title: Mathematical modeling of K-Ras nanocluster formation on the plasma membrane.
abstract: K-Ras functions as a critical node in the mitogen-activated protein kinase (MAPK) pathway that regulates key cellular functions including proliferation, differentiation, and apoptosis. Following growth factor receptor activation K-Ras.GTP forms nanoclusters on the plasma membrane through interaction with the scaffold protein galectin-3. The generation of nanoclusters is essential for high fidelity signal transduction via the MAPK pathway. To explore the mechanisms underlying K-Ras.GTP nanocluster formation, we developed a mathematical model of K-Ras-galectin-3 interactions. We designed a computational method to calculate protein collision rates based on experimentally determined protein diffusion rates and diffusion mechanisms and used a genetic algorithm to search the values of key model parameters. The optimal estimated model parameters were validated using experimental data. The resulting model accurately replicates critical features of K-Ras nanoclustering, including a fixed ratio of clustered K-Ras.GTP to monomeric K-Ras.GTP that is independent of the concentration of K-Ras.GTP. The model reproduces experimental results showing that the cytosolic level of galectin-3 determines the magnitude of the K-Ras.GTP clustered fraction and illustrates that nanoclustering is regulated by key nonequilibrium processes. Our kinetic model identifies a potential biophysical mechanism for K-Ras nanoclustering and suggests general principles that may be relevant for other plasma-membrane-localized proteins.
authors.affiliation: Department of Mathematics, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Tianhai
authors.initials: T
authors.lastname: Tian
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Plowman
authors.forename: Robert G
authors.initials: RG
authors.lastname: Parton
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
authors.forename: John F
authors.initials: JF
authors.lastname: Hancock
mesh_terms: D002462:Cell Membrane / Q000201:enzymology*; D003198:Computer Simulation; D004789:Enzyme Activation; D037502:Galectin 3 / Q000737:chemistry / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D008954:Models, Biological; D049329:Nanostructures / Q000737:chemistry*; D020836:Protein Structure, Quaternary; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D037502:Galectin 3; D006160:Guanosine Triphosphate; D018631:ras Proteins