Simon2019 - NIK-dependent p100 processing into p52 and IkBd degradation, Michaelis-Menten, SBML 2v4

  public model
Model Identifier
BIOMD0000000869
Short description

This model represents NIK-dependent p100 processing into p52 and NIK-dependent IkBd degradation with Michaelis-Menten kinetics. Compare this Michaelis-Menten representation to the mass action model in which the dose-response to increasing p100 mRNA is no longer 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 MODEL1904020002
BioModels Database BIOMD0000000869
BioModels Database MODEL1904020002

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_model3.xml SBML L2V4 NIK-dependent p100 processing into p52 and IkBd degradation, Michaelis-Menten 32.61 KB Preview | Download

Additional files
MM-p52-IkBd.xml old xml file 22.69 KB Preview | Download
Simon2019_model3.cps COPASI version 4.24 (Build 197) NIK-dependent p100 processing into p52 and IkBd degradation, Michaelis-Menten 55.23 KB Preview | Download
Simon2019_model3.sedml SEDML L1V2 NIK-dependent p100 processing into p52 and IkBd degradation, Michaelis-Menten 1.01 KB Preview | Download

  • Model originally submitted by : Simon Mitchell
  • Submitted: May 2, 2019 9:54:55 PM
  • Last Modified: Jan 9, 2020 1:44:54 PM
Revisions
  • Version: 8 public model Download this version
    • Submitted on: Jan 9, 2020 1:44:54 PM
    • Submitted by: Mohammad Umer Sharif Shohan
    • With comment: Automatically added model identifier BIOMD0000000869
  • Version: 5 public model Download this version
    • Submitted on: Nov 18, 2019 5:17:14 PM
    • Submitted by: Mohammad Umer Sharif Shohan
    • With comment: Automatically added model identifier BIOMD0000000869
  • Version: 3 public model Download this version
    • Submitted on: May 2, 2019 9:54:55 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
p52

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

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

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

ENSG00000077150 		2.5 nmol
Reactions
Reactions Rate Parameters
p100 => p52; NIK compartment*NIK*kcat*p100/(Km+p100) Km=10.0; kcat=0.05
p100 => IkBd compartment*(k1*p100^2-k2*IkBd) k1=1.6E-5; k2=2.4E-4
IkBd => compartment*k1*IkBd k1=3.8E-4
p100t => p100 compartment*k1*p100t k1=0.2
p52 => compartment*k1*p52 k1=3.8E-4
IkBd => ; NIK compartment*NIK*kcat*IkBd/(Km+IkBd) Km=10.0; kcat=0.05
p100 => compartment*k1*p100 k1=3.8E-4
Curator's comment:
(added: 18 Nov 2019, 17:15:51, updated: 18 Nov 2019, 17:15:51)
The model has been encoded in COPASI 4.24 (Build 197 ) and the Figure 1f has been produced using COPASI.