ArticlePLoS computational biology2013
Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity.
Article in PLoS computational biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it, 55 citations in OpenAlex.
- A Systematic Review of the Efforts and Hindrances of Modeling and Simulation of CAR T-cell Therapy.The AAPS journal · 2021Pooled it
- Olfactory receptors as tumor suppressors in cutaneous T-cell lymphoma via p38γ pathway modulation.Blood neoplasia · 2025Article
- Parallel reactions on a single T cell receptor offer a robust kinetic proofreading mechanism.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- T cells in cancer: mechanistic insights and therapeutic advances.Biomarker research · 2025Review
- Early events in TCR signaling - the evolving role of ITAMs.Frontiers in immunology · 2025Review
- Advances in adoptive cellular immunotherapy and therapeutic breakthroughs in multiple myeloma.Experimental hematology & oncology · 2024Review
- Cardiac myosin binding protein-C phosphorylation as a function of multiple protein kinase and phosphatase activities.Nature communications · 2024Article
- Sensitive bispecific chimeric T cell receptors for cancer therapy.Research square · 2024Article
- CD3ζ ITAMs enable ligand discrimination and antagonism by inhibiting TCR signaling in response to low-affinity peptides.Nature immunology · 2023Article
- Intrinsic Disorder in the T Cell Receptor Creates Cooperativity and Controls ZAP70 Binding.Biophysical journal · 2021Article
- Clustering of the ζ-Chain Can Initiate T Cell Receptor Signaling.International journal of molecular sciences · 2020Article
- Targeting Cancer Stem Cells by Genetically Engineered Chimeric Antigen Receptor T Cells.Frontiers in genetics · 2020Review
- Engineering Cytoplasmic Signaling of CD28ζ CARs for Improved Therapeutic Functions.Frontiers in immunology · 2020Review
- T Cell Reprogramming Against Cancer.Methods in molecular biology (Clifton, N.J.) · 2020Review
- The Influence of Molecular Reach and Diffusivity on the Efficacy of Membrane-Confined Reactions.Biophysical journal · 2019Article
- Article
- Understanding the Dynamics of T-Cell Activation in Health and Disease Through the Lens of Computational Modeling.JCO clinical cancer informatics · 2019Review
- Computational Model of Chimeric Antigen Receptors Explains Site-Specific Phosphorylation Kinetics.Biophysical journal · 2018Article
- Tuning ITAM multiplicity on T cell receptors can control potency and selectivity to ligand density.Science signaling · 2018Article
- Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.