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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...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2010
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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. |
format | Text |
id | pubmed-2836964 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
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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