Modification by covalent reaction or oxidation of cysteine residues in the tandem-SH2 domains of ZAP-70 and Syk can block phosphopeptide binding

Visperas, Patrick R.; Winger, Jonathan A.; Horton, Timothy M.; Shah, Neel H.; Aum, Diane J.; Tao, Alyssa; Barros, Tiago; Yan, Qingrong; Wilson, Christopher G.; Arkin, Michelle R.; Weiss, Arthur; Kuriyan, John

doi:10.1042/bj20140793

Cited by 23 publications

(27 citation statements)

References 43 publications

(44 reference statements)

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“…inactivated phosphatases were hypothesized to shift the equilibrium of inactive to active kinases resulting in enhanced kinase activity (18,25,26). By now, a large number of redox modifications in phosphatases, kinases, adapters, receptors, and transcription factors have been proposed to modulate signaling, among them multiple components of the BCR signaling pathway such as tyrosine-protein kinase Lyn, tyrosine-protein kinase SYK (Syk), tyrosine-protein phosphatase nonreceptor types 6 and 11 (SHP1/PTPN6; SHP2/PTPN11), phosphatase and tensin homolog, and a mitogen activated protein (MAP) kinase serine/threonine phosphatase (27)(28)(29)(30)(31)(32)(33)(34)(35)(36). However, it has been challenging to prove or disprove the physiological relevance of such a mechanism, and results have been difficult to reconcile as a whole (3,26,35).…”

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confidence: 99%

A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling

Patterson

Gerbeth

Thiru

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) govern cellular homeostasis by inducing signaling. H2O2 modulates the activity of phosphatases and many other signaling molecules through oxidation of critical cysteine residues, which led to the notion that initiation of ROS signaling is broad and nonspecific, and thus fundamentally distinct from other signaling pathways. Here, we report that H2O2 signaling bears hallmarks of a regular signal transduction cascade. It is controlled by hierarchical signaling events resulting in a focused response as the results place the mitochondrial respiratory chain upstream of tyrosine-protein kinase Lyn, Lyn upstream of tyrosine-protein kinase SYK (Syk), and Syk upstream of numerous targets involved in signaling, transcription, translation, metabolism, and cell cycle regulation. The active mediators of H2O2 signaling colocalize as H2O2 induces mitochondria-associated Lyn and Syk phosphorylation, and a pool of Lyn and Syk reside in the mitochondrial intermembrane space. Finally, the same intermediaries control the signaling response in tissues and species responsive to H2O2 as the respiratory chain, Lyn, and Syk were similarly required for H2O2 signaling in mouse B cells, fibroblasts, and chicken DT40 B cells. Consistent with a broad role, the Syk pathway is coexpressed across tissues, is of early metazoan origin, and displays evidence of evolutionary constraint in the human. These results suggest that H2O2 signaling is under control of a signal transduction pathway that links the respiratory chain to the mitochondrial intermembrane space-localized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.

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confidence: 99%

A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling

Patterson

Gerbeth

Thiru

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Another study has shown that treatment with peroxide impaired CD3-mediated phosphorylation of Zap-70 (Chakravarti and Abraham, 2002). A more recent study has identified C39, which is located in the phosphotyrosine-binding pocket of the N-terminal SH2 domain of Zap-70, as a possible target of oxidation (Visperas et al, 2015). The proposed model postulates that H 2 O 2 oxidizes this cysteine, thus preventing the recruitment of the Zap-70 SH2 domain to the phosphorylated ITAMs and ultimately attenuating TCR signaling (Figure 2).…”

Section: What Are the Targets Of Ros?mentioning

confidence: 96%

Redox regulation of T-cell receptor signaling

Simeoni

Bogeski

2015

Biological Chemistry

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T-cell receptor (TCR) triggering by antigens activates a sophisticated intracellular signaling network leading to transcriptional activation, proliferation and differentiation of T cells. These events ultimately culminate in adaptive immune responses. Over recent years it has become evident that reactive oxygen species (ROS) play an important role in T-cell activation. It is now clear that ROS are involved in the regulation of T-cell mediated physiological and pathological processes. Upon TCR triggering, T cells produce oxidants, which originate from different cellular sources. In addition, within inflamed tissues, T cells are exposed to exocrine ROS produced by activated phagocytes or other ROS-producing cells. Oxidative modifications can have different effects on T-cell function. Indeed, they can stimulate T-cell activation but they can be also detrimental. These opposite effects of oxidation likely depend on different factors such as ROS concentration and source and also on the differentiation status of the T cells. Despite the well-stablished fact that ROS represent important modulators of T-cell activation, the precise molecular mechanisms of their action are far from clear. Here, we summarize the present knowledge on redox regulation of T-cell function with a particular emphasis on the redox regulation of TCR signaling.

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“…We have previously reported FP assays for measuring the ZAP-70:ITAM interaction. 8,10 Here, we describe the development and optimization of this assay for use in a high-throughput screen.…”

Section: Resultsmentioning

confidence: 99%

“…Further analysis showed these hit compounds to be cysteine-dependent covalent modifiers of ZAP-70, as described. 8 …”

Section: Resultsmentioning

confidence: 99%

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Identification of Inhibitors of the Association of ZAP-70 with the T Cell Receptor by High-Throughput Screen

et al. 2017

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ZAP-70 is a critical molecule in the transduction of T-cell antigen receptor signaling and the activation of T cells. Upon activation of the T-cell antigen receptor, ZAP-70 is recruited to the intracellular ζ chains of the T-cell receptor, where ZAP-70 is activated and colocalized with its substrates. Inhibitors of ZAP-70 could potentially function as treatments for autoimmune diseases or organ transplantation. In this work, we present the design, optimization, and implementation of a screen for inhibitors that would disrupt the interaction between ZAP-70 and the T-cell antigen receptor. The screen is based on a fluorescence polarization assay for peptide binding to ZAP-70.

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Modification by covalent reaction or oxidation of cysteine residues in the tandem-SH2 domains of ZAP-70 and Syk can block phosphopeptide binding

Cited by 23 publications

References 43 publications

A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling

A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling

Redox regulation of T-cell receptor signaling

Identification of Inhibitors of the Association of ZAP-70 with the T Cell Receptor by High-Throughput Screen

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