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Modelling Cell Polarization Driven by Synthetic Spatially Graded Rac Activation

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 syn...

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Detalles Bibliográficos
Autores principales: Holmes, William R., Lin, Benjamin, Levchenko, Andre, Edelstein-Keshet, Leah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380869/
https://www.ncbi.nlm.nih.gov/pubmed/22737059
http://dx.doi.org/10.1371/journal.pcbi.1002366
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author Holmes, William R.
Lin, Benjamin
Levchenko, Andre
Edelstein-Keshet, Leah
author_facet Holmes, William R.
Lin, Benjamin
Levchenko, Andre
Edelstein-Keshet, Leah
author_sort Holmes, William R.
collection PubMed
description 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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spelling pubmed-33808692012-06-26 Modelling Cell Polarization Driven by Synthetic Spatially Graded Rac Activation Holmes, William R. Lin, Benjamin Levchenko, Andre Edelstein-Keshet, Leah PLoS Comput Biol Research Article 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. Public Library of Science 2012-06-21 /pmc/articles/PMC3380869/ /pubmed/22737059 http://dx.doi.org/10.1371/journal.pcbi.1002366 Text en Holmes et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Holmes, William R.
Lin, Benjamin
Levchenko, Andre
Edelstein-Keshet, Leah
Modelling Cell Polarization Driven by Synthetic Spatially Graded Rac Activation
title Modelling Cell Polarization Driven by Synthetic Spatially Graded Rac Activation
title_full Modelling Cell Polarization Driven by Synthetic Spatially Graded Rac Activation
title_fullStr Modelling Cell Polarization Driven by Synthetic Spatially Graded Rac Activation
title_full_unstemmed Modelling Cell Polarization Driven by Synthetic Spatially Graded Rac Activation
title_short Modelling Cell Polarization Driven by Synthetic Spatially Graded Rac Activation
title_sort modelling cell polarization driven by synthetic spatially graded rac activation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380869/
https://www.ncbi.nlm.nih.gov/pubmed/22737059
http://dx.doi.org/10.1371/journal.pcbi.1002366
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