Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of T cell activation and function by the CIN85 adaptor protein

ABSTRACT: CIN85 is ubiquitously expressed adaptor protein. In T cells, CIN85 is recruited to the TCR signaling complex and inhibit TCR signaling. To reveal the molecular function of CIN85-mediated inhibition, we performed Flag-CIN85 (CIN85dA) immuno-precipitation and identified the binding proteins. As a negative control, we used deletion mutant of CIN85 (CIN85PR).

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Takashi Saito

PROVIDER: PXD012369 | JPOST Repository | Wed Jan 16 00:00:00 GMT 2019

REPOSITORIES: jPOST

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	CIN85PR_1.wiff	Wiff
	CIN85PR_1.wiff.scan	Wiff
	CIN85PR_1a_SWATH.wiff	Wiff
	CIN85PR_1a_SWATH.wiff.scan	Wiff
	CIN85PR_2.wiff	Wiff

Items per page:

1 - 5 of 20

Publications

Inhibition of T cell activation and function by the adaptor protein CIN85.

Kong Mei Suen MS Hashimoto-Tane Akiko A Kawashima Yusuke Y Sakuma Machie M Yokosuka Tadashi T Kometani Kohei K Onishi Reiko R Carpino Nick N Ohara Osamu O Kurosaki Tomohiro T Phua Kia Kien KK Saito Takashi T

Science signaling 20190205 567

T cell activation is initiated by signaling molecules downstream of the T cell receptor (TCR) that are organized by adaptor proteins. CIN85 (Cbl-interacting protein of 85 kDa) is one such adaptor protein. Here, we showed that CIN85 limited T cell responses to TCR stimulation. Compared to activated wild-type (WT) T cells, those that lacked CIN85 produced more IL-2 and exhibited greater proliferation. After stimulation of WT T cells with their cognate antigen, CIN85 was recruited to the TCR signal ...[more]

PMID: 30723173

Similar Datasets

A novel gain-of-function phosphorylation site modulates PTPN22 inhibition of TCR signaling

Project description:A novel gain-of-function phosphorylation site modulates PTPN22 inhibition of TCR signaling

| PRJNA1102292 | ENA

Inhibition of p300 impairs Foxp3+ T-regulatory cell function and promotes anti-tumor immunity

Project description:Foxp3+ T-regulatory (Treg) cells maintain immune homeostasis and limit autoimmunity, but can also curtail host responses to cancers. Tregs are therefore promising targets to enhance anti-tumor immunity. Histone/protein acetyltransferases (HATs) promote chromatin accessibility, gene transcription and the function of multiple transcription factors and non-histone proteins. We found that conditional deletion or pharmacologic inhibition of one specific HAT, p300, in Foxp3+ Tregs, increased TCR-induced apoptosis in Tregs, impaired Treg suppressive function and iTreg peripheral conversion, and limited tumor growth in immunocompetent, but not in immunodeficient, hosts. Our data demonstrate that p300 is important for Foxp3+ Treg function and homeostasis in vivo and in vitro, and identify a novel mechanism to diminish Treg function without overtly impairing effector Tcell responses or inducing autoimmunity. Collectively, these data suggest a new approach for cancer immunotherapy. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of fl-p300/Foxp3cre mice, compared to wild type (Foxp3cre) control (all C57Bl/6 background).

2013-08-18 | E-GEOD-47989 | biostudies-arrayexpress

Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

Project description:Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARFBP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells. MIZ1 and MYC ChIPseq experiments in HUWE1 inhibitor-treated Ls174T cells as well as RNAseq experiments in HUWE1- or MIZ1-depleted Ls174T cells after HUWE1 inhibitor treatment. Sequencing was performed on an Illumina Genome Analyzer IIx.

2014-10-21 | E-GEOD-59223 | biostudies-arrayexpress

Cell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function

Project description:To become fully functional effector T cells, naïve T cells undergo a drastic metabolic status shift from quiescence to substantial biosynthesis. The synthesis of biomass initiated by T cell receptor (TCR) signals drives the cell volume increase during T cell activation (T lymphoblast), which resembles the slowest extreme of hypotonic cell swelling. However, the fundamental role of cell volume regulation in TCR signaling during T lymphoblast and its underlying mechanisms remain a long-standing enigma. Here we show that optimal T cell activation and function require appropriate cell volume regulation by regulated volume decrease (RVD) mediated via volume-regulated anion channels (VRACs) during T cell blast. Pharmacological blockade of VRACs and genetic deletion of LRRC8A in T cells, the essential component of VRACs, impair T cell activation and function, particularly under weak TCR stimulation, such as low-affinity TCR-pMHC engagement and unsaturated anti-CD3e crosslinking. Additionally, LRRC8A has distinct influences on mRNA transcriptional profiles driven by various TCR signal strengths, revealing the prominent effects of cell volume regulation for T cell functions. More importantly, LRRC8A-deficient mice have defective antiviral immunity and obstacles in effector-memory transition of CD8+ T cells. Furthermore, LRRC8A escorts the thymic selection of T cells and shapes the T cell repertoire in the thymus. Mechanistically, LRRC8A governs stringent cell volume increase via RVD during T cell blast induced by activation-driven intracellular osmolytes accumulation to keep the proximal TCR signaling molecules at adequate density. T cell blast driven by TCR signal feedbacks to control T cell activation. Together, our results reveal a previously unappreciated layer of T cell activation regulation that LRRC8A acts as a cell volume controlling "valve" to facilitate T cell activation and function

2023-09-23 | GSE243574 | GEO

A novel gain-of-function phosphorylation site modulates PTPN22 inhibition of TCR signaling

