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


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Reference Publication
Publication ID: 23555234
Mukhopadhyay H, Cordoba SP, Maini PK, van der Merwe PA, Dushek O.
Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity.
PLoS Comput. Biol. 2013; 9(3): e1003004
Sir William Dunn School of Pathology, University of Oxford, Oxford, Oxfordshire, United Kingdom.  [more]
Original Model: BioNetGen rule-based descr...
Submitter: Omer Dushek
Submission Date: 10 Apr 2016 05:05:43 UTC
Last Modification Date: 03 Nov 2016 17:22:41 UTC
Creation Date: 03 Nov 2016 16:21:29 UTC
Mukhopadhyay2013 - T cell receptor proximal signaling reveals emergent ultrasensitivity

This model is described in the article:

Mukhopadhyay H, Cordoba SP, Maini PK, van der Merwe PA, Dushek O.
PLoS Comput. Biol. 2013; 9(3): e1003004


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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