Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP

Gjörloff-Wingren, Anette; Saxena, Manju; Williams, Scott; Hammi, Don; Mustelin, Tomas

doi:10.1002/(sici)1521-4141(199912)29:12<3845::aid-immu3845>3.0.co;2-u

Cited by 172 publications

(144 citation statements)

References 35 publications

(49 reference statements)

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“…The inhibitory effect that is seen following overexpression of wild type TC-PTP is then most likely related with dephosphorylation of some transcription factors in the nucleus, leading to a decrease in COX-2 transcriptional activity. Last, we cannot totally exclude the implication of the Pro-Glu-Ser-Thr (PEST)-enriched phosphatase that acts as a potent negative regulator of T cell activation through an association with Csk and a possible direct dephosphorylation of Src family PTK (27).…”

Section: The Implication Of P36mentioning

confidence: 99%

Treatment of Human T Cells with Bisperoxovanadium Phosphotyrosyl Phosphatase Inhibitors Leads to Activation of Cyclooxygenase-2 Gene

Barat

Tremblay

2003

Journal of Biological Chemistry

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Protein-tyrosine phosphatase (PTP) inhibitors are potent activators of T lymphocytes, most likely by affecting the early steps of T cell receptor (TCR) signaling. We have analyzed the effect of the PTP inhibitor bisperoxovanadium (bpV) on expression of the human cyclooxygenase 2 (COX-2) gene, which is induced following TCR triggering. Here we show that COX-2 promoter activity is markedly up-regulated following exposure of Jurkat T cells to bpV(pic). Interestingly enough, treatment of Jurkat cells with cyclic AMP-elevating agents such as forskolin, in combination with bpV, resulted in a more important COX-2 transcriptional activation. Such activation is inhibited by the immunosuppressive drugs FK506 and cyclosporin A. The two nuclear factor of activated T cells (NFAT) binding sites located within the COX-2 promoter region are involved in bpV-mediated positive effect on COX-2 promoter. Electromobility shift assays showed that NFAT1 and activator protein-1 are both translocated to the nucleus following bpV treatment. The active participation of p56 lck , ZAP-70, p36 LAT , and calcium in the bpV-dependent signaling cascade leading to COX-2 transcriptional activation was demonstrated using deficient cell lines and specific inhibitors. Although several PTPs are most likely targeted by bpV, our data suggest that the bpV-mediated signaling cascade is initiated by inhibition of SHP-1, which leads to phosphorylation of p56 lck and ZAP-70 and, ultimately, to NFAT and activator protein-1 nuclear translocation. These results suggest that PTP inhibitors can activate COX-2 gene expression in a manner very similar to the stimulation induced by TCR triggering.Prostaglandins are important mediators in many physiological processes including cell growth, ovulation, and immune functions. These potent lipid molecules play key roles in the inflammatory response, and inhibition of their synthesis is the target of most non-steroidal anti-inflammatory drugs. Prostaglandin biosynthesis is controlled by the cyclooxygenase (COX) 1 enzyme, which catalyzes the initial conversion of arachidonic acid to prostaglandin H 2 , a precursor common to all prostanoids. Two COX isoenzymes are expressed in mammalian tissues, COX-1 and COX-2. COX-1 is expressed constitutively in most tissues, whereas COX-2 is induced by various proinflammatory cytokines and mitogenic agents in different cell types and is thought to be responsible for the increased production of prostaglandins in inflammatory disorders (1). COX-2 synthesis is regulated primarily at the transcriptional level via distinct pathways in various cell types (including vascular endothelial cells, epithelial cells, pancreatic cells, mast cells, and monocytes) and involves transcription factors such as nuclear factor of chain in B cells (NF-B), activator protein-1 (AP-1), CCAAT/enhancer-binding protein (C/EBP), cAMP-responsive element-binding protein (CREB), and nuclear factor of activated T cells (NFAT) (2-10). COX-2 seems to act as an early T cell receptor (TCR)-responsive gene, because TCR engage...