Project description:Protein Tyrosine Phosphatase Non-receptor type 22 (PTPN22) is encoded by a major autoimmunity gene and is a known inhibitor of T cell receptor (TCR) signaling and drug target for cancer immunotherapy. However, little is known about PTPN22 post-translational regulation. Here we characterize a phosphorylation site at Ser325 situated C-terminal to the catalytic domain of PTPN22, and its roles in altering protein function. Signaling through the major TCR-dependent pathway under PTPN22 control was enhanced by CRISPR/Cas9 mediated suppression of Ser325 phosphorylation and inhibited by mimicking it via glutamic acid substitution. Next-generation sequencing (NGS) revealed it differentially regulates the expression of chemokines and T cell activation pathways. In conclusion, this study explores the function of a novel phosphorylation site of PTPN22 that is involved in complex regulation of TCR signaling .

2024-07-17 | GSE264373 | GEO

Cish inhibits CD8+ T cell immunity and disrupts proximal T cell receptor signaling

Project description:T cell receptor (TCR) signaling is a critical process in immunity to infectious disease and cancer. Recently, a genome-wide association study has implicated polymorphisms in the CISH locus with susceptibility to infectious diseases. However, the role of Cish in the immune responses and its molecular underpinnings remains unclear. Here we demonstrate that Cish deletion resulted in protection against viral infection and enhanced CD8+ T cell tumor immunity. Transcriptome profiling revealed a hyper-TCR activation signature in Cish-deficient CD8+ T cells. Subsequent analysis revealed an inhibitory role for Cish in PLCγ1 activation, ensuing Ca2+ release and downstream signaling. In the steady-state Cish was found to physically interact with PLCγ1, however, PLCγ1 was only found to be ubiquitinated after acute TCR stimulation in the presence of Cish. These data implicate Cish as a potent negative regulator of TCR signaling and T cell immunity to infection and cancer and may have significant clinical applications. 4 biological replicates from wild-type mice and 3 biological replicates from Cish knock-out (-/-) mice were analyzed.

2015-04-30 | E-GEOD-56328 | biostudies-arrayexpress

Vav1 regulates T cell activation through a feedback mechanism and crosstalk between the T cell receptor and CD28 in CD3-stimulated T cells

Project description:Vav1, a Rac/Rho guanine nucleotide exchange factor and a critical component of the T cell receptor (TCR) signaling cascade, is rapidly tyrosine phosphorylated in response to T cell activation. Previous studies using Vav1 knockout models have demonstrated its importance in TCR signaling. Although Vav1 has established roles in proliferation, cytokine secretion, Ca2+ responses, and cytoskeletal regulation, its function in the regulation of phosphorylation of TCR components, including the ζ chain, the CD3 δ, ε, γ chains, and the associated kinases Lck, and ZAP-70 is not well established. To obtain a more comprehensive picture of the role of Vav1 in receptor proximal signaling, we performed a wide-scale characterization of Vav1-dependent tyrosine phosphorylation events using quantitative phosphoproteomic analysis of Vav1-deficient T cells across a time course of TCR stimulation. Among the 642 tyrosine phosphorylation sites identified and quantified in cells with or without Vav1, we observed statistically significant alterations in phosphorylation on proteins implicated in canonical actin cytoskeletal rearrangement and cell cycle progression, supporting the previously established role of Vav1 in these functions of TCR signaling. Critically, this study revealed a new role for Vav1 in negative feedback regulation of the phosphorylation of immunoreceptor tyrosine-based activation motifs within the ζ chains, CD3 δ, ε, γ chains, as well as activation sites on the critical T cell tyrosine kinases Itk, Lck, and ZAP-70. Our study also uncovered a previously unappreciated role for Vav1 in crosstalk between the CD28 and TCR signaling pathways.

2016-05-31 | PXD002022 | Pride

Continuous requirement for the T cell receptor for regulatory T cell function

Project description:Foxp3+ regulatory T cells (Treg cells) maintain immunological tolerance and their deficiency results in fatal multi-organ autoimmunity. Although heightened T cell receptor (TCR) signaling is critical for the differentiation of Treg cells, the role of TCR signaling in Treg cell function remains largely unknown. Here we demonstrate inducible ablation of the TCR results in Treg cell dysfunction which cannot be attributed to impaired Foxp3 expression, decreased expression of Treg cell signature genes or altered ability to sense and consume interleukin 2. Rather, TCR signaling was required for maintaining the expression of a limited subset of genes comprising 25% of the activated Treg cell transcriptional signature. Our results reveal a critical role for the TCR in Treg cell suppressor capacity. Array expression of Foxp3-CreERT2 CalphaFL/WT mice

2014-09-08 | E-GEOD-61077 | biostudies-arrayexpress

Gene expression profile of TGFβ3 stimulation and TRPV4 activation/inhibition in the TC28a2 human chondrocyte cell line

Project description:RNA-seq of TC28a2 cells following TRPV4 activation/inhibition in the presence and absence of prior TGFβ3 stimulation. The experiment was performed to determine the effect of TRPV4 activity on gene expression in the presence and absence of TGFβ stimulation. TGFβ3 was used to stimulate TGFβ signalling, GSK1016790A (GSK101) was used to activate TRPV4, GSK2193874 (GSK219) was used to inhibit TRPV4 and DMSO was used as a vehicle control.

2022-01-17 | E-MTAB-10279 | biostudies-arrayexpress

Inhibition of p300 impairs Foxp3+ T-regulatory cell function and promotes anti-tumor immunity

2013-08-18 | GSE47989 | GEO