Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bacterial superantigens (SAgs) are potent activators of T lymphocytes and play a pathophysiological role in Gram-positive septic shock and food poisoning. To characterize potential MHC class II binding sites of the bacterial SAg staphylococcal enterotoxin (SE) A, we performed alanine substitution mutagenesis throughout the C-terminus and at selected sites in the N-terminal domain. Four amino acids in the C-terminus were shown to be involved in MHC class II binding. Three of these amino acids, H225, D227 and H187, had a major influence on MHC class II binding and appeared to be involved in coordination of a Zn2+ ion. Alanine substitution of H225 and D227 resulted in a 1000-fold reduction in MHC class II affinity. Mutation at F47, which is equivalent to the F44 previously shown to be central in the MHC class II binding site of the SAg, SEB, resulted in a 10-fold reduction in MHC class II affinity. The combination of these mutations in the N- and C-terminal sites resulted in a profound loss of activity. The perturbation of MHC class II binding in the various mutants was accompanied by a corresponding loss of ability to induce MHC class II-dependent T cell proliferation and cytotoxicity. All of the SEA mutants were expressed as Fab-SEA fusion proteins and found to retain an intact T cell receptor (TCR) epitope, as determined in a mAb targeted MHC class II-independent T cell cytotoxicity assay.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of two distinct MHC class II binding sites in the superantigen staphylococcal enterotoxin A. 754 84

To identify genes involved in signal transduction pathways that regulate T cell activation and development, murine fetal thymocytes were screened for expression of protein tyrosine kinase family members by the polymerase chain reaction. Using this approach, a non-receptor protein tyrosine kinase, txk, was identified and cloned. Tsk is expressed in thymocytes as early as fetal day 13.5 and its expression at the mRNA level continues throughout development. Txk transcripts are present in thymocytes, peripheral T cells and mast cell lines, but are not detectable in B cell macrophage/monocyte cell lines or in non-hematopoietic fetal or adult tissues. In both thymocytes and T cells, txk transcripts are down-regulated after activation with PMA and ionomycin, concanavalin A or T cell receptor cross-linking. Sequence analysis indicates that txk contains SH2, SH3 and kinase catalytic domains and belongs to the tec family of cytoplasmic protein tyrosine kinases which includes tec, itk and btk. Its unique N-terminus contains a proline-rich region, but unlike the other tec family members, does not contain a pleckstrin homology domain. The restricted expression pattern of txk and its regulation by T cell activation make it an excellent candidate for involvement in signal transduction during thymocyte development.
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PMID:Murine txk: a protein tyrosine kinase gene regulated by T cell activation. 754 61

The mechanisms by which Trypanosoma cruzi causes dysfunction in normal human lymphocytes was studied by using an in vitro system in which purified parasites and normal peripheral blood mononuclear cells are co-cultured in the presence or absence of mitogens. Our results have shown that T. cruzi impairs the expression of receptors for interleukin-2 (IL-2R) and transferrin, activated lymphocyte membrane molecules which play key roles in controlling progression through the cell cycle. T. cruzi also downregulates the expression of constitutive lymphocyte molecules (e.g., CD4, and CD8) involved in the interactions between antigen-presenting cells and T lymphocytes as well as the expression of T cell receptor (TCR) and CD3 molecules. The latter molecular structures are physically associated and are responsible for signaling and transducing activation events resulting from antigen binding. Stimulated B lymphocytes also display reduced IL-2R expression in the presence of T. cruzi. In contrast, neither the expression of EA-1 molecules by T lymphocytes nor that of CD19 and CD20 molecules by B lymphocytes is affected by this parasite. Thus, the T. cruzi effects are selective, not indiscriminate. The activated T cell populations affected by T. cruzi show concomitant reductions in the levels of expression of IL-2R and CD4, IL-2R and CD8, IL-2R and CD3 or IL-2R and TCR as well as in their capacity to proliferate; 3H-thymidine uptake decreases and there is a massive arrest of cells at the G0/G1a phase of the cell cycle. The immunosuppressive effects of T. cruzi are reproduced by a protein molecule(s) released spontaneously by the parasite termed TIF (for trypanosomal immunosuppressive factor). We report herein that TIF does not compete with IL-2 for binding to IL-2R and that shedding of IL-2R is decreased in the presence of T. cruzi. Moreover, the intracellular level of IL-2R was found to be lower than that found in control cells cultured in the absence of parasites. These results suggest that suppressed IL-2R reflects a modification induced by T. cruzi at a time coinciding with or preceding IL-2R mRNA translation. Studies are underway to identify the earliest process targeted by T. cruzi.
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PMID:Molecular basis of Trypanosoma cruzi-induced immunosuppression. Altered expression by activated human lymphocytes of molecules which regulate antigen recognition and progression through the cell cycle. 767 May 32

