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The catalytic activity of the kinase Zap-70 mediates basal signaling and negative feedback of the T cell receptor pathway

ABSTRACT: T cell activation must be properly regulated to ensure normal T cell development and effective immune responses to pathogens and transformed cells, while avoiding autoimmunity. Our knowledge of the mechanisms controlling the fine-tuning of T cell receptor (TCR) signaling and T cell activation is still incomplete. The Syk family kinase ζ chain–associated protein kinase of 70 kD (ZAP-70) plays a critical role as part of the TCR signaling machinery that leads to T cell activation. To elucidate potential feedback targets that are dependent on the kinase activity of ZAP-70, we performed a mass spectrometry–based phosphoproteomic study to quantify temporal changes in phosphorylation patterns after inhibition of ZAP-70 catalytic activity. Our results provide insights into the fine-tuning of the T cell signaling network before as well as after TCR engagement. The data indicate that the kinase activity of ZAP-70 stimulates negative feedback pathways that target the Src family kinase Lck and modulate the phosphorylation patterns of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3 and ζ-chains, as well as of downstream signaling molecules, including ZAP-70 itself. We developed a computational model that provides a unified mechanistic explanation for the experimental data on ITAM phosphorylation in wild-type cells, ZAP-70-deficient cells, and cells with inhibited ZAP-70 catalytic activity. This model describes the requirements of the ZAP-70 kinase–dependent negative feedback that influences Lck activation, and makes specific predictions for the order in which tyrosines in the ITAMs of TCR ζ-chains must be phosphorylated to be consistent with the experimental data.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Jurkat Cell

DISEASE(S): Lymphoma

SUBMITTER: Arthur Salomon

LAB HEAD: Arthur Salomon

PROVIDER: PXD002023 | Pride | 2016-05-31

REPOSITORIES: Pride

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The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway.

Goodfellow Hanna Sjölin HS Frushicheva Maria P MP Ji Qinqin Q Cheng Debra A DA Kadlecek Theresa A TA Cantor Aaron J AJ Kuriyan John J Chakraborty Arup K AK Salomon Arthur A Weiss Arthur A

Science signaling 20150519 377

T cell activation by antigens binding to the T cell receptor (TCR) must be properly regulated to ensure normal T cell development and effective immune responses to pathogens and transformed cells while avoiding autoimmunity. The Src family kinase Lck and the Syk family kinase ZAP-70 (ζ chain-associated protein kinase of 70 kD) are sequentially activated in response to TCR engagement and serve as critical components of the TCR signaling machinery that leads to T cell activation. We performed a ma ...[more]

PMID: 25990959

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Project 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. This model is hosted on BioModels Database and identified by: MODEL1604100000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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