Abstract
FoxO3 is a member of the forkhead class of transcription factors and plays a major role in the regulation of diverse cellular processes, including cell cycle arrest, DNA repair, and protection from stress stimuli by detoxification of reactive oxygen species. In addition, FoxO3 is a tumor suppressor and has been considered as a novel target for cancer therapeutics. Phosphorylation of FoxO3 via the AKT, IKK, and ERK pathways leads to deregulation, cytoplasmic retention, degradation of FoxO3 and favors tumor progression. Identification of the amino acid residues that are the target of different posttranslational modifications (PTMs) provides a foundation for understanding the molecular mechanisms of FoxO3 modifications and associated outcomes. In addition to phosphorylation, serine and threonine residues of several proteins are regulated by a unique type of PTM known as O-β-glycosylation, which serves as a functional switch. We sought to investigate the crosstalk of different PTMs on the FoxO3 which leads to the onset/progression of various cancers and that could also potentially be targeted as a therapeutic point of intervention. A computational workflow and set of selection parameters have been defined for the identification of target sites and crosstalk between different PTMs. We identified phosphorylation, O-β-GlcNAc modification, and Yin Yang sites on Ser/Thr residues, and propose a potential novel mechanism of crosstalk between these PTMs. Furthermore, methylation potential of human FoxO3 at arginine and lysine residues and crosstalk between methylation and phosphorylation have also been described. Our findings may facilitate the study of therapeutic strategies targeting posttranslational events.
Highlights
Since the initial discovery of the forkhead gene in Drosophila melanogaster, more than 100 forkhead genes and 19 human subgroups that extend from FOXA to FOXS are known to exist
The prediction of generic phosphorylation sites in human FoxO3 was performed using neural network algorithm that is implemented via NetPhos 2.0 server
From the schematic mapping of predicted phosphorylation sites using the primary structure of FoxO3, we observed several Ser/Thr/Tyr residues that were identified in this study and in previous experimental studies present in functionally important domains (Figure 1C)
Summary
Since the initial discovery of the forkhead gene in Drosophila melanogaster, more than 100 forkhead genes and 19 human subgroups that extend from FOXA to FOXS are known to exist. FoxO transcription factors belong to the “O” (“other”) class of the FOX superfamily. Four members of FoxO have been identified: FoxO1, FoxO3, FoxO4, and FoxO6 [1]. These transcription factors are found to be distributed throughout the body. Expression of FoxO proteins is not the same across tissues, suggesting that individual FoxO proteins have specific cellular functions, thereby, forming the most divergent FOX subfamily due to a unique five amino acid (GDSNS). Insertion immediately prior to helix H3 within the forkhead domain. This motif is directly involved in sequence specific interaction with DNA binding sites [2]
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