A defining characteristic of superantigens is their ability to stimulate T cells based predominantly on the type of variable segment of the T cell receptor (TCR) beta chain (V beta). The V beta specificity of these toxins most likely results from direct contact between the toxin and the TCR, although the low affinity nature of this binding has prevented direct assessment of this interaction. To identify important functional sites on the toxin, we created chimeric enterotoxin genes between staphylococcal enterotoxins A and E (SEA and SEE) and tested the V beta specificity of the chimeric toxins. This approach allowed us to identify three amino acid residues in the extreme COOH terminus of these toxins that are largely responsible for their ability to stimulate either human V beta 5- or V beta 8-bearing T cells, or mouse V beta 3 or V beta 11. We also found that residues in the NH2 terminus were required for wild-type levels of V beta-specific T cell activation, suggesting that the NH2 and COOH ends of these superantigens may come together to form the full TCR V beta contact site. SEA and SEE also differ with respect to their class II binding characteristics. Using the same chimeric molecules, we demonstrate that the first third of the molecule controls the class II binding phenotype. These data lead us to propose that for SEA and SEE, and perhaps for all bacterial-derived superantigens, the COOH and NH2 termini together form the contact sites for the TCR and therefore largely determine the V beta specificity of the toxin, while the NH2 terminus alone binds major histocompatibility complex class II molecules. The predominant role of the COOH terminus of bacterial superantigens in determining V beta specificity resembles current models being proposed for virally encoded superantigens, suggesting that these molecules may demonstrate some structural relationship not seen at the amino acid level.
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PMID:Localization of a site on bacterial superantigens that determines T cell receptor beta chain specificity. 767 49

The T cell receptor (TcR) V beta-specific expansion, deletion and induction of nonresponsiveness among murine T cells responding to superantigens in the periphery has been well characterized. Here we demonstrate that clonal deletion of staphylococcal enterotoxin (SE) B-reactive V beta 8.2+ cells can be significantly increased when mice are injected with hydrocortisone (HC) following superantigen stimulation in vivo. The induced sensitivity to HC persists for at least 30 days after SEB injection, making it unlikely that proliferating cells were uniquely responsible for the enhanced deletion. Superantigen-induced HC sensitivity was a general phenomenon and could also be observed among V beta 11+ cells after the injection of SEA. Experiments conducted on thymectomized mice indicated that HC-sensitive, SEB-responsive cells could not be accounted for by rapidly produced, immature lymphocytes recently exported from the thymus. Further, V beta 8.1+ peripheral lymphocytes from TcR transgenic mice expressing the Mls-1a superantigen were sensitive to HC. These results imply that the majority of cells remaining after superantigen-induced clonal expansion and deletion in vivo have indeed reacted with the superantigen. Implications for differential superantigen recognition by T cells expressing the same TcR V beta domain, perhaps due to a significant V alpha contribution to the interaction in vivo, are discussed.
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PMID:Peripheral clonal deletion of superantigen-reactive T cells is enhanced by cortisone. 767 51

Staphylococcal enterotoxins (SEs) can bind major histocompatibility antigens and stimulate T cells which bear particular types of T cell receptor. Therefore, it has been postulated that SEs may trigger or modulate the development of autoimmune diseases caused by T cells. In the present study, we examined the effects of SEs on rat encephalitogenic T cells and the clinical manifestation of experimental autoimmune encephalomyelitis (EAE). SED, but not other SEs, stimulated encephalitogenic T cells. Furthermore, culture of lymphoid cells from myelin basic protein (MBP)-immunized rats with SED augmented the clinical manifestation of passively transferred EAE, whereas SEA and SEB showed no significant EAE-transfer ability. Flow cytometric analysis demonstrated that in vitro SED stimulation of T cells from MBP-immunized rats, but not from normal rats, resulted in selective expansion of V beta 8.2+ T cells. Consistent with in vitro findings, in vivo administration of SED modulated EAE elicited by immunization with MBP. SED given after the immunization augmented clinical manifestation, especially at low doses. On the other hand, SED given 7 days before the immunization suppressed the development of EAE in a dose-dependent manner. Interestingly, the same toxin given at a dose of 20 micrograms to thymectomized rats induced enhanced EAE regardless of the timing of administration. It has already been established that SEs stimulate T cells bearing a particular type of TCR V beta chain and subsequently induce unresponsiveness of these T cells. The present results suggest that a similar mechanism may operate in rats after the toxin treatment and MBP immunization. However, in vitro assay showed that the proliferative responses of T cells from EAE-suppressed rats to MBP and SED were not eliminated, suggesting that SED-induced suppressor T cells may also play some roles in EAE suppression. The present study has shown that SED, one of the superantigens, modulates an autoimmune disease. More importantly, its effects are not uniform, but instead are closely related to the dose of the toxin, timing of toxin exposure, and the status of hosts.
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PMID:Immunomodulation of experimental autoimmune encephalomyelitis by staphylococcal enterotoxin D. 768 98

