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

M Salazar; M Lorente; E García-Taboada; E Pérez Gómez; D Dávila; P Zúñiga-García; J María Flores; A Rodríguez; Z Hegedus; D Mosén-Ansorena; A M Aransay; S Hernández-Tiedra; I López-Valero; M Quintanilla; C Sánchez; J L Iovanna; N Dusetti; M Guzmán; S E Francis; A Carracedo; E Kiss-Toth; G Velasco

doi:10.1038/cdd.2014.133

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

Cell Death Differ. 2015 Jan;22(1):131-44. doi: 10.1038/cdd.2014.133. Epub 2014 Aug 29.

Authors

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

Affiliations

¹ 1] Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain [2] Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain.
² Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
³ 1] Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain [2] Instituto de Investigación Hospital 12 de Octubre (I+12), Madrid, Spain.
⁴ CIC bioGUNE, Bizkaia Technology Park, Derio, Spain.
⁵ Department of Animal Surgery and Medicine, School of Veterinary, Complutense University, Madrid, Spain.
⁶ Institute of Biophysics, Hungarian Academy of Sciences, Szeged, Hungary.
⁷ CIC bioGUNE-CIBERehd, Bizkaia Technology Park, Derio, Spain.
⁸ Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.
⁹ Centre de Recherche en Carcérologie de Marseille (CRCM), INSERM UMR, CNRS UMR 7258, Aix Marseille Université and Institut Paoli Calmette, Marseille, France.
¹⁰ 1] Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Madrid, Spain.
¹¹ Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
¹² 1] CIC bioGUNE, Bizkaia Technology Park, Derio, Spain [2] Ikerbasque, Basque Foundation for Science, Bilbao, Spain [3] Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), Bilbao, Spain.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
Forkhead Box Protein O3
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism*
Humans
Mechanistic Target of Rapamycin Complex 2
Mice
Mice, Knockout
Mice, Nude
Multiprotein Complexes / genetics
Multiprotein Complexes / metabolism
Neoplasms / genetics
Neoplasms / metabolism*
Neoplasms / pathology
Phosphorylation / genetics
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism*
Repressor Proteins / genetics
Repressor Proteins / metabolism*
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*

Substances

Cell Cycle Proteins
FOXO3 protein, human
Forkhead Box Protein O3
Forkhead Transcription Factors
FoxO3 protein, mouse
Multiprotein Complexes
Repressor Proteins
TRB3 protein, mouse
TRIB3 protein, human
Tumor Suppressor Proteins
Mechanistic Target of Rapamycin Complex 2
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases