title: Protein phosphatase 2A reactivates FOXO3a through a dynamic interplay with 14-3-3 and AKT.
abstract: Forkhead box transcription factor FOXO3a, a key regulator of cell survival, is regulated by reversible phosphorylation and subcellular localization. Although the kinases regulating FOXO3a activity have been characterized, the role of protein phosphatases (PP) in the control of FOXO3a subcellular localization and function is unknown. In this study, we detected a robust interaction between FOXO3a and PP2A. We further demonstrate that 14-3-3, while not impeding the interaction between PP2A and FOXO3a, restrains its activity toward AKT phosphorylation sites T32/S253. Disruption of PP2A function revealed that after AKT inhibition, PP2A-mediated dephosphorylation of T32/S253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of FOXO3a. Our findings reveal that distinct phosphatases dephosphorylate conserved AKT motifs within the FOXO family and that PP2A is entwined in a dynamic interplay with AKT and 14-3-3 to directly regulate FOXO3a subcellular localization and transcriptional activation.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Amrik
authors.initials: A
authors.lastname: Singh
authors.forename: Min
authors.initials: M
authors.lastname: Ye
authors.forename: Octavian
authors.initials: O
authors.lastname: Bucur
authors.forename: Shudong
authors.initials: S
authors.lastname: Zhu
authors.forename: Maria
authors.initials: M
authors.lastname: Tanya Santos
authors.forename: Isaac
authors.initials: I
authors.lastname: Rabinovitz
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
authors.forename: Daming
authors.initials: D
authors.lastname: Gao
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: Roya
authors.initials: R
authors.lastname: Khosravi-Far
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D048948:14-3-3 Proteins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D010455:Peptides; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2