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Section: The Implication Of P36mentioning

confidence: 99%

Treatment of Human T Cells with Bisperoxovanadium Phosphotyrosyl Phosphatase Inhibitors Leads to Activation of Cyclooxygenase-2 Gene

Barat

Tremblay

2003

Journal of Biological Chemistry

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“…4,5 LYP is an important molecule in the regulation of T-cell antigen receptor signalling in memory/effector T cells. 6 The PTPN22 gene is situated on chromosome 1p13 in a region suggested to be linked with RA 7 and systemic lupus erythematosus (SLE).…”

Section: Introductionmentioning

confidence: 99%

Association analysis of the 1858C>T polymorphism in the PTPN22 gene in juvenile idiopathic arthritis and other autoimmune diseases

et al. 2005

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A functional single nucleotide polymorphism, 1858C4T, in the PTPN22 gene, encoding a tyrosine phosphatase, has been reported to be associated with type I diabetes and some other autoimmune diseases. To further investigate whether this polymorphism may be a general susceptibility factor for autoimmunity, we performed an association study in five different autoimmune diseases, three previously not tested. We found an association with juvenile idiopathic arthritis (OR ¼ 1.41; P ¼ 0.04), not previously reported, and a tendency for an association with coeliac disease (OR ¼ 1.35; P ¼ 0.08). In primary sclerosing cholangitis, no association was observed (OR ¼ 0.95; P ¼ 0.8). Furthermore, we confirmed the increased risk in rheumatoid arthritis (OR ¼ 1.58; P ¼ 0.001), but could not find support for an association with systemic lupus erythematosus (OR ¼ 0.94; P ¼ 0.8). Altogether, we have provided further evidence of an association between autoimmune diseases and the 1858C4T polymorphism in PTPN22.

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“…This inhibition is accomplished by the direct dephosphorylation of the activating tyrosine residue, Y394, located within the catalytic domain of these Src family kinases (8). This inhibition is further enhanced by the association of Ptpn22 with the C-terminal Src kinase (Csk) (9), which works in synergy with the phosphatase to negatively regulate the activity of Lck and Fyn (8,10). The interaction between Csk and Ptpn22 also potentially promotes the association of the latter with yet unknown substrates located proximal to the cell membrane.…”

mentioning

confidence: 99%

A Functional Polymorphism of Ptpn22 Is Associated with Type 1 Diabetes in the BioBreeding Rat

Sarmiento

Wallis

Ning

et al. 2015

The Journal of Immunology

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The R620W variant of PTPN22 is one of the major genetic risk factors for several autoimmune disorders including type 1 diabetes (T1D) in humans. In the BioBreeding T1D-prone (BBDP) rat, a single nucleotide polymorphism in Ptpn22 results in an A629T substitution immediately C-terminal to the aliphatic residues central to the Ptpn22–C-terminal Src kinase interaction. This variant exhibits a 50% decrease in C-terminal Src kinase binding affinity and contributes to T cell hyperresponsiveness. Examination of BBDP sublines congenic for the Iddm26.2 locus that includes Ptpn22 has not only shown an expansion of activated CD4+25+ T lymphocytes in animals homozygous for the BBDP allele, consistent with enhanced TCR-mediated signaling, but also a decrease in their proportion of peripheral Foxp3+ regulatory T cells. Furthermore, clinical assessment of both an F2(BBDP × ACI.1u.Lyp) cohort and Iddm26.2 congenic BBDP sublines has revealed an association of Ptpn22 with T1D. Specifically, in both cases, T1D risk is significantly greater in BBDP Ptpn22 homozygous and heterozygous animals. These findings are consistent with a role for rat Ptpn22 allelic variation within Iddm26.2 in the regulation of T cell responses, and subsequently the risk for development of T1D.

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Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP

Cited by 172 publications

References 35 publications

Treatment of Human T Cells with Bisperoxovanadium Phosphotyrosyl Phosphatase Inhibitors Leads to Activation of Cyclooxygenase-2 Gene

Treatment of Human T Cells with Bisperoxovanadium Phosphotyrosyl Phosphatase Inhibitors Leads to Activation of Cyclooxygenase-2 Gene

Association analysis of the 1858C>T polymorphism in the PTPN22 gene in juvenile idiopathic arthritis and other autoimmune diseases

A Functional Polymorphism of Ptpn22 Is Associated with Type 1 Diabetes in the BioBreeding Rat

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