Mukhopadhyay2013 - T cell receptor proximal signaling reveals emergent ultrasensitivity

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MODEL1604100000
Short description
Mukhopadhyay2013 - T cell receptor proximal signaling reveals emergent ultrasensitivity

This model is described in the article:

Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity.
Mukhopadhyay H, Cordoba SP, Maini PK, van der Merwe PA, Dushek O.
PLoS Comput. Biol. 2013; 9(3): e1003004

Abstract:

Receptor phosphorylation is thought to be tightly regulated because phosphorylated receptors initiate signaling cascades leading to cellular activation. The T cell antigen receptor (TCR) on the surface of T cells is phosphorylated by the kinase Lck and dephosphorylated by the phosphatase CD45 on multiple immunoreceptor tyrosine-based activation motifs (ITAMs). Intriguingly, Lck sequentially phosphorylates ITAMs and ZAP-70, a cytosolic kinase, binds to phosphorylated ITAMs with differential affinities. The purpose of multiple ITAMs, their sequential phosphorylation, and the differential ZAP-70 affinities are unknown. Here, we use a systems model to show that this signaling architecture produces emergent ultrasensitivity resulting in switch-like responses at the scale of individual TCRs. Importantly, this switch-like response is an emergent property, so that removal of multiple ITAMs, sequential phosphorylation, or differential affinities abolishes the switch. We propose that highly regulated TCR phosphorylation is achieved by an emergent switch-like response and use the systems model to design novel chimeric antigen receptors for therapy.

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SBML (L2V3)
Related Publication
  • Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity.
  • Mukhopadhyay H, Cordoba SP, Maini PK, van der Merwe PA, Dushek O
  • PLoS computational biology , 0/ 2013 , Volume 9 , pages: e1003004 , PubMed ID: 23555234
  • Sir William Dunn School of Pathology, University of Oxford, Oxford, Oxfordshire, United Kingdom.
  • Receptor phosphorylation is thought to be tightly regulated because phosphorylated receptors initiate signaling cascades leading to cellular activation. The T cell antigen receptor (TCR) on the surface of T cells is phosphorylated by the kinase Lck and dephosphorylated by the phosphatase CD45 on multiple immunoreceptor tyrosine-based activation motifs (ITAMs). Intriguingly, Lck sequentially phosphorylates ITAMs and ZAP-70, a cytosolic kinase, binds to phosphorylated ITAMs with differential affinities. The purpose of multiple ITAMs, their sequential phosphorylation, and the differential ZAP-70 affinities are unknown. Here, we use a systems model to show that this signaling architecture produces emergent ultrasensitivity resulting in switch-like responses at the scale of individual TCRs. Importantly, this switch-like response is an emergent property, so that removal of multiple ITAMs, sequential phosphorylation, or differential affinities abolishes the switch. We propose that highly regulated TCR phosphorylation is achieved by an emergent switch-like response and use the systems model to design novel chimeric antigen receptors for therapy.
Contributors
Submitter of the first revision: Omer Dushek
Submitter of this revision: Omer Dushek
Modellers: Omer Dushek

Metadata information

is (1 statement)
BioModels Database MODEL1604100000

hasProperty (1 statement)
Mathematical Modelling Ontology Ordinary differential equation model

Curation status
Non-curated
Modelling approach(es)
ordinary differential equation model
Original model(s)
BioNetGen rule-based description (original file can be found in the supplement of our manuscript)
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  • Model originally submitted by : Omer Dushek
  • Submitted: Apr 10, 2016 6:05:43 AM
  • Last Modified: Nov 3, 2016 5:22:41 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Nov 3, 2016 5:22:41 PM
    • Submitted by: Omer Dushek
    • With comment: Current version of Mukhopadhyay2013 - T cell receptor proximal signaling reveals emergent ultrasensitivity
  • Version: 1 public model Download this version
    • Submitted on: Apr 10, 2016 6:05:43 AM
    • Submitted by: Omer Dushek
    • With comment: Original import of MODEL1604100000.xml.origin

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