A Mathematical Model of the Phosphoinositide Pathway

• Type of Material: Article
• Authors: Daniel V. Olivenca, University of Lisbon; Inna Uliyakina, University of Lisbon; Luis L. Fonseca, Georgia Institute of Technology; Margarida D. Amaral, University of Lisbon; Eberhard Otto Voit, Emory University; Francisco R. Pinto, University of Lisbon
• Language: English
• Date: 2018-03-02
• Publisher: Nature Publishing Group: Open Access Journals - Option C
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-018-22226-8
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 8
• Issue: 1
• Start Page: 3904
• End Page: 3904
• Grant/Funding Information: DO is a recipient of a PhD fellowship from BioSys PhD programme (Ref: SFRH/BD/52486/2014) and IU of SFRH/BD/69180/2010, both from FCT, Portugal.; The funding agencies are not responsible for the content of this article.; This work was supported in part by the grants MCB-1517588 (PI: EOV) of the U.S. National Science Foundation.; Work supported by UID/MULTI/04046/2013 centre grant (to BioISI) and DIFFTARGET PTDC/BIM-MEC/2131/2014 grant (to MDA), both from FCT, Portugal.
• Keywords: DISEASE; Multidisciplinary Sciences; TURNOVER; LIPIDS; DYNAMICS; Science & Technology - Other Topics; MEMBRANE; TRAFFICKING; SYSTEM; CELL REGULATION; Science & Technology; CYSTIC-FIBROSIS; KINASES
• Research Categories: Engineering, Biomedical

Abstract

Phosphoinositides are signalling lipids that constitute a complex network regulating many cellular processes. We propose a computational model that accounts for all species of phosphoinositides in the plasma membrane of mammalian cells. The model replicates the steady-state of the pathway and most known dynamic phenomena. Sensitivity analysis demonstrates model robustness to alterations in the parameters. Model analysis suggest that the greatest contributor to phosphatidylinositol 4,5-biphosphate (PI(4,5)P 2 ) production is a flux representing the direct transformation of PI into PI(4,5)P 2 , also responsible for the maintenance of this pool when phosphatidylinositol 4-phosphate (PI(4)P) is decreased. PI(5)P is also shown to be a significant source for PI(4,5)P 2 production. The model was validated with siRNA screens that knocked down the expression of enzymes in the pathway. The screen monitored the activity of the epithelium sodium channel (ENaC), which is activated by PI(4,5)P 2 . While the model may deepen our understanding of other physiological processes involving phosphoinositides, we highlight therapeutic effects of ENaC modulation in Cystic Fibrosis (CF). The model suggests control strategies where the activities of the enzyme phosphoinositide 4-phosphate 5-kinase I (PIP5KI) or the PI4K + PIP5KI + DVL protein complex are decreased and cause an efficacious reduction in PI(4,5)P 2 levels while avoiding undesirable alterations in other phosphoinositide pools.