title: A single-cell model of PIP3 dynamics using chemical dimerization.
abstract: Most cellular processes are driven by simple biochemical mechanisms such as protein and lipid phosphorylation, but the sum of all these conversions is exceedingly complex. Hence, intuition alone is not enough to discern the underlying mechanisms in the light of experimental data. Toward this end, mathematical models provide a conceptual and numerical framework to formally evaluate the plausibility of biochemical processes. To illustrate the use of these models, here we built a mechanistic computational model of PI3K (phosphatidylinositol 3-kinase) activity, to determine the kinetics of lipid metabolizing enzymes in single cells. The model is trained to data generated upon perturbation with a reversible small-molecule based chemical dimerization system that allows for the very rapid manipulation of the PIP3 (phosphatidylinositol 3,4,5-trisphosphate) signaling pathway, and monitored with live-cell microscopy. We find that the rapid relaxation system used in this work decreased the uncertainty of estimating kinetic parameters compared to methods based on in vitro assays. We also examined the use of Bayesian parameter inference and how the use of such a probabilistic method gives information on the kinetics of PI3K and PTEN activity.
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Aidan
authors.initials: A
authors.lastname: MacNamara
authors.affiliation: Cell Biology & Biophysics Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Stein
authors.affiliation: Cell Biology & Biophysics Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Suihan
authors.initials: S
authors.lastname: Feng
authors.affiliation: Cell Biology & Biophysics Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Electronic address: saezrodriguez@gmail.com.
authors.forename: Julio
authors.initials: J
authors.lastname: Saez-Rodriguez
mesh_terms: D000818:Animals; D001499:Bayes Theorem; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000378:metabolism
chemical_list: D018129:Phosphatidylinositol Phosphates; D054852:Small Molecule Libraries; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase
keywords: Bayesian; Dynamic; Modeling; Parameter estimation; Phosphoinositide signaling