Computational Analysis of Rho GTPase Cycling
Publication Date
January 10, 2013
Journal
PLOS Computational Biology
Authors
Cibele Vieira Falkenberg & Leslie M. Loew
Volume
9
Issue
1
Pages
e1002831
DOI
https://dx.plos.org/10.1371/journal.pcbi.1002831
Publisher URL
http://journals.plos.org/ploscompbiol/article?id=10.1371%2Fjournal.pcbi.1002831
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/23326220
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542069
Europe PMC
http://europepmc.org/abstract/MED/23326220
Web of Science
000314595600005
Scopus
84873497475
Mendeley
http://www.mendeley.com/research/computational-analysis-rho-gtpase-cycling
Events
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Mendeley | Further Information

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Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/277255"], "description"=>"<div><p>The Rho family of GTPases control actin organization during diverse cellular responses (migration, cytokinesis and endocytosis). Although the primary members of this family (RhoA, Rac and Cdc42) have different downstream effects on actin remodeling, the basic mechanism involves targeting to the plasma membrane and activation by GTP binding. Our hypothesis is that the details of GTPase cycling between membrane and cytosol are key to the differential upstream regulation of these biochemical switches. Accordingly, we developed a modeling framework to analyze experimental data for these systems. This analysis can reveal details of GDI-mediated cycling and help distinguish between GDI-dependent and -independent mechanisms, including vesicle trafficking and direct association-dissociation of GTPase with membrane molecules. Analysis of experimental data for Rac membrane cycling reveals that the lower apparent affinity of GDI for RacGTP compared to RacGDP can be fully explained by the faster dissociation of the latter from the membrane. Non-dimensional steady-state solutions for membrane fraction of GTPase are presented in multidimensional charts. This methodology is then used to analyze glucose stimulated Rac cycling in pancreatic β-cells. The charts are used to illustrate the effects of GEFs/GAPs and regulated affinities between GTPases and membrane and/or GDI on the amount of membrane bound GTPase. In a similar fashion, the charts can be used as a guide in assessing how targeted modifications may compensate for altered GTPase-GDI balance in disease scenarios.</p> </div>", "links"=>[], "tags"=>["computational", "rho", "gtpase", "cycling"], "article_id"=>114660, "categories"=>["Mathematics", "Chemistry"], "users"=>["Cibele Vieira Falkenberg", "Leslie M. Loew"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002831", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Computational_Analysis_of_Rho_GTPase_Cycling__/114660", "title"=>"Computational Analysis of Rho GTPase Cycling", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-01-10 01:17:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/509212"], "description"=>"<p>The asterisk represents the product between binding rates and concentration of GDI (subscripts that carry the numbers 1 and 3) or effector proteins <i>Eff</i> (subscript 5). In all models presented, the numbers used as subscripts for the cycling rates are consistent: 1 stands for interactions between membrane bound GTPase and GDI; 2 for membrane cycling of the complex GTPase-GDI; 3 for interactions between cytosolic GTPase and GDI; and 4 for membrane cycling of GTPase free from GDI. A. Detailed model. B. GDI dependent and independent GTPase cycling. Rates with subscript “+” represent binding (to GDI, effector proteins or membrane). C. Apparent membrane dissociation rate (<i>k<sub>offAp</sub></i>) normalized by the GDI mediated dissociation rate <i>k<sub>2−</sub></i> as a function of <i>K<sub>D1</sub></i>, <i>K<sub>D5</sub></i>, <i>GDI</i> and <i>Eff</i>.</p>", "links"=>[], "tags"=>["gtpase", "membrane"], "article_id"=>179717, "categories"=>["Mathematics", "Chemistry"], "users"=>["Cibele Vieira Falkenberg", "Leslie M. Loew"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002831.g001", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Models_for_GTPase_membrane_cycling_/179717", "title"=>"Models for GTPase membrane cycling.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-10 02:41:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/509426"], "description"=>"<p>A–B. effect of GEF/GAP ratio. C–D. Effect of Rac concentration, relative to experimental condition ‘wt’. Vertical lines: GDI concentration for ‘wt’ (solid), and for ‘wt−GDI’ (dashed). While the fraction of active Rac doubled for ‘wt−GDI’, the total amount of active Rac is the same when Rac concentration is decreased by half (curve with crosses relative to open circles).</p>", "links"=>[], "tags"=>["gtpase", "membrane", "dissociation", "rac", "gdi"], "article_id"=>179921, "categories"=>["Mathematics", "Chemistry"], "users"=>["Cibele Vieira Falkenberg", "Leslie M. Loew"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002831.g004", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dependence_of_fraction_of_GTPase_at_the_membrane_r0_membrane_dissociation_rate_k_offAp_and_fraction_of_active_Rac_on_GDI_concentration_/179921", "title"=>"Dependence of fraction of GTPase at the membrane r0, membrane dissociation rate <i>k<sub>offAp</sub></i>, and fraction of active Rac on GDI concentration.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-10 02:45:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/509354"], "description"=>"<p>A. Percentage of Rac at the membrane r0. B. Apparent membrane dissociation rate koff Ap (s<sup>−1</sup>). C. Total active GFP-Rac in the cell. The nomenclature for each of the eight experimental conditions is defined in Section Detailed model. Experimental measurements of koff Ap were not performed for 2 conditions and of Active Rac for one condition; the model predictions for those conditions are provided.