Vizan2013 - TGF pathway long term signaling

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  • Controlling long-term signaling: receptor dynamics determine attenuation and refractory behavior of the TGF-β pathway.
  • Vizán P, Miller DS, Gori I, Das D, Schmierer B, Hill CS
  • Science signaling , 12/ 2013 , Volume 6 , pages: ra106 , PubMed ID: 24327760
  • 1Developmental Signalling Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
  • Understanding the complex dynamics of growth factor signaling requires both mechanistic and kinetic information. Although signaling dynamics have been studied for pathways downstream of receptor tyrosine kinases and G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors, they have not been investigated for the transforming growth factor-β (TGF-β) superfamily pathways. Using an integrative experimental and mathematical modeling approach, we dissected the dynamic behavior of the TGF-β to Smad pathway, which is mediated by type I and type II receptor serine/threonine kinases, in response to acute, chronic, and repeated ligand stimulations. TGF-β exposure produced a transient response that attenuated over time, resulting in desensitized cells that were refractory to further acute stimulation. This loss of signaling competence depended on ligand binding, but not on receptor activity, and was restored only after the ligand had been depleted. Furthermore, TGF-β binding triggered the rapid depletion of signaling-competent receptors from the cell surface, with the type I and type II receptors exhibiting different degradation and trafficking kinetics. A computational model of TGF-β signal transduction from the membrane to the nucleus that incorporates our experimental findings predicts that autocrine signaling, such as that associated with tumorigenesis, severely compromises the TGF-β response, which we confirmed experimentally. Thus, we have shown that the long-term signaling behavior of the TGF-β pathway is determined by receptor dynamics, does not require TGF-β-induced gene expression, and influences context-dependent responses in vivo.
Submitter of the first revision: Bernhard Schmierer
Submitter of this revision: Bernhard Schmierer
Modellers: Bernhard Schmierer

Metadata information

BioModels Database MODEL1203120000
BioModels Database BIOMD0000000499
BioModels Database BIOMD0000000173
PubMed 24327760
Taxonomy Homo sapiens

Curation status


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Model files

BIOMD0000000499_url.xml SBML L2V4 representation of Vizan2013 - TGF pathway long term signaling 94.87 KB Preview | Download

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BIOMD0000000499-biopax2.owl Auto-generated BioPAX (Level 2) 11.85 KB Preview | Download
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  • Model originally submitted by : Bernhard Schmierer
  • Submitted: Mar 12, 2012 4:12:51 PM
  • Last Modified: Feb 24, 2014 9:47:15 AM
  • Version: 2 public model Download this version
    • Submitted on: Feb 24, 2014 9:47:15 AM
    • Submitted by: Bernhard Schmierer
    • With comment: Current version of Vizan2013 - TGF pathway long term signaling
  • Version: 1 public model Download this version
    • Submitted on: Mar 12, 2012 4:12:51 PM
    • Submitted by: Bernhard Schmierer
    • With comment: Original import of New Model

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

: Variable used inside SBML models

Reactions Rate Parameters
species_1 = 1/(1+parameter_13)*(parameter_9*(parameter_13*species_20^2+species_15^2)-parameter_8*(parameter_13*species_13+species_11)) 1/(1+parameter_13)*(parameter_9*(parameter_13*species_20^2+species_15^2)-parameter_8*(parameter_13*species_13+species_11)) parameter_9 = 350.877192982456; parameter_8 = 60.0; parameter_13 = 2.27
species_7 = parameter_1*((parameter_4*species_5-(1-parameter_28)*species_25)-parameter_18*species_4*species_9) parameter_1*((parameter_4*species_5-(1-parameter_28)*species_25)-parameter_18*species_4*species_9) parameter_28 = 0.0; parameter_1 = 0.32; parameter_18 = 100.0; parameter_4 = 0.08
species_2 = 1/(parameter_13+1)*(parameter_9*(parameter_13*species_18*species_20+species_15*species_21)-parameter_8*(parameter_13*species_17+species_16)) 1/(parameter_13+1)*(parameter_9*(parameter_13*species_18*species_20+species_15*species_21)-parameter_8*(parameter_13*species_17+species_16)) parameter_9 = 350.877192982456; parameter_8 = 60.0; parameter_13 = 2.27
species_12 = (parameter_13+1)*parameter_15-parameter_13*species_19 [] parameter_13 = 2.27; parameter_15 = 1.0
species_17 = parameter_9*species_18*species_20-(parameter_8+parameter_3*parameter_11)*species_17 parameter_9*species_18*species_20-(parameter_8+parameter_3*parameter_11)*species_17 parameter_9 = 350.877192982456; parameter_8 = 60.0; parameter_3 = 9.36; parameter_11 = 5.7
species_3 = 1/(1+parameter_13)*(parameter_13*parameter_6*species_26*parameter_17/(parameter_17+species_22)*species_6-parameter_7*species_15) 1/(1+parameter_13)*(parameter_13*parameter_6*species_26*parameter_17/(parameter_17+species_22)*species_6-parameter_7*species_15) parameter_7 = 24.0; parameter_13 = 2.27; parameter_6 = 21.3715; parameter_17 = 0.196565
species_14 = (parameter_13+1)*species_3-parameter_13*species_8 [] parameter_13 = 2.27
species_24 = parameter_1*(parameter_18*species_4*species_9-(parameter_22+parameter_12*(1-parameter_28))*species_24) parameter_1*(parameter_18*species_4*species_9-(parameter_22+parameter_12*(1-parameter_28))*species_24) parameter_22 = 24.5383; parameter_28 = 0.0; parameter_1 = 0.32; parameter_12 = 4.0; parameter_18 = 100.0
species_20 = (species_8-2*species_13)-species_17 [] []
species_13 = parameter_9*species_20^2-(parameter_8+parameter_3*parameter_11)*species_13 parameter_9*species_20^2-(parameter_8+parameter_3*parameter_11)*species_13 parameter_9 = 350.877192982456; parameter_8 = 60.0; parameter_3 = 9.36; parameter_11 = 5.7
Curator's comment:
(added: 15 Jan 2014, 11:32:18, updated: 15 Jan 2014, 11:32:18)
The curation figure reproduces the results shown in Figure 4B of the reference publication, and was generated using SBMLsimulator 1.1.The names given to the physical entity names in the model do not correspond with those in the reference publication. The curation figure provides the latter in parentheses.