It has been hypothesized that the progressive deletion of CD4+ T cells in the course of infection due to human immunodeficiency virus (HIV) may be mediated in part by interaction with a superantigen inherent in an HIV protein. Consequently, selective loss of CD4+ cells with a T cell receptor V beta-chain capable of interaction with superantigen would produce a CD4+ population less or totally unresponsive to superantigen such as staphylococcal enterotoxins B and A (SEB and SEA respectively), but not to other mitogens such as concanavalin A, anti-CD3 (OKT3), or pokeweed mitogen. We tested this hypothesis by comparing the proliferative response of SEB and SEA with the other mitogens for 25 controls, 20 HIV+, and 15 donors with acquired immune deficiency syndrome (AIDS). We found that peripheral blood mononuclear cells, as well as the CD4+ and CD8+ subsets from both HIV+ and AIDS sources, the degree of suppression of mitogenesis for SEB and SEA was approximately equal to or less than that of the other mitogens. Moreover, suppression of HIV+ CD4+ and CD8+ T cell responses to SEB and SEA was equal (26%). If HIV superantigens exist, our data suggest that they are not responsible for the selective depletion of the CD4+ T cell subset as evaluated by SEB and SEA specificity.
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PMID:Proliferative response of CD4+ and CD8+ T cell subsets from Hispanics with HIV+ and AIDS: the superantigen hypothesis. 790 21

Bacterial and retroviral superantigens (SAGs) interact with major histocompatibility complex (MHC) class II molecules and stimulate T cells upon binding to the V beta portion of the T cell receptor. Whereas both types of molecules exert similar effects on T cells, they have very different primary structures. Amino acids critical for the binding of bacterial toxins to class II molecules have been identified but little is known of the molecular interactions between class II and retroviral SAGs. To determine whether both types of superantigens interact with the same regions of MHC class II molecules, we have generated mutant HLA-DR molecules which have lost the capacity to bind three bacterial toxins (Staphylococcus aureus enterotoxin A [SEA], S. aureus enterotoxin B [SEB], and toxic shock syndrome toxin 1 [TSST-1]). Cells expressing these mutated class II molecules efficiently presented two retroviral SAGs (Mtv-9 and Mtv-7) to T cells while they were unable to present the bacterial SAGs. These results demonstrate that the binding sites for both types of SAGs can be dissociated.
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PMID:Binding sites for bacterial and endogenous retroviral superantigens can be dissociated on major histocompatibility complex class II molecules. 811 71

Stimulation of T cells with antibodies directed towards the T cell receptor complex results in the activation of mitogen-associated protein kinase (MAPK). Two pathways have been described in other cell types that can lead to MAPK activation. One of these pathways involves the activation of Ras, leading to the activation of Raf-1, and the subsequent activation of MEK (MAPK or ERK kinase). The contribution of this pathway in T cells for anti-CD3 or phorbol myristate acetate (PMA)-mediated MAPK activation was examined. We detected the kinase activities of Raf-1 and MEK towards their substrates (MEK for Raf-1 and MAPK for MEK) in this pathway leading to the activation of MAPK. Stimulation of the T cells with either anti-CD3 antibody or PMA resulted in a rapid activation of both Ras and Raf-1. MEK activity towards kinase-active or -inactive recombinant MAPK also increased upon stimulation. In addition, both MAPK and p90rsk were activated in these cells. We suggest that activation of MAPK and the subsequent activation of ribosomal S6 kinase (p90rsk) occurs by the Ras/Raf-1/MEK cascade in T lymphocytes stimulated by ligation of the T cell receptor complex.
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PMID:Ligation of the T cell receptor complex results in activation of the Ras/Raf-1/MEK/MAPK cascade in human T lymphocytes. 818 45

The in vitro T cell nonresponsiveness or anergy to restimulation with staphylococcal enterotoxin B (SEB) following the in vivo injection of the superantigen is well characterized. Here we use mice transgenic for a V beta 8.2+ T cell receptor (TcR) (reactive with SEB) to establish a large population of anergic T cells in vivo. As expected, peripheral T cells from the SEB injected transgenic mice failed to proliferate or produce interleukin (IL)-2 following restimulation with the superantigen in vitro. However, in this system superantigen reactivity could be restored by either addition of exogenous IL-2, or stimulation with immobilized anti-TcR antibody. To evaluate the effects of superantigen-induced anergy in vivo, SEB-injected or noninjected control transgenic mice were immunized and boosted with the T cell-dependent antigen tetanus toxin (TT). SEB injection of the V beta 8.2+ transgenic mice 5 days prior to the TT immunization inhibited the anti-TT antibody response as measured over a 100-day period, whereas injection of a superantigen which does not interact with the V beta 8.2% TcR (such as SEA) did not. Furthermore, SEB injection of control nontransgenic mice did not interfere with the induction of a high titer anti-TT antibody response. In contrast to the inhibition seen when SEB was given prior to TT immunization, injection of transgenics with SEB either after the priming TT immunization or after the recall booster injection did not significantly influence the titers of anti-TT antibodies produced. These results demonstrate that the establishment of peripheral T cell anergy to superantigens inhibits the specific antigenic priming of helper T cells in vivo, but does not prevent primed T cells from helping B cells to mount an effective antibody response.
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PMID:Differential effects of superantigen-induced "anergy" on priming and effector stages of a T cell-dependent antibody response. 829 94


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