ArticleMolecular and cellular biology2003
Phosphorylation-dependent regulation of T-cell activation by PAG/Cbp, a lipid raft-associated transmembrane adaptor.
Article in Molecular and cellular biology, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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Who cites it
81 citing papers in PubMed, 195 citations in OpenAlex.
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- CAR T cell engineering impacts antigen-independent activation and co-inhibition.Molecular therapy. Methods & clinical development · 2025Article
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- A novel GPI-anchored dominant-negative TGF-β receptor II renders T cells unresponsive to TGF-β signaling.Molecular therapy oncolytics · 2023Article
- A Story of Kinases and Adaptors: The Role of Lck, ZAP-70 and LAT in Switch Panel Governing T-Cell Development and Activation.Biology · 2023Review
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- SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding.Scientific reports · 2022Article
- Apoptosis regulation by the tyrosine-protein kinase CSK.Frontiers in cell and developmental biology · 2022Review
- Mitochondrial trafficking and redox/phosphorylation signaling supporting cell migration phenotypes.Frontiers in molecular biosciences · 2022Review
- Combination Approaches to Target PD-1 Signaling in Cancer.Frontiers in immunology · 2022Review
- T cell receptor (TCR) signaling in health and disease.Signal transduction and targeted therapy · 2021Review
- Analysis of merged whole blood transcriptomic datasets to identify circulating molecular biomarkers of feed efficiency in growing pigs.BMC genomics · 2021Article
- Transmembrane adaptor protein PAG is a mediator of PD-1 inhibitory signaling in human T cells.Communications biology · 2021Article
- Influence of pentoxifylline on gene expression of PAG1/ miR-1206/ SNHG14 in ischemic heart disease.Biochemistry and biophysics reports · 2021Article
- Function of Protein S-Palmitoylation in Immunity and Immune-Related Diseases.Frontiers in immunology · 2021Review
- Structural Modifications Controlling Membrane Raft Partitioning and Curvature in Human and Viral Proteins.The journal of physical chemistry. B · 2020Article
- Potentiating the Antitumor Activity of Cytotoxic T CellsFrontiers in immunology · 2020Article
- Modulation of TCR Signaling by Tyrosine Phosphatases: From Autoimmunity to Immunotherapy.Frontiers in cell and developmental biology · 2020Review
- Protein Palmitoylation in Leukocyte Signaling and Function.Frontiers in cell and developmental biology · 2020Review
21 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 4 institutions in 4 countries.
Funding
Abstract
PAG/Cbp (hereafter named PAG) is a transmembrane adaptor molecule found in lipid rafts. In resting human T cells, PAG is tyrosine phosphorylated and associated with Csk, an inhibitor of Src-related protein tyrosine kinases. These modifications are rapidly lost in response to T-cell receptor (TCR) stimulation. Overexpression of PAG was reported to inhibit TCR-mediated responses in Jurkat T cells. Herein, we have examined the physiological relevance and the mechanism of PAG-mediated inhibition in T cells. Our studies showed that PAG tyrosine phosphorylation and association with Csk are suppressed in response to activation of normal mouse T cells. By expressing wild-type and phosphorylation-defective (dominant-negative) PAG polypeptides in these cells, we found that the inhibitory effect of PAG is dependent on its capacity to be tyrosine phosphorylated and to associate with Csk. PAG-mediated inhibition was accompanied by a repression of proximal TCR signaling and was rescued by expression of a constitutively activated Src-related kinase, implying that it is due to an inactivation of Src kinases by PAG-associated Csk. We also attempted to identify the protein tyrosine phosphatases (PTPs) responsible for dephosphorylating PAG in T cells. Through cell fractionation studies and analyses of genetically modified mice, we established that PTPs such as PEP and SHP-1 are unlikely to be involved in the dephosphorylation of PAG in T cells. However, the transmembrane PTP CD45 seems to play an important role in this process. Taken together, these data provide firm evidence that PAG is a bona fide negative regulator of T-cell activation as a result of its capacity to recruit Csk. They also suggest that the inhibitory function of PAG in T cells is suppressed by CD45. Lastly, they support the idea that dephosphorylation of proteins on tyrosine residues is critical for the initiation of T-cell activation.
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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.