A Mathematical Model of the Phosphoinositide Pathway

ABSTRACT

Phosphoinositides are signaling lipids that constitute a complex network regulating many cellular processes. We propose a computational model that accounts for all known species of phosphoinositides in the plasma membrane of mammalian cells. The model replicates the steady-state of the phosphoinositide pathway and most known dynamic phenomena. Furthermore, sensitivity analysis demonstrates model robustness to moderate alterations in any of the parameters. Model analysis suggest that the greatest contributor to PI(4,5)P₂ production is a flux representing the direct transformation of PI into PI(4,5)P₂ and is also responsible for the maintenance of this pool when PI(4)P is decreased. PI(5)P is also shown to be a significant source for PI(4,5)P₂ production. The model was validated with data from siRNA screens that knocked down the expression of several enzymes in the pathway. The screen monitored the activity of the epithelium sodium channel, ENaC, which is activated by PI(4,5)P₂. Moderating ENaC activity can have a therapeutic effect in Cystic Fibrosis (CF) patients. Our model suggests control strategies where the activities of the enzyme PIP5KI or the PI4K+PIP5KI+DVL protein complex are decreased and cause an efficacious reduction in PI(4,5)P₂ levels while avoiding undesirable alterations in other phosphoinositide pools.