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.

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
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 2
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt