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Author Notes:

Daniel V. Olivença University of Lisbon, Faculty of Sciences, BIOISI: Biosystems and Integrative Sciences Institute. Campo Grande, 1749–016, Lisbon, Portugal Email: dvolivenca@fc.ul.pt

The authors are also grateful to Luís Marques (BioISI) and to staff from EMBL, Heidelberg (Germany), from ALMF-Advanced Light Microscopy (Beate Neumann, Christian Tischer) core facility for technical assistance.

D.V.O., L.L.F., E.V. and F.R.P. contributed to the conception of this project and the drafting of the manuscript.

D.V.O. did the literature review, retrieved results regarding phenomena that characterize the pathway, created the model and performed the analysis.

I.U. and M.D.A. performed experiments.

All authors reviewed the manuscript.

The authors declare no competing interests.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Subject:

Research Funding:

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.

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.

This work was supported in part by the grants MCB-1517588 (PI: EOV) of the U.S. National Science Foundation.

The funding agencies are not responsible for the content of this article.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • CYSTIC-FIBROSIS
  • CELL REGULATION
  • MEMBRANE
  • DYNAMICS
  • DISEASE
  • TRAFFICKING
  • TURNOVER
  • KINASES
  • SYSTEM
  • LIPIDS

A Mathematical Model of the Phosphoinositide Pathway

Tools:

Journal Title:

Scientific Reports

Volume:

Volume 8, Number 1

Publisher:

, Pages 3904-3904

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2018 The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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