title: Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation.
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.
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Salazar
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Lorente
authors.affiliation: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: García-Taboada
authors.affiliation: 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.
authors.forename: E
authors.initials: E
authors.lastname: Pérez Gómez
authors.affiliation: 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.
authors.forename: D
authors.initials: D
authors.lastname: Dávila
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Derio, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Zúñiga-García
authors.affiliation: Department of Animal Surgery and Medicine, School of Veterinary, Complutense University, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: María Flores
authors.affiliation: Department of Animal Surgery and Medicine, School of Veterinary, Complutense University, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez
authors.affiliation: Institute of Biophysics, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Hegedus
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Derio, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Mosén-Ansorena
authors.affiliation: CIC bioGUNE-CIBERehd, Bizkaia Technology Park, Derio, Spain.
authors.forename: A M
authors.initials: AM
authors.lastname: Aransay
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Hernández-Tiedra
authors.affiliation: 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.
authors.forename: I
authors.initials: I
authors.lastname: López-Valero
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Quintanilla
authors.affiliation: 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.
authors.forename: C
authors.initials: C
authors.lastname: Sánchez
authors.affiliation: Centre de Recherche en Carcérologie de Marseille (CRCM), INSERM UMR, CNRS UMR 7258, Aix Marseille Université and Institut Paoli Calmette, Marseille, France.
authors.forename: J L
authors.initials: JL
authors.lastname: Iovanna
authors.affiliation: Centre de Recherche en Carcérologie de Marseille (CRCM), INSERM UMR, CNRS UMR 7258, Aix Marseille Université and Institut Paoli Calmette, Marseille, France.
authors.forename: N
authors.initials: N
authors.lastname: Dusetti
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Guzmán
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
authors.forename: S E
authors.initials: SE
authors.lastname: Francis
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
authors.forename: E
authors.initials: E
authors.lastname: Kiss-Toth
authors.affiliation: 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.
authors.forename: G
authors.initials: G
authors.lastname: Velasco
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D046912:Multiprotein Complexes; D012097:Repressor Proteins; C474830:TRB3 protein, mouse; C474831:TRIB3 protein, human; D025521:Tumor Suppressor Proteins; D000076225:Mechanistic Target of Rapamycin Complex 2; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases