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)

Human gammadelta T cells expressing the Vgamma2Vdelta2 antigen receptors recognize nonpeptide prenyl pyrophosphate and alkylamine antigens. We find that they also recognize staphylococcal enterotoxin A superantigens in a manner distinct from the recognition of nonpeptide antigens. Using chimeric and mutant toxins, SEA amino acid residues 20-27 were shown to be required for gammadelta TCR recognition of SEA. Residues at 200-207 that are critical for specific alphabeta TCR recognition of SEA do not affect gammadelta TCR recognition. SEA residues 20-27 are located in an area contiguous with the binding site of V beta chains. This study defines a superantigen recognition site for a gammadelta T cell receptor and demonstrates the differences between Vgamma2Vdelta2+ T cell recognition of superantigens and nonpeptide antigens.
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PMID:Superantigen recognition by gammadelta T cells: SEA recognition site for human Vgamma2 T cell receptors. 1129 Mar 41

In this study, the ability of purified bovine gammadelta T cells in vitro to be activated by superantigens (SAg) was investigated. Freshly isolated WC1(+) gammadelta T cells, in the presence of autologous glutaraldehyde-fixed or gamma-irradiated antigen presenting cells (APC) and IL-2, were incubated with staphylococcal enterotoxins A and B (SEA and SEB), and toxic shock syndrome toxin-1 (TSST-1). Both a proliferative response and the expression of particular T cell receptor genes of the gamma variable (TCR Vgamma) repertoire family were induced. Genes encoding TCR Vgamma1 and TCR Vgamma2 family, but not TCR Vgamma5 were detected. The cells also expressed cytokine transcripts, namely, those of IL-12, IFN-gamma and TNF-alpha, but not IL-2, IL-4, IL-6, IL-7 and IL-10. The activation and proliferation of freshly isolated gammadelta T cells by non-processed antigens required two signals, one originating from the APC and a second dependent on exogenous IL-2. Our results show that purified bovine WC1(+) gammadelta T cells could be driven to proliferate and to express a particular TCRVgamma profile in response to superantigen activation. The possible implication of cytokines expressed by bovine gammadelta T cells in immunopathogenesis is discussed.
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PMID:Purified bovine WC1+ gamma delta T lymphocytes are activated by staphylococcal enterotoxins and toxic shock syndrome toxin-1 superantigens: proliferation response, TCR V gamma profile and cytokines expression. 1137 2

Tolerance in vivo and its in vitro counterpart, anergy, are defined as the state in which helper T lymphocytes are alive but incapable of producing IL-2 and expanding in response to optimal antigenic stimulation. Anergy is induced when the T cell receptor (TCR) is engaged by antigen in the absence of costimulation or IL-2. This leads to unique intracellular signaling events that stand in contrast to those triggered by coligation of the TCR and costimulatory receptors. Specifically, anergy is characterized by lack of activation of lck, ZAP 70, Ras, ERK, JNK, AP-1, and NF-AT. In contrast, anergizing stimuli appear to activate the protein tyrosine kinase fyn, increase intracellular calcium levels, and activate Rap1. Moreover, anergizing TCR signals result in increased intracellular concentrations of the second messenger cAMP. This second messenger upregulates the cyclin-dependent kinase (cdk) inhibitor p27kip1, sequestering cyclin D2-cdk4, and cyclin E/cdk2 complexes and preventing progression of T cells through the G1 restriction point of the cell cycle. In contrast, costimulation through CD28 prevents p27kip1 accumulation by decreasing the levels of intracellular cAMP and promotes p27kip1 down-regulation due to direct degradation of the protein via the ubiquitin-proteasome pathway. Subsequent autocrine action of IL-2 leads to further degradation of p27kip1 and entry into S phase. Understanding the biochemical and molecular basis of T cell anergy will allow the development of new assays to evaluate the immune status of patients in a variety of clinical settings in which tolerance has an important role, including cancer, autoimmune diseases, and organ transplantation. Precise understanding of these biochemical and molecular events is necessary in order to develop novel treatment strategies against cancer. One of the mechanisms by which tumors down-regulate the immune system is through the anergizing inactivation of helper T lymphocytes, resulting in the absence of T cell help to tumor-specific CTLs. Although T-cells specific for tumor associated antigens are detected in cancer patients they often are unresponsive. Reversal of the defects that block the cell cycle progression is mandatory for clonal expansion of tumor specific T cells during the administration of tumor vaccines. Reversal of the anergic state of tumor specific T cells is also critical for the sufficient expansion of such T cells ex vivo for adoptive immunotherapy. On the other hand, understanding the molecular mechanisms of anergy will greatly improve our ability to design novel clinical therapeutic approaches to induce antigen-specific tolerance and prevent graft rejection and graft-versus-host disease. Such treatment approaches will allow transplantation of bone marrow and solid organs between individuals with increasing HLA disparity and therefore expand the donor pool, enable reduction in the need for nonspecific immunosuppression, minimize the toxicity of chemotherapy, and reduce the risk of opportunistic infections.
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PMID:Helper T cell anergy: from biochemistry to cancer pathophysiology and therapeutics. 1143 20

