, C. Sánchez and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.Cell Death and Differentiation advance online publication, 29 August 2014; doi:10.1038/cdd.2014.133.