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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoids have potent immunosuppressive properties, but their effects are often modulated by the conditions prevailing in the local immune milieu. In this study we determined whether the action of glucocorticoids is influenced by the degree of signaling during T cell activation. We found that dexamethasone (Dex) effectively suppressed T cell receptor-induced (TCR-induced) proliferation of naive CD4+ T cells, through a mechanism involving downregulation of c-Fos expression and inhibition of activator protein-1 (AP-1), nuclear factor of activated T cells (NF-AT), and NF-kappaB transcriptional activity. However, enhancement of TCR signaling by CD28- or IL-2-mediated costimulation abrogated the suppressive effect of Dex on c-Fos expression and AP-1 function and restored cellular proliferation. The amount of signaling through the MAPK pathway was critical in determining the effect of Dex on T cell activation. In particular, costimulatory signaling via MAPK kinase (MEK) and extracellular signal-regulated kinase (ERK) was essential for the development of T cell resistance to Dex. Selective blockade of MEK/ERK signal transduction abolished the costimulation-induced resistance. In contrast, transmission of IL-2 signals via STAT5 and CD28 signals via NF-kappaB remained inhibited by Dex. These results imply that the immune system, by regulating the degree of local costimulation through MEK/ERK, can modify the effect of glucocorticoids on T cells. Moreover, these findings suggest that MAPK inhibitors may offer a therapeutic solution for glucocorticoid resistance.
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PMID:Enhancement of MEK/ERK signaling promotes glucocorticoid resistance in CD4+ T cells. 1496 71

The E protein family transcription factors encoded by the E2A and HEB genes are known to play critical roles in the coordinate regulation of lymphocyte development. Previous studies have shown that T cell receptor (TCR) signals rapidly induce Id3, a dominant negative antagonist of E2A activity and allow thymocytes to survive selection events in the thymus. Here we show that SRG3 acts as a novel downstream target of E2A/HeLa E box-binding (HEB) complex and modulates glucocorticoid (GC) susceptibility in thymocytes in response to TCR signals. We have identified a putative E box element in the SRG3 promoter that is required for optimal promoter activity. The transcription factors E2A and HEB specifically associate with the E box element. Moreover, E2A-HEB heterodimers cooperated to activate SRG3 transcription, which was inhibited by the expression of Id proteins. TCR-mediated signals rapidly induced Id3 via MEK/ERK activation and thereby kept the E2A/HEB complex from binding to the E box element in the SRG3 promoter. Retroviral transduction of Id3 also repressed the SRG3 expression by inhibiting the E box binding activity of the E2A/HEB complex. Intriguingly, enforced Id3 expression conferred thymocyte resistance to GCs, which could be overcome by the overexpression of SRG3. Taken together, these results suggest that Id3 may enhance the viability of immature thymocytes by at least rendering them resistant to GCs through SRG3 down-regulation.
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PMID:E2A/HEB and Id3 proteins control the sensitivity to glucocorticoid-induced apoptosis in thymocytes by regulating the SRG3 expression. 1501 15

A T cell receptor (TCR) recognizes and responds to an antigenic peptide in the context of major histocompatibility complex-encoded molecules. This provokes T cells to produce interleukin-2 (IL-2) through extracellular signal-regulated kinase (ERK) activation. We investigated the roles of B-Raf in TCR-mediated IL-2 production coupled with ERK activation in the Jurkat human T cell line. We found that TCR cross-linking could induce up-regulation of both B-Raf and Raf-1 activities, but Raf-1 activity was decreased rapidly. On the other hand, TCR-stimulated kinase activity of B-Raf was sustained. Expression of a dominant-negative mutant of B-Raf abrogated sustained but not transient TCR-mediated MEK/ERK activation. The inhibition of sustained ERK activation by either expression of a dominant-negative B-Raf or treatment with a MEK inhibitor resulted in a decrease of the TCR-stimulated nuclear factor of activated T cells (NFAT) activity and IL-2 production. Collectively, our data provide the first direct evidence that B-Raf is a positive regulator of TCR-mediated sustained ERK activation, which is required for NFAT activation and the full production of IL-2.
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PMID:B-Raf contributes to sustained extracellular signal-regulated kinase activation associated with interleukin-2 production stimulated through the T cell receptor. 1533 34

