title: Regulation of Early Steps of GPVI Signal Transduction by Phosphatases: A Systems Biology Approach.
abstract: We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction. At each stage model simulations were compared to our own quantitative, high-temporal experimental data that guides further experimental design, data collection and model refinement. Much is known about the linear forward reactions within platelet signalling pathways but knowledge of the roles of putative reverse reactions are poorly understood. An initial model, that includes a simple constitutively active phosphatase, was unable to explain experimental data. Model revisions, incorporating a complex pathway of interactions (and specifically the phosphatase TULA-2), provided a good description of the experimental data both based on observations of phosphorylation in samples from one donor and in those of a wider population. Our model was used to investigate the levels of proteins involved in regulating the pathway and the effect of low GPVI levels that have been associated with disease. Results indicate a clear separation in healthy and GPVI deficient states in respect of the signalling cascade dynamics associated with Syk tyrosine phosphorylation and activation. Our approach reveals the central importance of this negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatases in controlling the rate, and therefore extent, of GPVI-stimulated platelet activation.
authors.affiliation: Department of Mathematics and Statistics, University of Reading, Reading, Berkshire, United Kingdom.|Institute for Cardiovascular and Metabolic Research and School of Biological Sciences, University of Reading, Reading, Berkshire, United Kingdom.
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Dunster
authors.affiliation: Institute for Cardiovascular and Metabolic Research and School of Biological Sciences, University of Reading, Reading, Berkshire, United Kingdom.
authors.forename: Francoise
authors.initials: F
authors.lastname: Mazet
authors.affiliation: Institute for Cardiovascular and Metabolic Research and School of Biological Sciences, University of Reading, Reading, Berkshire, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fry
authors.affiliation: Institute for Cardiovascular and Metabolic Research and School of Biological Sciences, University of Reading, Reading, Berkshire, United Kingdom.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gibbins
authors.affiliation: Department of Mathematics and Statistics, University of Reading, Reading, Berkshire, United Kingdom.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Tindall
mesh_terms: D001792:Blood Platelets / Q000378:metabolism; D006801:Humans; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D015539:Platelet Activation / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D049490:Systems Biology / Q000379:methods*
chemical_list: D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D010744:Phosphoric Monoester Hydrolases