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A Mathematical Model of the Phosphoinositide Pathway

View ORCID ProfileDaniel V Olivença, Inna Uliyakina, View ORCID ProfileLuis L Fonseca, Margarida D Amaral, Eberhard Voit, Francisco R Pinto
doi: https://doi.org/10.1101/182634
Daniel V Olivença
1University of Lisbon, Faculty of Sciences, BIOISI: Biosystems and Integrative Sciences Institute, Campo Grande 1749-016 Lisbon, Portugal
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  • For correspondence: dvolivenca@fc.ul.pt
Inna Uliyakina
1University of Lisbon, Faculty of Sciences, BIOISI: Biosystems and Integrative Sciences Institute, Campo Grande 1749-016 Lisbon, Portugal
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Luis L Fonseca
2The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 950 Atlantic Drive, Atlanta, Georgia, 30332-2000 USA
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Margarida D Amaral
1University of Lisbon, Faculty of Sciences, BIOISI: Biosystems and Integrative Sciences Institute, Campo Grande 1749-016 Lisbon, Portugal
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Eberhard Voit
2The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 950 Atlantic Drive, Atlanta, Georgia, 30332-2000 USA
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Francisco R Pinto
1University of Lisbon, Faculty of Sciences, BIOISI: Biosystems and Integrative Sciences Institute, Campo Grande 1749-016 Lisbon, Portugal
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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.

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
Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 30, 2017.
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A Mathematical Model of the Phosphoinositide Pathway
Daniel V Olivença, Inna Uliyakina, Luis L Fonseca, Margarida D Amaral, Eberhard Voit, Francisco R Pinto
bioRxiv 182634; doi: https://doi.org/10.1101/182634
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A Mathematical Model of the Phosphoinositide Pathway
Daniel V Olivença, Inna Uliyakina, Luis L Fonseca, Margarida D Amaral, Eberhard Voit, Francisco R Pinto
bioRxiv 182634; doi: https://doi.org/10.1101/182634

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