The pathogenesis of allergic asthma involves the interplay of inflammatory cells and resident airway cells, and of their secreted mediators including cytokines, chemokines, growth factors and inflammatory mediators. Tyrosine kinase signaling cascades play a critical role in the pathogenesis of allergic airway inflammation. Receptor tyrosine kinases (e.g. epidermal growth factor receptor [EGFR] and platelet-derived growth factor receptor) are important for the pathogenesis of airway remodeling. Stimulation of non-receptor tyrosine kinases (e.g. Lyn, Lck, Syk, ZAP-70, Btk, Itk and JAK) is the earliest detectable signaling response upon activation of immune receptors (T cell receptor, B cell receptor and FCepsilonR1), cytokine receptors and chemokine receptors in inflammatory cells. Activation of tyrosine kinases invokes multiple downstream signaling pathways, including phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB), leading to cell differentiation, survival, proliferation, degranulation and chemotaxis. Inhibitors targeted at different enzyme molecules of the tyrosine kinase signaling cascade might afford therapeutic potential for asthma. Anti-inflammatory effects of pharmacological agents targeted at tyrosine kinases, Syk, Itk, signal transducer and activator of transcription-1, NF-kappaB, GATA3, EGFR, PI3K, MEK1/2, p38 MAPK and JNK have been reported in animal models of allergic airway inflammation. Therefore, development of inhibitors targeted at the tyrosine kinase signaling cascade is an attractive strategy for the treatment of asthma.
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PMID:Inhibitors of the tyrosine kinase signaling cascade for asthma. 1590 13

Activation of T lymphocytes through costimulation of the T cell receptor/CD3 complex (TCR/CD3) and coreceptors (e.g. CD2 or CD28) leads to production of the growth factor interleukin-2 (IL-2) and subsequent proliferation. For these activation processes, remodelling of the actin cytoskeleton plays an important functional role. We have shown that the activity of the actin-remodelling protein cofilin is crucially involved in T lymphocyte activation processes. In unstimulated human peripheral blood T lymphocytes (PB-T) cofilin exists in its inactive ser-3-phosphorylated form. T lymphocyte activation through costimulation of TCR plus the coreceptors CD28 or CD2, respectively, induces the dephosphorylation of cofilin. Concomitantly, cofilin associates with the actin cytoskeleton. The functional importance of cofilin for T lymphocyte activation was shown employing cell permeable peptides which block binding of cofilin to actin. In human PB-T these peptides impair the formation of the immunological synapse and inhibit the induction of T lymphocyte proliferation and cytokine production. The serine phosphatases PP1 and PP2A dephosphorylate cofilin in T lymphocytes. Importantly, a PKC-Ras-MEK/PI3K-cascade links costimulation of PB-T through TCR/CD3 and CD28 to activation of cofilin through dephosphorylation. Notably, the induction of cofilin dephosphorylation requires the combined activities of two Ras-effectors, namely MEK and PI3K. With respect to PI3K, this result was unexpected since so far it was generally assumed that-unlike in other cell types-Ras is not able to activate PI3K in T lymphocytes, as concluded from experiments performed with the human T-lymphoma line Jurkat. This discrepancy implied that the signalling events upstream of PI3K differ between PB-T and Jurkat cells. In line with this, we found that in PB-T the PI3K-inhibitors wortmannin and LY294002 block activation induced cofilin dephosphorylation and its association with the actin cytoskeleton. In Jurkat cells, however, where cofilin is present mainly in its non-phosphorylated form and permanently associated with the actin cytoskeleton, wortmannin and LY294002 do not block these events. Studies by others employing these PI3K-inhibitors have also led to such contradictory results: While in stimulated PB-T these inhibitors repress expression of IL-2, they even enhance IL-2 expression in Jurkat cells. These findings show that signalling events in Jurkat cells are not representative for signalling processes in untransformed human T lymphocytes. Importantly, our data demonstrate that-rebutting a persistent dogma-a T-cell specific uncoupling of PI3K from Ras does not exist.
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PMID:Ras initiates phosphatidyl-inositol-3-kinase (PI3K)/PKB mediated signalling pathways in untransformed human peripheral blood T lymphocytes. 1608 47

