The Mathematical Institute, University of Oxford, Eprints Archive

Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity

Mukhopadhyay, H and Cordoba, S P and Maini, P. K. and van der Merwe, A and Dushek, O (2013) Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity. PLOS Computational Biology, 9 (3). e1003004-8 pages.

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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.

Item Type:Article
Subjects:A - C > Biology and other natural sciences
Research Groups:Centre for Mathematical Biology
ID Code:1693
Deposited By: Philip Maini
Deposited On:05 Apr 2013 07:42
Last Modified:29 May 2015 19:23

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