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Protein Phosphatase 2A Reactivates FOXO3a through a Dynamic Interplay with 14-3-3 and AKT

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 loc...

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Autores principales: Singh, Amrik, Ye, Min, Bucur, Octavian, Zhu, Shudong, Tanya Santos, Maria, Rabinovitz, Isaac, Wei, Wenyi, Gao, Daming, Hahn, William C., Khosravi-Far, Roya
Formato: Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836964/
https://www.ncbi.nlm.nih.gov/pubmed/20110348
http://dx.doi.org/10.1091/mbc.E09-09-0795
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author Singh, Amrik
Ye, Min
Bucur, Octavian
Zhu, Shudong
Tanya Santos, Maria
Rabinovitz, Isaac
Wei, Wenyi
Gao, Daming
Hahn, William C.
Khosravi-Far, Roya
author_facet Singh, Amrik
Ye, Min
Bucur, Octavian
Zhu, Shudong
Tanya Santos, Maria
Rabinovitz, Isaac
Wei, Wenyi
Gao, Daming
Hahn, William C.
Khosravi-Far, Roya
author_sort Singh, Amrik
collection PubMed
description 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.
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spelling pubmed-28369642010-05-30 Protein Phosphatase 2A Reactivates FOXO3a through a Dynamic Interplay with 14-3-3 and AKT Singh, Amrik Ye, Min Bucur, Octavian Zhu, Shudong Tanya Santos, Maria Rabinovitz, Isaac Wei, Wenyi Gao, Daming Hahn, William C. Khosravi-Far, Roya Mol Biol Cell Articles 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. The American Society for Cell Biology 2010-03-15 /pmc/articles/PMC2836964/ /pubmed/20110348 http://dx.doi.org/10.1091/mbc.E09-09-0795 Text en © 2010 by The American Society for Cell Biology
spellingShingle Articles
Singh, Amrik
Ye, Min
Bucur, Octavian
Zhu, Shudong
Tanya Santos, Maria
Rabinovitz, Isaac
Wei, Wenyi
Gao, Daming
Hahn, William C.
Khosravi-Far, Roya
Protein Phosphatase 2A Reactivates FOXO3a through a Dynamic Interplay with 14-3-3 and AKT
title Protein Phosphatase 2A Reactivates FOXO3a through a Dynamic Interplay with 14-3-3 and AKT
title_full Protein Phosphatase 2A Reactivates FOXO3a through a Dynamic Interplay with 14-3-3 and AKT
title_fullStr Protein Phosphatase 2A Reactivates FOXO3a through a Dynamic Interplay with 14-3-3 and AKT
title_full_unstemmed Protein Phosphatase 2A Reactivates FOXO3a through a Dynamic Interplay with 14-3-3 and AKT
title_short Protein Phosphatase 2A Reactivates FOXO3a through a Dynamic Interplay with 14-3-3 and AKT
title_sort protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and akt
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836964/
https://www.ncbi.nlm.nih.gov/pubmed/20110348
http://dx.doi.org/10.1091/mbc.E09-09-0795
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