Protein phosphatase 2A reactivates FOXO3a through a dynamic interplay with 14-3-3 and AKT.

Molecular Biology of the Cell
Amrik SinghRoya Khosravi-Far

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.

References

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Citations

Aug 7, 2013·Apoptosis : an International Journal on Programmed Cell Death·Octavian BucurRoya Khosravi-Far
Mar 20, 2012·The Journal of Biological Chemistry·Wai-chi HoPeter A Greer
Nov 28, 2013·The Journal of Biological Chemistry·Alexandra J CandasamyMetin Avkiran
Jul 14, 2010·Antioxidants & Redox Signaling·Maaike C W van den Berg, Boudewijn M T Burgering
Aug 3, 2010·Antioxidants & Redox Signaling·Kelvin YenHeidi A Tissenbaum
Jun 15, 2011·Journal of Molecular Cell Biology·Ying ZhaoWei-Guo Zhu
Nov 21, 2012·Molecular and Cellular Biology·R Montgomery GillMichael P Scheid
Dec 25, 2013·PloS One·Lidija K GorsicM Eileen Dolan
Jun 17, 2016·Molecular & Cellular Oncology·Paola TronoPaola Nisticò
Jun 24, 2014·Chemico-biological Interactions·Lauy Al-AnatiUlla Stenius
May 31, 2011·Biochimica Et Biophysica Acta·Melissa DobsonGuri Tzivion
Jun 29, 2011·Biochimica Et Biophysica Acta·Guri TzivionGopalakrishnan Ramakrishnan
Jul 28, 2016·Molecular Cell·Emil Peter Thrane HertzJakob Nilsson
May 12, 2015·Scientific Reports·Octavian BucurRoya Khosravi-Far
Jan 1, 2011·Cancers·Savitha SridharanAlakananda Basu
Oct 28, 2016·Cell Death & Disease·Soha JawhariMireille Verdier
Mar 13, 2010·The Journal of Biological Chemistry·Richard Seonghun Nho, Judy Kahm
May 12, 2016·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Tihomir MiralemMahin D Maines
Jul 27, 2018·Molecular Cancer·Ying LiuJianxun Wang

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Methods Mentioned

BETA
nuclear translocation
immunoprecipitation
Assay
tandem affinity purification
co-IP
coimmunoprecipitation
fluorescence microscopy
transfection

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