Bimodal regulation of FoxO3 by AKT and 14-3-3

被引:98
作者
Dobson, Melissa [3 ,4 ]
Ramakrishnan, Gopalakrishnan [1 ,2 ]
Ma, Stephanie [3 ,4 ]
Kaplun, Ludmila [3 ,4 ]
Balan, Vitaly [3 ,4 ]
Fridman, Rafael [3 ,4 ]
Tzivion, Guri [1 ,2 ,3 ,4 ]
机构
[1] Univ Mississippi, Med Ctr, Inst Canc, Jackson, MS 39216 USA
[2] Univ Mississippi, Med Ctr, Dept Biochem, Jackson, MS 39216 USA
[3] Wayne State Univ, Dept Pathol, Detroit, MI 48201 USA
[4] Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48201 USA
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH | 2011年 / 1813卷 / 08期
关键词
AKT; 14-3-3; FoxO; Forkhead domain; Transcription factors; Protein phosphorylation; FORKHEAD TRANSCRIPTION FACTOR; PROTEIN-KINASE B; CELL-SURVIVAL; OXIDATIVE-STRESS; GENE-EXPRESSION; DNA-BINDING; PROMOTES TUMORIGENESIS; SIGNALING PATHWAY; FACTOR AFX; PHOSPHORYLATION;
D O I
10.1016/j.bbamcr.2011.05.001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
FoxO3 is a member of FoxO family transcription factors that mediate cellular functions downstream of AKT. FoxO3 phosphorylation by AKT generates binding sites for 14-3-3, which in-turn regulates FoxO3 transcriptional activity and localization. We examine here the functional significance of AKT-FoxO3 interaction and further detail the mechanistic aspects of FoxO3 regulation by AKT and 14-3-3. Our data show that AKT overexpression increases the steady-state levels of FoxO3 protein in a manner dependent on AKT activity and its ability to bind FoxO3. Characterization of the AKT-FoxO3 interaction shows that the three AKT phosphorylation-site-recognition motifs (RxRxxS/T) present on FoxO3, which are required for FoxO3 phosphorylation, are dispensable for AKT binding, suggesting that Ala has a docking point on FoxO3 distinct from the phosphorylation-recognition motifs. Development of a FoxO3 mutant deficient in 14-3-3 binding (P34A), which can be phosphorylated by AKT, established that 14-3-3 binding and not AKT phosphorylation per se controls FoxO3 transcriptional activity. Intriguingly, 14-3-3 binding was found to stabilize FoxO3 by inhibiting its dephosphorylation and degradation rates. Collectively, our data support a model where both AKT and 14-3-3 positively regulate FoxO3 in addition to their established negative roles and that 14-3-3 availability could dictate the fate of phosphorylated FoxO3 toward degradation or recycling. (C) 2011 Elsevier B.V. All rights reserved.
引用
收藏
页码:1453 / 1464
页数:12
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