Quantitative Phosphoproteomic Analysis of T Cell Receptor Signaling in Diabetes Prone and Resistant Mice

Iwai, Leo Kei; Benoist, Christophe; Mathis, Diane; White, Forest M.

doi:10.1021/pr100035b

Cited by 44 publications

(41 citation statements)

References 42 publications

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“…One might also speculate that there is a molecular relationship between this Treg phenotype and the overreactivity of mature CD4 + Tconv cells, manifest as increased phosphorylation cascades immediately downstream of TCR engagement and more robust proliferation (12,50). NOD Tconv cells might keep a "molecular memory" of these robust responses, with an inefficient induction of the Lrrc32 cluster, even while Foxp3 is normally induced.…”

Section: Discussionmentioning

confidence: 99%

A cluster of coregulated genes determines TGF-β–induced regulatory T-cell (Treg) dysfunction in NOD mice

D’Alise

Ergün

Hill

et al. 2011

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

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Foxp3 + regulatory T cells (Tregs) originate in the thymus, but the Treg phenotype can also be induced in peripheral lymphoid organs or in vitro by stimulation of conventional CD4 + T cells with IL-2 and TGF-β. There have been divergent reports on the suppressive capacity of these TGF-Treg cells. We find that TGF-Tregs derived from diabetes-prone NOD mice, although expressing normal Foxp3 levels, are uniquely defective in suppressive activity, whereas TGF-Tregs from control strains (B6g7) or ex vivo Tregs from NOD mice all function normally. Most Treg-typical transcripts were shared by NOD or B6g7 TGF-Tregs, except for a small group of differentially expressed genes, including genes relevant for suppressive activity ( Lrrc32 , Ctla4 , and Cd73 ). Many of these transcripts form a coregulated cluster in a broader analysis of T-cell differentiation. The defect does not map to idd3 or idd5 regions. Whereas Treg cells from NOD mice are normal in spleen and lymph nodes, the NOD defect is observed in locations that have been tied to pathogenesis of diabetes (small intestine lamina propria and pancreatic lymph node). Thus, a genetic defect uniquely affects a specific Treg subpopulation in NOD mice, in a manner consistent with a role in determining diabetes susceptibility.

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Section: Discussionmentioning

confidence: 99%

A cluster of coregulated genes determines TGF-β–induced regulatory T-cell (Treg) dysfunction in NOD mice

D’Alise

Ergün

Hill

et al. 2011

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

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“…To carry out a dynamic phosphoproteomic analysis, we utilized a multiplexed labeling strategy (iTRAQ) allowing analysis of four distinct time points following the addition of vasopressin. Other studies have utilized various phosphoproteomic strategies to quantify biological responses (12)(13)(14)(15)(16)(17)(18). To our knowledge, the present study is the first temporal quantitative phosphoproteomic analysis of a physiological response using a native mammalian model.…”

mentioning

confidence: 95%

Dynamics of the G Protein-coupled Vasopressin V2 Receptor Signaling Network Revealed by Quantitative Phosphoproteomics

Hoffert

Pisitkun

Saeed

et al. 2012

Molecular & Cellular Proteomics

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G protein-coupled receptors (GPCRs) regulate diverse physiological processes, and many human diseases are due to defects in GPCR signaling. To identify the dynamic response of a signaling network downstream from a prototypical G s -coupled GPCR, the vasopressin V2 receptor, we have carried out multireplicate, quantitative phosphoproteomics with iTRAQ labeling at four time points following vasopressin exposure at a physiological concentration in cells isolated from rat kidney. A total of 12,167 phosphopeptides were identified from 2,783 proteins, with 273 changing significantly in abundance with vasopressin. Two-dimensional clustering of phosphopeptide time courses and Gene Ontology terms revealed that ligand binding to the V2 receptor affects more than simply the canonical cyclic adenosine monophosphateprotein kinase A and arrestin pathways under physiological conditions. The regulated proteins included key components of actin cytoskeleton remodeling, cell-cell adhesion, mitogen-activated protein kinase signaling, Wnt/␤-catenin signaling, and apoptosis pathways. These data suggest that vasopressin can regulate an array of cellular functions well beyond its classical role in regulating water and solute transport. These results greatly expand the current view of GPCR signaling in a physiological context and shed new light on

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“…This modification, regulated by kinases and phosphatases that phosphorylate and dephosphorylate these amino acids respectively, controls many aspects of protein biochemistry including stability, localization, ability to interact with other molecules and enzymatic activity (1,2). In addition to playing a pivotal role in regulating most biological processes, alterations in biochemical pathways regulated by protein phosphorylation contribute to the pathophysiology of various diseases including cancer, diabetes and neurodegeneration (2)(3)(4)(5)(6).…”

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confidence: 99%

Environmental Stress Affects the Activity of Metabolic and Growth Factor Signaling Networks and Induces Autophagy Markers in MCF7 Breast Cancer Cells

Casado

Bilanges

Rajeeve

et al. 2014

Molecular & Cellular Proteomics

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Phosphoproteomic techniques are contributing to our understanding of how signaling pathways interact and regulate biological processes. This technology is also being used to characterize how signaling networks are remodeled during disease progression and to identify biomarkers of signaling pathway activity and of responses to cancer therapy. A potential caveat in these studies is that phosphorylation is a very dynamic modification that can substantially change during the course of an experiment or the retrieval and processing of cellular samples. Here, we investigated how exposure of cells to ambient conditions modulates phosphorylation and signaling pathway activity in the MCF7 breast cancer cell line. About 1.5% of 3,500 sites measured showed a significant change in phosphorylation extent upon exposure of cells to ambient conditions for 15 min. The effects of this perturbation in modifying phosphorylation patterns did not involve random changes due to stochastic activation of kinases and phosphatases. Instead, exposure of cells to ambient conditions elicited an environmental stress reaction that involved a coordinated response to a metabolic stress situation, which included: (1) the activation of AMPK; (2) the inhibition of PI3K, AKT, and ERK; (3) an increase in markers of protein synthesis inhibition at the level of translation elongation; and (4) an increase in autophagy markers. We also observed that maintaining cells in ice modified but did not completely abolish this metabolic stress response. In summary, exposure of cells to ambient conditions affects the activity of signaling networks previously implicated in metabolic and growth factor signaling. Mass spectrometry data have been deposited to the ProteomeXchange with identifier PXD000472. Molecular

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Quantitative Phosphoproteomic Analysis of T Cell Receptor Signaling in Diabetes Prone and Resistant Mice

Cited by 44 publications

References 42 publications

A cluster of coregulated genes determines TGF-β–induced regulatory T-cell (Treg) dysfunction in NOD mice

A cluster of coregulated genes determines TGF-β–induced regulatory T-cell (Treg) dysfunction in NOD mice

Dynamics of the G Protein-coupled Vasopressin V2 Receptor Signaling Network Revealed by Quantitative Phosphoproteomics

Environmental Stress Affects the Activity of Metabolic and Growth Factor Signaling Networks and Induces Autophagy Markers in MCF7 Breast Cancer Cells

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