NIK-dependent p100 processing into p52 with RelB binding and IkBd degradation, mass action, SBML 2v4

  public model
Model Identifier
BIOMD0000000871
Short description

This model represents NIK-dependent p100 processing into p52 followed by binding to RelB and NIK-dependent IkBd degradation. This model assesses the impact of substrate complex competition on RelB-p52.
Format
SBML (L2V4)
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.
Contributors
Submitter of the first revision: Simon Mitchell
Submitter of this revision: Mohammad Umer Sharif Shohan
Modellers: Simon Mitchell, Mohammad Umer Sharif Shohan

Metadata information

hasProperty (2 statements)
Curation status
Curated
Tags

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Name Description Size Actions

Model files
Simon2019_Figure3b.xml SBML L2V4 NIK-dependent p100 processing into p52 with RelB binding and IkBd degradation, mass action 48.94 KB Preview | Download

Additional files
MA-p52-IkBd-Fig3B.xml old xml file 36.74 KB Preview | Download
Simon2019_Figure3b.cps COPASI version 4.24 (Build 197) NIK-dependent p100 processing into p52 with RelB binding and IkBd degradation, mass action 74.66 KB Preview | Download
Simon2019_Figure3b.sedml SEDML L1V2 NIK-dependent p100 processing into p52 with RelB binding and IkBd degradation, mass action 1.01 KB Preview | Download

  • Model originally submitted by : Simon Mitchell
  • Submitted: May 2, 2019 9:51:51 PM
  • Last Modified: Nov 21, 2019 2:52:39 PM
Revisions
  • Version: 5 public model Download this version
    • Submitted on: Nov 21, 2019 2:52:39 PM
    • Submitted by: Mohammad Umer Sharif Shohan
    • With comment: Automatically added model identifier BIOMD0000000871
  • Version: 3 public model Download this version
    • Submitted on: May 2, 2019 9:51:51 PM
    • Submitted by: Simon Mitchell
    • With comment: Added publication

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Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
p100

Nuclear factor NF-kappa-B p100 subunit 		0.0 nmol
RelB

Transcription factor RelB 		0.0 nmol
RelB p52

Nuclear factor NF-kappa-B p100 subunit ; Transcription factor RelB 		0.0 nmol
NIK

Mitogen-activated protein kinase kinase kinase 14 		10.0 nmol
p52

Nuclear factor NF-kappa-B p100 subunit 		0.0 nmol
IkBd

Nuclear factor NF-kappa-B p100 subunit 		0.0 nmol
Reactions
Reactions Rate Parameters
=> p100 compartment*k*canon/(Kd+canon) k=1000.0; Kd=50.0; canon = 1.0
=> RelB compartment*k*canon/(Kd+canon) k=42.0; Kd=50.0; canon = 1.0
RelB + p52 => RelB_p52 compartment*(k1*RelB*p52-k2*RelB_p52) k2=0.00144; k1=9.6E-4
RelB_p52 => compartment*k1*RelB_p52 k1=3.8E-4
RelB => compartment*k1*RelB k1=0.0228
IkBd + NIK => IkBd_NIK compartment*(k1*IkBd*NIK-k2*IkBd_NIK) k1=0.005; k2=2.4E-4
IkBd_NIK => NIK compartment*k1*IkBd_NIK k1=0.05
p100 => IkBd compartment*(k1*p100^2-k2*IkBd) k1=1.6E-5; k2=2.4E-4
Curator's comment:
(added: 21 Nov 2019, 14:52:29, updated: 21 Nov 2019, 14:52:29)
The model has been encoded in COPASI 4.24 (Build 197) and Figure 3B of the publication has been generated using ggplot package of R.