In Jurkat T lymphocytes, hydrogen peroxide (H(2)O(2)) potentiates the phosphorylation level of extracellular signal-regulated kinase 1 and 2 (ERK1/2) caused by T cell receptor (TCR) stimulation with anti-CD3 and anti-CD28 or anti-CD3 alone. Submillimolar concentrations of H(2)O(2)-induced phosphorylation of ERK1/2 and MAP/ERK kinase 1 and 2 (MEK1/2) without antigenic stimulation. H(2)O(2) also induced the electrophoretic mobility shift of Lck from 56 to 60 kDa. The MEK inhibitor, PD98059 attenuated ERK1/2 and MEK1/2 phosphorylation, as well as the migration shift of Lck induced by H(2)O(2). The phospholipase C (PLC) inhibitor, U73122, and EGTA reduced the phosphorylation of both ERK1/2 and MEK1/2 induced by H(2)O(2). Interestingly, an increase of intracellular cAMP level with forskolin or 8-(4-chlorophenylthio)-cAMP augmented ERK1/2 phosphorylation by H(2)O(2), while inhibiting MEK1/2 phosphorylation by H(2)O(2). These results demonstrate an alternative pathway that results in augmentation of ERK1/2 phosphorylation without concomitant MEK1/2 phosphorylation in T cells.
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PMID:cAMP potentiates H(2)O(2)-induced ERK1/2 phosphorylation without the requirement for MEK1/2 phosphorylation. 1149 22

The human immunodeficiency regulatory protein Nef enhances viral replication and is central to viral pathogenesis. Although Nef has displayed a capacity to associate with a diverse assortment of cellular molecules and to increase T cell activity, the biochemical activity of Nef in T cells remains poorly defined. In this report we examine the bioactivity of Nef in primary CD4 T cells and, in particular, focus on the biochemical pathways known to be central to T cell activity. The extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase pathway was dramatically affected by Nef expression with increases in ERK, MEK, and Elk induction. The capacity of Nef to increase the MAP kinase pathway activity was dependent on T cell receptor stimulation. By increasing ERK MAP kinase activity, Nef is functionally associated with a kinase known to affect T cell activity, viral replication, and viral infectivity.
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PMID:HIV Nef increases T cell ERK MAP kinase activity. 1172 57

Human retinal pigment epithelial (RPE) cells are capable of presenting bacterial superantigens (SAg) to T cells in vitro by ligation of MHC class II molecules on RPE cells with the T cell receptor. The purpose of this study was to evaluate the involvement of adhesion molecules in presentation of SAg. Cultured human fetal and adult RPE cells were treated with interferon-gamma (IFN-gamma, 500 U ml(-1) for 72 hr) and afterwards pulsed with the SAg staphylococcal enterotoxin A (SEA, 500 ng ml(-1) for 2 hr) followed by coculture with freshly obtained T cells isolated from peripheral blood. Proliferation was measured by (3)H-thymidine incorporation assay. In selected experiments, either RPE or T cells were pre-treated with blocking antibodies specific for cell surface molecules. For comparison, dendritic cells were used as superantigen presenting cells for T cells. This study showed that presentation of SEA by RPE cells to resting T cells was dependent on the presence of the molecules CD2, CD58 and CD18, CD54. The cycling status of T cells was decisive, thus resting T cells but not activated T cells were capable to proliferate in response to SEA presentation. Proliferation of T cells induced by adult RPE cells was comparable to the proliferation induced by dendritic cells at concentrations of SAg above 100 ng ml(-1), but at concentrations of SAg below 10 ng ml(-1) the response was significantly lower for SAg presented by RPE cells compared to dendritic cells. The results demonstrate that CD2-CD58 and CD18-CD54 interactions are critical for SAg presentation by RPE cells to T cells. The findings thus suggest that also presentation of peptides to resting T cells by RPE cells may be dependent upon these interactions.
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PMID:Superantigen presentation by human retinal pigment epithelial cells to T cells is dependent on CD2-CD58 and CD18-CD54 molecule interactions. 1174 72