</p>", "links"=>[], "tags"=>["bars"], "article_id"=>179857, "categories"=>["Mathematics", "Chemistry"], "users"=>["Cibele Vieira Falkenberg", "Leslie M. Loew"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002831.g003", "stats"=>{"downloads"=>1, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_between_experimental_data_Exp_black_bars_15_and_Model_/179857", "title"=>"Comparison between experimental data “Exp”, black bars [<b>15</b>] and “Model”.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-10 02:44:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/509650"], "description"=>"<p>Variables and parameters used in ‘Application to Rac cycling in pancreatic β-cells’.</p>", "links"=>[], "tags"=>["parameters", "rac", "cycling", "pancreatic"], "article_id"=>180149, "categories"=>["Mathematics", "Chemistry"], "users"=>["Cibele Vieira Falkenberg", "Leslie M. Loew"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002831.t003", "stats"=>{"downloads"=>3, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Variables_and_parameters_used_in_8216_Application_to_Rac_cycling_in_pancreatic_946_cells_8217_/180149", "title"=>"Variables and parameters used in ‘Application to Rac cycling in pancreatic β-cells’.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-01-10 00:02:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/509298"], "description"=>"<p>A. Model for lumped variables and rates. The term in the dotted box includes effector bound GTPases. The dashed arrows represent the GDI mediated membrane cycling of GTPases. B–F. Fraction of GTPase at the membrane free from GDI as <i>ρ<sub>Eq</sub></i> ranges from 0 to 10. The upper contour corresponds to 9% fraction at the membrane, while the lowest line represents 89%. Each pair of neighboring lines is 10% apart in membrane fraction. When <i>ρ<sub>Eq</sub></i> = 0, all membrane bound GTPase is free from GDI (<i>r0</i> = <i>r0<sub>f</sub></i>). The total fraction of GTPase at the membrane <i>r0</i> is represented by the dashed lines when <i>ρ<sub>Eq</sub></i>>0.</p>", "links"=>[], "tags"=>["gtpase"], "article_id"=>179800, "categories"=>["Mathematics", "Chemistry"], "users"=>["Cibele Vieira Falkenberg", "Leslie M. Loew"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002831.g002", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_for_analysis_of_fraction_of_GTPase_at_the_membrane_/179800", "title"=>"Model for analysis of fraction of GTPase at the membrane.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-10 02:43:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/509615"], "description"=>"<p>Variables and parameters used in ‘Vesicle traffic’.</p>", "links"=>[], "tags"=>["parameters"], "article_id"=>180121, "categories"=>["Mathematics", "Chemistry"], "users"=>["Cibele Vieira Falkenberg", "Leslie M. Loew"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002831.t001", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Variables_and_parameters_used_in_8216_Vesicle_traffic_8217_/180121", "title"=>"Variables and parameters used in ‘Vesicle traffic’.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-01-10 00:02:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/509525"], "description"=>"<p>A–C. Horizontal lines delimit <i>K<sub>Dm</sub></i> for minimum and maximum GEF/GAP based on values in Section Detailed model, for a cell with (B) Sfc/Vol = 0.544/µm, corresponding to NIH3T3 cells or the surface area of only the plasma membrane of β-cell, or (C) Sfc/Vol = 4.8/µm, corresponding to the surface area of both plasma and granular membranes of the β-cell. At time 0, <i>r0<sub>f</sub></i> = 0.28 (solid bold curve), and at 20 minutes <i>r0<sub>f</sub></i> = 0.57 (dashed black curve). Arrows represent effective trajectories that satisfy the 70% increase in sGDI and 40% decrease in cytosolic Rac. Arrow type for fold increase in dissociation constant between Rac and sGDI in comparison to unphosphorylated GDI (see text): 5, solid; 10, dashed; 100 (B) and 1000 (C), bold (solid and dotted). For solid arrowheads, GDI bound to Cdc42 was considered inert. White arrowheads consider the effect of phosphorylation of GDI bound to Cdc42. All arrows, 0.15 µM cytosolic Cdc42 bound to GDI, but for dotted, 0.25 µM. D) Transient translocation of Rac between cytosol (Rac<sub>c</sub>), plasma (Rac<sub>PM</sub>) and granular membranes (Rac<sub>gr</sub>) due to change in K<sub>DGDI</sub> only (cross), plus increased affinity for plasma membrane (star, b>0) and granular membrane (circle, c>0).</p>", "links"=>[], "tags"=>["rac", "sgdi"], "article_id"=>180029, "categories"=>["Mathematics", "Chemistry"], "users"=>["Cibele Vieira Falkenberg", "Leslie M. Loew"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002831.g005", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Membrane_fraction_of_Rac_before_and_after_increase_in_sGDI_due_to_stimulus_/180029", "title"=>"Membrane fraction of Rac before and after increase in sGDI due to stimulus.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-10 00:00:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/509680"], "description"=>"<p>Variables and parameters used in lumped and detailed models.</p>", "links"=>[], "tags"=>["parameters", "lumped"], "article_id"=>180181, "categories"=>["Mathematics", "Chemistry"], "users"=>["Cibele Vieira Falkenberg", "Leslie M. Loew"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002831.t002", "stats"=>{"downloads"=>6, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Variables_and_parameters_used_in_lumped_and_detailed_models_/180181", "title"=>"Variables and parameters used in lumped and detailed models.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-01-10 00:03:01"}

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Relative Metric

{"start_date"=>"2013-01-01T00:00:00Z", "end_date"=>"2013-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Biochemistry", "average_usage"=>[266, 468, 593, 703, 804, 903, 993, 1084, 1171, 1256, 1339, 1422, 1492]}, {"subject_area"=>"/Physical sciences/Chemistry", "average_usage"=>[247, 429, 544, 647, 747, 842, 929, 1012, 1099, 1179, 1263, 1339, 1409]}]}
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