These models are composed of partial differential equations and boundary conditions that model the receptor-mediated activation of phospholipase C (PLC) and protein kinase C (PKC) enzymes in mammalian cells. PLC hydrolyzes the membrane lipid, PIP2, to produce the lipid second messenger, diacylglycerol (DAG), which mediates PKC activation at the plasma membrane. Following indications in the literature, the equations also capture the influences of the regulatory protein, MARCKS, and the lipid intermediate, phosphatidic acid (PA). These regulatory links revealed putative positive feedback loops.
The primary purpose of these models is to explain how the PLC/PKC pathway might be polarized in cells with a shallow gradient of receptor activation, as is the case during the response to a chemotactic ligand. This follows evidence that the abundance of DAG is polarized during the chemotactic migration of fibroblasts to PDGF, a prominent chemoattractant that directs fibroblast invasion of cutaneous wounds. Another purpose of the models is to predict the robustness of the polarization response with respect to the external gradient conditions and to perturbation of the regulatory mechanisms involved. Yet another purpose is to define thresholds for polarization that can be used for multiscale modeling of wound invasion, where the concentrations of PDGF and other factors change dynamically in space and time.
Numerical validation has been performed by varying the spatial discretization of the domain to verify accuracy.
The models were implemented, and publicly available, in the Virtual Cell software environment (vcell.org), which is Systems Biology Markup Language (SBML)-compliant and allows users to build onto existing models or link to others.
Mohan K, Nosbisch JL, Elston TC, Bear JE, Haugh JM. A Reaction-Diffusion Model Explains Amplification of the PLC/PKC Pathway in Fibroblast Chemotaxis. Biophys J. 2017;113(1):185-194. doi:10.1016/j.bpj.2017.05.035
Nosbisch JL, Rahman A, Mohan K, Elston TC, Bear JE, Haugh JM. Mechanistic models of PLC/PKC signaling implicate phosphatidic acid as a key amplifier of chemotactic gradient sensing. PLoS Comput Biol. 2020;16(4):e1007708. Published 2020 Apr 7. doi:10.1371/journal.pcbi.1007708