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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Here we identify the hematopoietic proto-oncogene Vav1 as a caspase substrate during apoptosis in lymphoid cells. Cleavage of Vav1 is prevented by the caspase inhibitors zDEVD and zVAD as well as by expression of CrmA. Vav1 is cleaved in vivo at the evolutionary conserved caspase consensus cleavage site DLYD161C, generating the carboxy-terminal cleavage product Vav1p76 of intermediate stability. In vitro caspase assays reveal cleavage of Vav1 at position 161 either by apoptotic cell lysates or by recombinant caspase-3. Mutation of Asp 161 to Ala leads to the usage of the adjacent alternative cleavage sequence DQID150D. Mutation of both cleavage sites at position 150 and 161 protects Vav1 from caspase-mediated proteolysis in vitro and in vivo. The cleavage product Vav1p76 is capable of activating JNK in T-cells, but fails to induce the phosphorylation of p38/HOG1. Vav1p76 displays a diminished capacity to activate the transcription factors NF-AT, AP-1 and NF-kappaB, and thus completely fails to activate IL-2 transcription. Since Vav1 is essential for IL-2 production and plays a central role for cytoskeletal reorganization, its proteolytic inactivation during apoptosis affects multiple downstream targets.
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PMID:Caspase-dependent cleavage and inactivation of the Vav1 proto-oncogene product during apoptosis prevents IL-2 transcription. 1071 3

Vav and PKCtheta play an early and important role in the TCR/CD28-induced stimulation of MAP kinases and activation of the IL-2 gene. Vav is also essential for actin cytoskeleton reorganization and TCR capping. Here, we report that PKCtheta function was selectively required in a Vav signaling pathway that mediates the TCR/CD28-induced activation of JNK and the IL-2 gene and the upregulation of CD69 expression. Vav also promoted PKCtheta translocation from the cytosol to the membrane and cytoskeleton and induced its enzymatic activation in a CD3/CD28-initiated pathway that was dependent on Rac and on actin cytoskeleton reorganization. These findings reveal that the Vav/Rac pathway promotes the recruitment of PKCtheta to the T cell synapse and its activation, essential processes for T cell activation and IL-2 production.
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PMID:A novel functional interaction between Vav and PKCtheta is required for TCR-induced T cell activation. 1071 81

Induction of proliferation in primary resting T cells requires engagement of both the antigen-specific TCR and the co-stimulatory receptor CD28. Here we report that CD28 functions as an autonomous mitogenic receptor which is mobilized by TCR signaling through cytoskeletal rearrangement. Shortcutting of TCR-dependent CD28 recruitment by stimulation with monoclonal antibodies specific for mobilized CD28 results in maximum proliferation and IL-2 secretion in primary resting T cells without activation of ZAP-70, a central component of the TCR's signal transduction machinery. Engagement of mobilized CD28 fully activates the c-Jun N-terminal kinase cascade and translocation of NF-alphaB, two key targets of signal integration in co-stimulation. We propose a two-step activation model for co-stimulation in primary resting T cells in which antigen recognition recruits co-stimulatory receptors which then autonomously transduce signals promoting T cell proliferation.
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PMID:Autonomous induction of proliferation, JNK and NF-alphaB activation in primary resting T cells by mobilized CD28. 1074 4

In clinical transplantation, the occurrence of cyclosporin A (CsA)-resistant production of IL-2 in vitro correlates with graft rejection in vivo. In this study we investigated the role of the costimulatory molecules CD28 and LFA-1 in this process in the setting of TCR-induced proliferation of primary T lymphocytes in vitro. Co-stimulation with ICAM-1 and B7.2 led to strong and CsA-resistant proliferation, which was found to be largely IL-2 dependent. All of the known calcineurin-dependent events, such as induction of NF-AT and NF-kappaB or stress-activated protein kinase activation, were markedly modulated by CsA independently of costimulation. In contrast, both ICAM-1 and B7.2 enhanced the half-life of the inducible IL-2 transcript in a CsA-resistant manner. LFA-1- but not CD28-induced IL-2 mRNA stabilization required the integrity of the actin-based cytoskeleton, suggesting that the two costimulatory molecules impact on qualitatively different signaling pathways. This is further suggested by the demonstration that LFA-1 and CD28 acted synergistically to confer CsA resistance in a model of co-stimulation using superantigen-pulsed dendritic cells. We propose that IL-2 transcript accumulation and subsequent T cell proliferation at the low transcriptional rate imposed by CsA are the result of co-stimulation-dependent stabilization of IL-2 mRNA.
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PMID:CD28 and LFA-1 contribute to cyclosporin A-resistant T cell growth by stabilizing the IL-2 mRNA through distinct signaling pathways. 1076 Aug 3