T cell receptor (TCR) signaling plays an important role in early interleukin (IL)-4 production by naive CD4+ T cells. This "antigen-stimulated" early IL-4 is sufficient for in vitro Th2 differentiation. Here, we provide evidence that early IL-4 production by naive CD4+ T cells stimulated with cognate peptide requires TCR-induced early GATA-3 expression and IL-2 receptor signaling, both of which are controlled by the degree of activation of extracellular signal-regulated kinase (ERK). Stimulation of naive CD4+ T cells from TCR transgenic mice with low concentrations of peptide-induced IL-2-dependent STAT5 phosphorylation, IL-4-independent early GATA-3 expression, and IL-4 production. Neutralization of IL-2 abolished early IL-4 production without affecting early GATA-3 expression. In addition, naive CD4+ T cells from GATA-3 conditional KO mice failed to produce early IL-4 in response to TCR/CD28 stimulation. Stimulation with high concentrations of peptide abrogated early GATA-3 expression and IL-2-dependent STAT5 phosphorylation, and resulted in the failure to produce early IL-4. This high concentration-mediated suppression of early IL-4 production was reversed by blockade of the ERK pathway. A MEK inhibition rescued early GATA-3 expression and responsiveness to IL-2; these cells were now capable of producing early IL-4 and undergoing subsequent Th2 differentiation.
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PMID:Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment. 1617 58

The inducible costimulator (ICOS), a member of the CD28 family of costimulatory molecules, is rapidly induced upon T cell activation. Although the critical role of ICOS in costimulating T cell responses is well documented, little is known of the intracellular signaling pathways and mechanisms that regulate ICOS expression. Here, we report that Fyn, NFAT, and ERK signaling influence ICOS expression as various chemical inhibitors, such as PP2 that targets Src kinases, U0126 that targets MEK1/2, and cyclosporin A or FK506 that targets calcineurin and thereby affects NFAT, attenuate T cell receptor-mediated ICOS induction. Moreover, ectopic expression of NFATc2 or a constitutively active MEK2 amplifies ICOS transcription and transactivates a 288-bp core region of the icos promoter in luciferase reporter assays. We also identify a site on the icos promoter that is sensitive to ERK signaling and further show that NFATc2 can bind the icos promoter in vivo and that this binding is diminished when Fyn signaling is ablated. The normal activation of ERK but reduced nuclear translocation of NFATc2 in Fyn(-/-) CD4(+) T cells further suggest that Fyn and NFATc2 act in a common axis, separate from that involving ERK, to drive ICOS transcription. Taken together, our findings indicate that Fyn-calcineurin-NFATc2 and MEK2-ERK1/2 are two independent signaling pathways that cooperate to control T cell receptor-mediated ICOS induction.
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PMID:Regulation of mouse inducible costimulator (ICOS) expression by Fyn-NFATc2 and ERK signaling in T cells. 1688 Feb 6

