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    Modelling cell polarization driven by synthetic spatially graded Rac activation.

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    35
    Author
    Holmes, WR; Lin, B; Levchenko, A; Edelstein-Keshet, L
    Date
    2012
    Source Title
    PLoS Computational Biology
    Publisher
    Public Library of Science (PLoS)
    University of Melbourne Author/s
    HOLMES, WILLIAM
    Affiliation
    School of Mathematics and Statistics
    Metadata
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    Document Type
    Journal Article
    Citations
    Holmes, W. R., Lin, B., Levchenko, A. & Edelstein-Keshet, L. (2012). Modelling cell polarization driven by synthetic spatially graded Rac activation.. PLoS Comput Biol, 8 (6), pp.e1002366-. https://doi.org/10.1371/journal.pcbi.1002366.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/259119
    DOI
    10.1371/journal.pcbi.1002366
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380869
    Abstract
    The small GTPase Rac is known to be an important regulator of cell polarization, cytoskeletal reorganization, and motility of mammalian cells. In recent microfluidic experiments, HeLa cells endowed with appropriate constructs were subjected to gradients of the small molecule rapamycin leading to synthetic membrane recruitment of a Rac activator and direct graded activation of membrane-associated Rac. Rac activation could thus be triggered independent of upstream signaling mechanisms otherwise responsible for transducing activating gradient signals. The response of the cells to such stimulation depended on exceeding a threshold of activated Rac. Here we develop a minimal reaction-diffusion model for the GTPase network alone and for GTPase-phosphoinositide crosstalk that is consistent with experimental observations for the polarization of the cells. The modeling suggests that mutual inhibition is a more likely mode of cell polarization than positive feedback of Rac onto its own activation. We use a new analytical tool, Local Perturbation Analysis, to approximate the partial differential equations by ordinary differential equations for local and global variables. This method helps to analyze the parameter space and behaviour of the proposed models. The models and experiments suggest that (1) spatially uniform stimulation serves to sensitize a cell to applied gradients. (2) Feedback between phosphoinositides and Rho GTPases sensitizes a cell. (3) Cell lengthening/flattening accompanying polarization can increase the sensitivity of a cell and stabilize an otherwise unstable polarization.

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