A mathematical model of the phosphoinositide pathway
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 k...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
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Nature Publishing Group
2018
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| _version_ | 1797060086645915648 |
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| author | Olivença, DV Uliyakina, I Fonseca, LL Amaral, MD Voit, EO Pinto, FR |
| author_facet | Olivença, DV Uliyakina, I Fonseca, LL Amaral, MD Voit, EO Pinto, FR |
| author_sort | Olivença, DV |
| collection | OXFORD |
| description | 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)P2) production is a flux representing the direct transformation of PI into PI(4,5) P2, 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)P2 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)P2. 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)P2 levels while avoiding undesirable alterations in other phosphoinositide pools. |
| first_indexed | 2024-03-06T20:12:40Z |
| format | Journal article |
| id | oxford-uuid:2b19a5b5-1f0a-4fb0-b9b5-883f063b1c17 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:12:40Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:2b19a5b5-1f0a-4fb0-b9b5-883f063b1c172022-03-26T12:28:57ZA mathematical model of the phosphoinositide pathwayJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2b19a5b5-1f0a-4fb0-b9b5-883f063b1c17EnglishSymplectic Elements at OxfordNature Publishing Group2018Olivença, DVUliyakina, IFonseca, LLAmaral, MDVoit, EOPinto, FRPhosphoinositides 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)P2) production is a flux representing the direct transformation of PI into PI(4,5) P2, 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)P2 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)P2. 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)P2 levels while avoiding undesirable alterations in other phosphoinositide pools. |
| spellingShingle | Olivença, DV Uliyakina, I Fonseca, LL Amaral, MD Voit, EO Pinto, FR A mathematical model of the phosphoinositide pathway |
| title | A mathematical model of the phosphoinositide pathway |
| title_full | A mathematical model of the phosphoinositide pathway |
| title_fullStr | A mathematical model of the phosphoinositide pathway |
| title_full_unstemmed | A mathematical model of the phosphoinositide pathway |
| title_short | A mathematical model of the phosphoinositide pathway |
| title_sort | mathematical model of the phosphoinositide pathway |
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