Simon2019 - NIK-dependent p100 processing into p52 and IkBd degradation, mass action, SBML 2v4

  public model
Model Identifier
BIOMD0000000870
Short description

This model represents NIK-dependent p100 processing into p52 and NIK-dependent IkBd degradation with mass action kinetics. Compare this mass action representation to the Michaelis-Menten model. In this model the dose-response to increasing p100 mRNA is not monotonic due to substrate complex competition.
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

is (3 statements)
BioModels Database BIOMD0000000870
BioModels Database MODEL1904020003
BioModels Database MODEL1904020003

isDescribedBy (1 statement)
PubMed 31048505

hasProperty (2 statements)
Curation status
Curated
Tags

Connected external resources

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Name Description Size Actions

Model files
Simon2019_model4.xml SBML L2V4 NIK-dependent p100 processing into p52 and IkBd degradation, mass action 35.18 KB Preview | Download

Additional files
MA-p52-IkBd.xml old xml file 27.52 KB Preview | Download
Simon2019_model4.cps COPASI version 4.24 (Build 197) NIK-dependent p100 processing into p52 and IkBd degradation, mass action 58.86 KB Preview | Download
Simon2019_model4.sedml SEDML L1V2 NIK-dependent p100 processing into p52 and IkBd degradation, mass action 6.03 KB Preview | Download

  • Model originally submitted by : Simon Mitchell
  • Submitted: May 2, 2019 9:54:06 PM
  • Last Modified: Jan 9, 2020 1:44:43 PM
Revisions
  • Version: 9 public model Download this version
    • Submitted on: Jan 9, 2020 1:44:43 PM
    • Submitted by: Mohammad Umer Sharif Shohan
    • With comment: Automatically added model identifier BIOMD0000000870
  • Version: 6 public model Download this version
    • Submitted on: Nov 19, 2019 4:29:15 PM
    • Submitted by: Mohammad Umer Sharif Shohan
    • With comment: Automatically added model identifier BIOMD0000000870
  • Version: 3 public model Download this version
    • Submitted on: May 2, 2019 9:54:06 PM
    • Submitted by: Simon Mitchell
    • With comment: updated publication

(*) 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.

Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
IkBd NIK

Mitogen-activated protein kinase kinase kinase 14 ; Nuclear factor NF-kappa-B p100 subunit 		0.0 nmol
p100 NIK

Mitogen-activated protein kinase kinase kinase 14 ; Nuclear factor NF-kappa-B p100 subunit 		0.0 nmol
NIK

Mitogen-activated protein kinase kinase kinase 14 		10.0 nmol
IkBd

Nuclear factor NF-kappa-B p100 subunit 		0.0 nmol
p100t

ENSG00000077150 		2.5 nmol
p52

Nuclear factor NF-kappa-B p100 subunit 		0.0 nmol
Reactions
Reactions Rate Parameters
IkBd + NIK => IkBd_NIK compartment*(k1*IkBd*NIK-k2*IkBd_NIK) k1=0.005; k2=2.4E-4
p100 + NIK => p100_NIK compartment*(k1*p100*NIK-k2*p100_NIK) k1=0.005; k2=2.4E-4
p100_NIK => p52 + NIK compartment*k1*p100_NIK k1=0.05
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
p100t => p100 compartment*k1*p100t k1=0.2
Curator's comment:
(added: 19 Nov 2019, 16:27:24, updated: 19 Nov 2019, 16:27:24)
The model has been encoded in COPASI 4.24 (Build 197) and the figure 1g has been generated using COPASI