The Mitogen-Activated Protein Kinase Kinase 4 (MKK4), a member of the MAP kinase kinase family, directly phosphorylates and activates the c-Jun NH2-terminal kinases (JNK), in response to cellular stresses and proinflammatory cytokines. JNK is a member of the MAP kinase family and a key component of a stress activated protein kinase signalling pathway. MKK4 mRNA is widely expressed in adult mouse tissues, but is especially abundant in skeletal muscle and brain. Mice lacking the MKK4 gene had abnormal hepatogenesis and died before embryonic day 14. However cell lines lacking MKK4 have been obtained and these exhibited defective activation of JNK and AP-1 dependent transcription activity in response to some, but not all cellular stresses. Furthermore, T lymphocytes deficient in MKK4 showed impaired IL-2 production following activation of the T cell receptor, suggesting a key role of the MKK4/JNK pathway in inflammation. The mutation of the MKK4 gene in some carcinomas indicates that it may also have a role as a tumor suppressor. Control of the MKK4 activity and expression may provide novel approaches to cancer or anti-inflammatory therapy.
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PMID:Mitogen-activated protein kinase kinase 4 (MKK4). 1078 55

The subgroup of protein tyrosine phosphatases that contain an N-terminal ezrin-, radixin- and moesin homology (ERM) domain and a C-terminal catalytic domain is represented by three enzymes in Jurkat T cells, PTPH1, PTP-MEG1 and PTP36. These enzymes are located at the cytoplasmic face of the plasma membrane and may be involved in regulation of the membrane cytoskeleton, signal transduction, or both. Here we report that expression of PTPH1 in Jurkat T cells reduced the TCR-induced activation of reporter genes encompassing parts of the IL-2 gene promoter and driven by nuclear factor of activated T cells plus activator protein-1. PTP-MEG1 had a weaker inhibitory effect, while PTP36 had none. The catalytically inactive mutants PTPH1-CS and PTP-MEG1-CS lacked effects on gene transcription. Expression of active PTPH1 also reduced receptor-induced activation of Erk2 MAP kinase, its upstream activator, Mek, and the Jnk kinases. The effect of PTPH1 was reduced by deletion of its N-terminal ERM domain. We suggest that PTPH1 inhibits T cell activation by dephosphorylating membrane-associated targets involved in TCR signaling.
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PMID:Cytoskeletal protein tyrosine phosphatase PTPH1 reduces T cell antigen receptor signaling. 1082 Mar 77

IL-2 stimulates extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) in various immune cell populations. The functional roles that these kinases play are still unclear. In this study, we examined whether MAPK kinase (MKK)/ERK and p38 MAPK pathways are necessary for IL-2 to activate NK cells. Using freshly isolated human NK cells, we established that an intact MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and CD25 and CD69 expression. IL-2 induced ERK activation within 5 min. Treatment of NK cells with a specific inhibitor of MKK1/2, PD98059, during the IL-2 stimulation blocked in a dose-dependent manner each of four sequelae, with inhibition of lymphokine-activated killing induction being least sensitive to MKK/ERK pathway blockade. Activation of p38 MAPK by IL-2 was not detected in NK cells. In contrast to what was observed by others in T lymphocytes, SB203850, a specific inhibitor of p38 MAPK, did not inhibit IL-2-activated NK functions. This data indicate that p38 MAPK activation was not required for IL-2 to activate NK cells for the four functions examined. These results reveal selective signaling differences between NK cells and T lymphocytes; in NK cells, the MKK/ERK pathway and not p38 MAPK plays a critical positive regulatory role during activation by IL-2.
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PMID:IL-2 activation of NK cells: involvement of MKK1/2/ERK but not p38 kinase pathway. 1084 77

