期刊
PLOS COMPUTATIONAL BIOLOGY
卷 9, 期 3, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pcbi.1003004
关键词
-
资金
- Medical Research Council [MR/J002011/1]
- Abraham Research Fund [BVRVBX0]
- Doctoral Training Centre Systems Biology studentship
- Engineering and Physical Sciences Research Council (EPSRC)
- Sir Henry Dale Fellowship
- Wellcome Trust and the Royal Society [098363]
- Medical Research Council [MR/J002011/1, G9722488] Funding Source: researchfish
- MRC [MR/J002011/1] Funding Source: UKRI
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据