title: IKBKE phosphorylation and inhibition of FOXO3a: a mechanism of IKBKE oncogenic function.
abstract: Forkhead box O (FOXO) transcription factors are emerging as key regulators of cell survival and growth. The transcriptional activity and subcellular localization of FOXO are tightly regulated by post-translational modifications. Here we report that IKBKE regulates FOXO3a through phosphorylation of FOXO3a-Ser644. The phosphorylation of FOXO3a resulted in its degradation and nuclear-cytoplasmic translocation. Previous studies have shown that IKBKE directly activates Akt and that Akt inhibits FOXO3a by phosphorylation of Ser32, Ser253 and Ser315. However, the activity of Akt-nonphosphorytable FOXO3a-A3 (i.e., converting 3 serine residues to alanine) was inhibited by IKBKE. Furthermore, overexpression of IKBKE correlates with elevated levels of pFOXO3a-S644 in primary lung and breast tumors. IKBKE inhibits cellular function of FOXO3a and FOXO3a-A3 but, to a much less extent, of FOXO3a-S644A. These findings suggest that IKBKE regulates FOXO3a primarily through phosphorylation of SerS644 and that IKBKE exerts its cellular function, at least to some extent, through regulation of FOXO3a.
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing, China.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Guo
authors.forename: Wei
authors.initials: W
authors.lastname: Tian
authors.forename: Shaokun
authors.initials: S
authors.lastname: Shu
authors.forename: Yu
authors.initials: Y
authors.lastname: Xin
authors.forename: Chengchao
authors.initials: C
authors.lastname: Shou
authors.forename: Jin Q
authors.initials: JQ
authors.lastname: Cheng
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009857:Oncogenes; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D010750:Phosphoproteins; D004247:DNA; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; C496565:IKBKE protein, human; C496566:Ikbke protein, mouse