Interleukin (IL)-2, a critical cytokine with indispensable functions in regulating lymphoid homeostasis, induces the activation of several biochemical pathways. Precisely how these pathways are linked and how they relate to the biological action of IL-2 is incompletely understood. We previously identified SHP-2 (Src homology 2 domain containing phosphatase 2) as an important intermediate in IL-2-dependent MAPK activation and showed its association with a 98-kDa phosphoprotein in response to IL-2. Here, we demonstrate that Gab2, a recently identified adapter molecule, is the major SHP-2 and phosphatidylinositol 3'-kinase-associated 98-kDa protein in normal, IL-2-activated lymphocytes. We further demonstrate that phosphorylation of both Gab2 and SHP-2 is largely dependent upon tyrosine 338 of the IL-2 receptor beta chain. Gab2 can be a substrate of all the three major classes of non-receptor tyrosine kinases associated with the IL-2R, but in terms of IL-2 signaling, JAK3 but not Lck or Syk is essential for Gab2 phosphorylation. We also demonstrate that only IL-2 and IL-15, but not other gammac cytokines induce Gab2 phosphorylation; the ability to phosphorylate Gab2 correlates with Shc phosphorylation and ERK1/ERK2 activation. Finally, we also show that Gab2 levels are regulated by T cell activation, and resting T cells express little Gab2. Therefore, up-regulation and activation of Gab2 may be important in linking the IL-2 receptor to activation of MAPK and may be an important means of achieving specificity in cytokine signaling.
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PMID:The docking molecule gab2 is induced by lymphocyte activation and is involved in signaling by interleukin-2 and interleukin-15 but not other common gamma chain-using cytokines. 1084 28

Two protein-tyrosine kinases, Bruton's tyrosine kinase (Btk) and Syk, and members of the protein kinase C (PKC) subfamily of serine/threonine kinases play crucial roles in signal transduction through antigen receptors in B lymphocytes and high-affinity IgE receptors (FcepsilonRI) in mast cells. The present study provides genetic, biochemical, and pharmacological evidence that, on FcepsilonRI stimulation, Syk regulates Btk, and Btk selectively regulates the membrane translocation and enzymatic activity of PKCbetaI among the conventional PKC isoforms (alpha, betaI, and betaII) expressed in mast cells. Syk/Btk-mediated PKCbetaI regulation is involved in transcriptional activation of the IL-2 and tumor necrosis factor alpha genes through the JNK pathway induced by FcepsilonRI stimulation. Accordingly, FcepsilonRI-induced production of these cytokines is inhibited by specific inhibitors of Btk and Syk, as well as broad-specificity inhibitors of PKC and a selective inhibitor of PKCbeta. Specific regulation of PKCbetaI by Btk is consistent with the selective association of Btk with PKCbetaI. Components of this signaling pathway may represent an attractive set of potential targets of pharmaceutical interference for the treatment of allergic and other immunologic diseases.
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PMID:Regulation of protein kinase CbetaI by two protein-tyrosine kinases, Btk and Syk. 1085 54

During the past 50 years, many immunosuppressive drugs have been described. Often their mechanisms of action were established long after their discovery. Eventually these mechanisms were found to fall into five groups: (i) regulators of gene expression; (ii) alkylating agents; (iii) inhibitors of de novo purine synthesis; (iv) inhibitors of de novo pyrimidine synthesis; and (v) inhibitors of kinases and phosphatases. Glucocorticoids exert immunosuppressive and anti-inflammatory activity mainly by inhibiting the expression of genes for interleukin-2 and other mediators. Cyclophosphamide metabolites alkylate DNA bases and preferentially suppress immune responses mediated by B-lymphocytes. Methotrexate and its polyglutamate derivatives suppress inflammatory responses through release of adenosine; they suppress immune responses by inducing the apoptosis of activated T-lymphocytes and inhibiting the synthesis of both purines and pyrimidines. Azathioprine metabolites inhibit several enzymes of purine synthesis. Mycophenolic acid and mizoribine inhibit inosine monophosphate dehydrogenase, thereby depleting guanosine nucleotides. Mycophenolic acid induces apoptosis of activated T-lymphocytes. A leflunomide metabolite and Brequinar inhibit dihydroorotate dehydrogenase, thereby suppressing pyrimidine nucleotide synthesis. Cyclosporine and FK-506 (Tacrolimus) inhibit the phosphatase activity of calcineurin, thereby suppressing the production of IL-2 and other cytokines. In addition, these compounds have recently been found to block the JNK and p38 signaling pathways triggered by antigen recognition in T-cells. In contrast, rapamycin inhibits kinases required for cell cycling and responses to IL-2. Rapamycin also induces apoptosis of activated T-lymphocytes. Immunosuppressive and anti-inflammatory compounds in development include inhibitors of p38 kinase and of the type IV isoform of cyclic AMP phosphodiesterase which is expressed in lymphocytes and monocytes.A promising future application of immunosuppressive drugs is their use in a regime to induce tolerance to allografts. The role of leukocytes in grafts, and the induction of apoptosis of clones of responding T-lymphocytes, is discussed.
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PMID:Immunosuppressive drugs: the first 50 years and a glance forward. 1087 84


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