Simon2019 - NIK-dependent p100 processing into p52, Mass Action, SBML 2v4

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This model represents NIK-dependent p100 processing into p52 with mass action kinetics. While this model shows identical dose-response to the Michaelis-Menten representation, when IkBd degradation is included the dose-response is no longer monotonic in mass action models due to substrate complex competition.

Related Publication
  • Substrate complex competition is a regulatory motif that allows NFκB RelA to license but not amplify NFκB RelB
  • Simon Mitchell, Alexander Hoffmann
  • Proceedings of the National Academy of Sciences of the United States of America , 4/ 2019 , DOI: 10.1073/pnas.1816000116
  • Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA 90095
  • Signaling pathways often share molecular components, tying the activity of one pathway to the functioning of another. In the NFκB signaling system, distinct kinases mediate inflammatory and developmental signaling via RelA and RelB, respectively. Although the substrates of the developmental, so-called noncanonical, pathway are induced by inflammatory/canonical signaling, crosstalk is limited. Through dynamical systems modeling, we identified the underlying regulatory mechanism. We found that as the substrate of the noncanonical kinase NIK, the nfkb2 gene product p100, transitions from a monomer to a multimeric complex, it may compete with and inhibit p100 processing to the active p52. Although multimeric complexes of p100 (IκBδ) are known to inhibit preexisting RelA:p50 through sequestration, here we report that p100 complexes can inhibit the enzymatic formation of RelB:p52. We show that the dose–response systems properties of this complex substrate competition motif are poorly accounted for by standard Michaelis–Menten kinetics, but require more detailed mass action formulations. In sum, although tonic inflammatory signaling is required for adequate expression of the noncanonical pathway precursors, the substrate complex competition motif identified here can prevent amplification of the active RelB:p52 dimer in elevated inflammatory conditions to ensure reliable RelB-dependent developmental signaling independent of inflammatory context.
Submitter of the first revision: Simon Mitchell
Submitter of this revision: Mohammad Umer Sharif Shohan
Modellers: Simon Mitchell, Mohammad Umer Sharif Shohan

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Model files

simon2019_model2.xml SBML L2V4 NIK-dependent p100 processing into p52, Mass Action 26.20 KB Preview | Download

Additional files

MA-p52.xml old xml file 18.47 KB Preview | Download
simon2019_model2.cps COPASI version 4.24 (Build 197) NIK-dependent p100 processing into p52, Mass Action 46.07 KB Preview | Download
simon2019_model2.sedml SEDML L1V2 NIK-dependent p100 processing into p52, Mass Action 4.15 KB Preview | Download

  • Model originally submitted by : Simon Mitchell
  • Submitted: May 2, 2019 9:55:28 PM
  • Last Modified: Nov 20, 2019 9:25:33 AM
  • Version: 7 public model Download this version
    • Submitted on: Nov 20, 2019 9:25:33 AM
    • Submitted by: Mohammad Umer Sharif Shohan
    • With comment: Edited model metadata online.
  • Version: 5 public model Download this version
    • Submitted on: Nov 18, 2019 3:59:25 PM
    • Submitted by: Mohammad Umer Sharif Shohan
    • With comment: Automatically added model identifier BIOMD0000000868
  • Version: 3 public model Download this version
    • Submitted on: May 2, 2019 9:55:28 PM
    • Submitted by: Simon Mitchell
    • With comment: Model revised without commit message

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: Variable used inside SBML models

Reactions Rate Parameters
p100t => p100 compartment*k1*p100t k1=0.2
p100 => compartment*k1*p100 k1=3.8E-4
p100_NIK => p52 + NIK compartment*k1*p100_NIK k1=0.05
p100 + NIK => p100_NIK compartment*(k1*p100*NIK-k2*p100_NIK) k1=0.005; k2=2.4E-4
p52 => compartment*k1*p52 k1=3.8E-4
Curator's comment:
(added: 18 Nov 2019, 15:59:17, updated: 18 Nov 2019, 15:59:17)
The model has been encoded in COPASI 4.24 (Build 197) and figure 1e of the publication has been generated using COPASI