A Mathematical Model of the Phosphoinositide Pathway
Authors: Olivença Daniel V , Uliyakina Inna , Fonseca Luis L , Amaral Margarida D , Voit Eberhard , Pinto Francisco R 
Published: August 2017

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)P2production is a flux representing the direct transformation of PI into PI(4,5)P2and 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)P2production. 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)P2levels while avoiding undesirable alterations in other phosphoinositide pools.

Abbreviations

AKT

Protein Kinase B, a serine/threonine-specific protein kinase

ASL

Airway surface liquid

BST

Biochemical systems theory

CF

Cystic fibrosis

DAG

Diacylglycerol

ENaC

Epithelial Sodium Channel

ER

Endoplasmic Reticulum

GMA

Generalized mass action

INPP5

Inositol polyphosphate 5-phosphatases

IP3

Inositol triphosphate

LTPs

lipid transport proteins

MCSs

membrane contact sites

MDCK cells

Madin-Darby Canine Kidney Epithelial Cells

MTM

Myotubularin

OCRL

Lowe Oculocerebrorenal Syndrome Protein; OCRL is an INPP5

ODE

Ordinary differential equations

PI

Phosphatidylinositol

PI(3)P

phosphatidylinositol 3-phosphate

PI(3,4)P2

Phosphatidylinositol 3,4-biphosphate

PI(3,4,5)P3

phosphatidylinositol 3,4,5-triphosphate, with phosphates in the third, fourth and fifth positions

PI(3,5)P2

Phosphatidylinositol 3,5-biphosphate

PI(4)P

phosphatidylinositol 4-phosphate

PI(4,5)P2

Phosphatidylinositol 4,5-biphosphate with phosphates in the fourth and fifth positions of the inositol ring

PI(5)P

phosphatidylinositol 5-phosphate

PI3K

Phosphoinositide 3-kinase

PI4K

Phosphoinositide 4-kinase

PIP5K

Phosphoinositide 4-phosphate 5-kinase

PIKfyve

FYVE finger-containing phosphoinositide kinase.

PLC

Phospholipase C

PLD

Phospholipase D

PLIP

PTEN-like lipid phosphatase

PTEN

Phosphatase and tensin homolog

PKC

Protein kinase C

SAC

Suppressor of actin

SHIP1

SH2 domain-containing phosphatidylinositol 5’-phosphatase

SKIP

Skeletal muscle and kidney enriched inositol polyphosphate phosphatase

SYNJ

Synaptojanins

TPIP

PTEN-Like Inositol Lipid Phosphatase

Wnt3a

Wingless-Type MMTV Integration Site Family, Member 3A

DVL

Segment Polarity Protein Dishevelled Homolog DVL