Murine experimental autoimmune thyroiditis (EAT) is a T-cell-mediated disease, but the T cell receptor (TCR) Vbeta gene usage in pathogenesis has not been well delineated. One approach is to utilize bacterial superantigens, such as staphylococcal enterotoxin (SE) A and B, to stimulate known sets of TCR Vbeta families in mouse thyroglobulin (mTg)-primed cells for thyroiditis transfer. Our previous use of SEB to activate mTg-primed cells led to no thyroiditis transfer, despite a major increase in Vbeta8(+) T cells. Unlike SEB, SEA activation did transfer thyroiditis. To determine which thyroiditogenic Vbeta(+) T cells were involved, SEA-activated T cells have now been analyzed. After repeated SEA activation in vitro, both mTg-reactive and thyroiditogenic cells persisted. FACS analysis indicated that most Vbeta13(+) cells were "large" cells (IL-2R(+)) and expressed the activation marker, transferrin receptor (CD71). RT-PCR analysis also showed the presence of both Vbeta13(+) and SEA-reactive Vbeta1(+) cells. Since our previous analyses by RT-PCR of the thyroid infiltrate after either induction or adoptive transfer have implicated both Vbeta13(+) and Vbeta1(+) cells, their activation by SEA to transfer thyroiditis further supports their role.
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PMID:Participation of Vbeta13(+) and Vbeta1(+) T cells in transfer thyroiditis after activation of mouse thyroglobulin-primed T cells by superantigen staphylococcal enterotoxin A. 1183 77

Tumor immunity requires the participation of lymphocyte effector cells that display powerful processes to destroy malignant cells. Natural killer (NK) cells and CTLs, once activated, use the same lytic processes for mediating target cell death. However, they are triggered through distinctly separate antigen receptors. NK cells are currently known to express at least three families of receptors unrelated to the T cell receptor, i.e., NKG2, KIR, and NCR, to mediate cytotoxicity. This review provides a view to a kill, bringing together a unifying concept for a common signal pathway that dictates lytic function. What emerges is a specific Syk/Zap70 --> PI3K --> Rac --> PAK --> MEK --> ERK signal cascade triggered by target cell recognition, which is responsible for mobilizing the lytic granules containing perforin and granzyme B toward the contacted target cell.
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PMID:A view to a kill: signals triggering cytotoxicity. 1189 90

Chronic engagement of the T cell receptor mediates the induction of T lymphocyte unresponsiveness called clonal anergy. The development of such unresponsiveness has been suggested as one of the mechanisms that regulate peripheral tolerance to self-antigens and hamper the capacity of tumor antigen-specific T cells to eliminate cancerous cells. In the attempt to enhance the effector function of CD4(+) T lymphocytes and their resistance to clonal anergy induction, we have transduced primary T cells with a retroviral vector encoding active p21(ras) (Ras(Leu61)). Here we show that Ras(Leu61) elicited TCR-independent activation of the Ras-Raf-ERK pathway and conferred primary T cells with the ability to secrete IL-2 in response to stimulation with a Ca(2+) ionophore alone, without altering antigen-, CD3/CD28- and PMA/ionomycin-driven IL-2 secretion and T cell proliferation in vitro. However, chronic engagement of the TCR onthe surface of Ras(Leu61) T cells still led to an inability of the cells to produce IL-2 upon restimulation. These results indicate that enforced p21(ras) functionality enhances primary T cells responses to calcium-generated signals, but is insufficient to prevent TCR-driven T cell unresponsiveness and suggest that additional biochemical mechanisms, independent of p21(ras), negatively regulate IL-2 production in unresponsive T cells.
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PMID:Constitutive active p21ras enhances primary T cell responsiveness to Ca2+ signals without interfering with the induction of clonal anergy. 1220 34

Most post transplantation lymphoproliferative disorders (PTLDs) are Epstein-Barr virus (EBV) associated B cell proliferations. We report a case of aggressive anaplastic large cell lymphoma expressing the anaplastic lymphoma kinase (ALK) protein in a 58 year old man who had previously undergone liver transplantation. A definite diagnosis was not possible on histopathological examination. Immunostaining clearly showed a predominant population of small irregular lymphocytes, admixed with large cells strongly positive for CD30, epithelial membrane antigen, and the ALK protein. Neoplastic cells were of the T/cytotoxic phenotype. In situ hybridisation with EBV encoded early RNA probes showed only a few scattered positive non-neoplastic small lymphocytes. Polymerase chain reaction analysis of immunoglobulin and T cell receptor rearrangements was negative. The NPM-ALK fusion transcript associated with the t(2;5) translocation was detected by reverse transcription polymerase chain reaction. A review of the literature revealed 76 cases of T cell PTLD, showing a broad spectrum of morphological features and clinical behaviour. Most of these cases were EBV negative (61 of 76) and occurred after renal transplantation (48 of 76). To our knowledge, this is the first case of ALK positive lymphoma occurring in the setting of organ transplantation. This observation stresses the need for accurate immunostaining for diagnosing this rare, apparently aggressive, lymphoma in immunosuppressed patients.
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PMID:Anaplastic lymphoma kinase (ALK) protein expressing lymphoma after liver transplantation: case report and literature review. 1240 29


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