Members of the c-Jun NH(2)-terminal kinase (JNK) family play crucial roles in cell activation, differentiation, and apoptosis. Although many studies have indicated that JNK1 and JNK2 have functional differences and redundancy, the upstream signaling pathway that selectively activates JNK1 or JNK2 remains unknown. In this study, we have revealed a selective mechanism of JNK activation, in which JNK2, but not JNK1, was regulated by CARMA1, a scaffold molecule, after stimulation of the T cell receptor (TCR). This CARMA1-dependent regulation of JNK2 worked through the scaffold molecule Bcl10, which was inducibly associated with JNK2 and served as a JNK-interacting protein (JIP)-like scaffold to assemble the kinases JNK2, MKK7, and TAK1. Finally, we showed that CARMA1- and Bcl10-mediated JNK2 activation had a critical role in regulating the amount of c-Jun protein. Together, our studies provide genetic evidence that JNK1 and JNK2 are differentially regulated in the TCR-signaling pathway and play different functions.
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PMID:The CARMA1-Bcl10 signaling complex selectively regulates JNK2 kinase in the T cell receptor-signaling pathway. 1718 6

CD4+ T lymphocytes, which orchestrate immune responses, receive a cognitive signal when clonally distributed receptors are occupied by peptides bound to major histocompatibility complex (MHC) class II molecules on antigen-presenting cells. The latter cells provide costimulatory or accessory signals through macromolecules such as B7.1 and B7.2, which interact with coreceptors on T cells to regulate outcomes in terms of T cell activation or specific nonresponsiveness. Complementary studies of the interactions between antigen-presenting cells and T helper cells at the chemical level have implicated Schiff base formation between specialised carbonyls and amines, constitutively expressed on the surfaces of antigen-presenting cells and T cells, as an essential element in specific T cell activation. Small Schiff base-forming molecules can substitute for the natural donor of carbonyl groups and provide a costimulatory signal to the T cell. From this class of Schiff base-forming costimulatory molecules, the small xenobiotic substituted benzaldehyde, tucaresol, has been selected for development and testing as an immunopotentiatory drug. Tucaresol, which is orally bioavailable and systemically active, enhances CD4+ T helper cell and CD8+ cytotoxic T cell responses in vivo, and selectively favours a T helper 1 profile of cytokine production. In murine models of virus infection and syngeneic tumour growth it has substantial therapeutic activity. Schiff base formation by tucaresol on T cell surface amines provides a costimulatory signal to the T cell through a mechanism that activates clofilium-sensitive K(+) and Na(+) transport. The pathway utilised by tucaresol converges with T cell receptor signalling at the level of mitogen-activated protein (MAP) kinase, promoting the activation of MAP kinase kinase (MEK) and consequential tyrosyl phosphorylation of ERK2. Tucaresol is the first orally active, mechanism-based immunopotentiatory drug available for therapeutic testing. It is currently undergoing phase I/II clinical trials in chronic hepatitis B virus infection, HIV infection and malignant melanoma.
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PMID:[Not Available]. 1803 Oct 95

The propensity of T cells to generate coordinated cytokine responses is critical for the host to develop resistance to pathogens while maintaining the state of immunotolerance to self-antigens. The exact mechanisms responsible for preventing the overproduction of proinflammatory cytokines including interferon (IFN)-gamma are not fully understood, however. In this study, we examined the role of a recently described Ras GTPase effector and repressor of the Raf/MEK/ERK cascade called impedes mitogenic signal propagation (Imp) in limiting the induction of T-cell cytokines. We found that stimulation of the T cell receptor complex leads to the rapid development of a physical association between Ras and Imp. Consistent with the hypothesis that Imp inhibits signal transduction, we also found that disengagement of this molecule by the Ras(V12G37) effector loop mutant or RNA interference markedly enhances the activation of the NFAT transcription factor and IFN-gamma secretion. A strong output of IFN-gamma is responsible for the distinct lymphocyte traffic pattern observed in vivo because the transgenic or retroviral expression of Ras(V12G37) caused T cells to accumulate preferentially in the lymph nodes and delayed their escape from the lymphoid tissue, respectively. Together, our results describe a hitherto unrecognized negative regulatory role for Imp in the production of IFN-gamma in T cells and point to Ras-Imp binding as an attractive target for therapeutic interventions in conditions involving the production of this inflammatory cytokine.
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PMID:p21 Ras/impedes mitogenic signal propagation regulates cytokine production and migration in CD4 T cells. 1857 12


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