Department of Pathology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA 02215, USA.
Mol Biol Cell. 2010 Mar 15;21(6):1140-52. doi: 10.1091/mbc.e09-09-0795. Epub 2010 Jan 28.
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.
叉头框转录因子 FOXO3a 是细胞存活的关键调节因子，其活性受到可逆磷酸化和亚细胞定位的调控。尽管已经鉴定出调节 FOXO3a 活性的激酶，但蛋白磷酸酶 (PP) 在控制 FOXO3a 亚细胞定位和功能中的作用尚不清楚。在本研究中，我们检测到 FOXO3a 与 PP2A 之间存在强烈的相互作用。我们进一步证明，14-3-3 虽然不阻碍 PP2A 与 FOXO3a 的相互作用，但限制其对 AKT 磷酸化位点 T32/S253 的作用。破坏 PP2A 的功能表明，在 AKT 抑制后，PP2A 介导的 T32/S253 去磷酸化对于 14-3-3 的解离、核转位和 FOXO3a 的转录激活是必需的。我们的发现揭示了不同的磷酸酶使 FOXO 家族内保守的 AKT 基序去磷酸化，并且 PP2A 与 AKT 和 14-3-3 交织在一起，直接调节 FOXO3a 的亚细胞定位和转录激活。
