Next Article in Journal
Previous Article in Journal
Int. J. Mol. Sci. 2012, 13(3), 2918-2938; doi:10.3390/ijms13032918
Article

Computational Identification and Modeling of Crosstalk between Phosphorylation, O-β-glycosylation and Methylation of FoxO3 and Implications for Cancer Therapeutics

1,2,†
, 2,†
, 1
, 3
 and 2,*
Received: 30 January 2012; in revised form: 23 February 2012 / Accepted: 28 February 2012 / Published: 5 March 2012
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
View Full-Text   |   Download PDF [701 KB, uploaded 19 June 2014]
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.
Keywords: FoxO3; FoxO; in silico; posttranslational modifications; phosphorylation; O-β-glycosylation; methylation; cancer; Yin Yang sites FoxO3; FoxO; in silico; posttranslational modifications; phosphorylation; O-β-glycosylation; methylation; cancer; Yin Yang sites
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Export to BibTeX |
EndNote


MDPI and ACS Style

Butt, A.M.; Feng, D.; Idrees, M.; Tong, Y.; Lu, J. Computational Identification and Modeling of Crosstalk between Phosphorylation, O-β-glycosylation and Methylation of FoxO3 and Implications for Cancer Therapeutics. Int. J. Mol. Sci. 2012, 13, 2918-2938.

AMA Style

Butt AM, Feng D, Idrees M, Tong Y, Lu J. Computational Identification and Modeling of Crosstalk between Phosphorylation, O-β-glycosylation and Methylation of FoxO3 and Implications for Cancer Therapeutics. International Journal of Molecular Sciences. 2012; 13(3):2918-2938.

Chicago/Turabian Style

Butt, Azeem Mehmood; Feng, Dandan; Idrees, Muhammad; Tong, Yigang; Lu, Jun. 2012. "Computational Identification and Modeling of Crosstalk between Phosphorylation, O-β-glycosylation and Methylation of FoxO3 and Implications for Cancer Therapeutics." Int. J. Mol. Sci. 13, no. 3: 2918-2938.


Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert