Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

A compelling body of evidence suggests a role for Thy-1 (CD90), a cell surface glycoprotein of mouse T lymphocytes, in signal transduction resulting in T cell activation. Despite more than 3 decades of investigation, intracellular biochemical events governing the Thy-1 signaling cascade are only vaguely understood. We have employed selective pharmacological inhibitors of signaling molecules to compare downstream elements participating in the Thy-1 signal transduction pathway with those involved in the T cell receptor (TCR)/CD3-associated signaling pathway. Mitogenic anti-Thy-1 or anti-CD3 monoclonal antibody (mAb) were used to cause T cells from C57BL/6 mice to proliferate in the presence or absence of different pharmacological inhibitors. Cyclosporine A, herbimycin A, LY294002, calphostin C and PD98059 all inhibited anti-Thy-1-induced T lymphocyte proliferation, indicating the involvement of calcineurin, protein tyrosine kinases, phosphatidylinositol 3-kinase, protein kinase C, and MEK1 (MAPK kinase 1), respectively, in Thy-1 signaling. Similar results were obtained when T cells were stimulated through the TCR with anti-CD3 monoclonal antibody in the presence or absence of the different inhibitors. Interestingly, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 augmented anti-Thy-1-induced T cell proliferation, whereas anti-CD3-induced proliferative response was partially suppressed by the same inhibitor. The Thy-1 signal transduction pathway, therefore, shares a requirement for calcineurin and several major kinase families with the TCR signaling pathway. However, Thy-1 and TCR-associated signaling pathways are differentially regulated by p38 MAPK.
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PMID:Selective pharmacological inhibitors reveal differences between Thy-1- and T cell receptor-mediated signal transduction in mouse T lymphocytes. 1135 81

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 E2A gene encodes the E47 and E12 basic helix-loop-helix (bHLH) transcription factors. T cell development in E2A-deficient mice is partially arrested before lineage commitment. Here we demonstrate that E47 expression becomes uniformly high at the point at which thymocytes begin to commit towards the T cell lineage. E47 protein levels remain high until the double positive developmental stage, at which point they drop to relatively moderate levels, and are further downregulated upon transition to the single positive stage. However, stimuli that mimic pre-T cell receptor (TCR) signaling in committed T cell precursors inhibit E47 DNA-binding activity and induce the bHLH inhibitor Id3 through a mitogen-activated protein kinase kinase-dependent pathway. Consistent with these observations, a deficiency in E2A proteins completely abrogates the developmental block observed in mice with defects in TCR rearrangement. Thus E2A proteins are necessary for both initiating T cell differentiation and inhibiting development in the absence of pre-TCR expression. Mechanistically, these data link pre-TCR mediated signaling and E2A downstream target genes into a common pathway.
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PMID:Early thymocyte development is regulated by modulation of E2A protein activity. 1156 Sep 90

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

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

Activation of CD4(+) T cells is governed by interplay between stimulatory and inhibitory receptors; predominance of stimulatory signals favors autoimmune reactions. In patients with rheumatoid arthritis, expression of the critical costimulatory molecule, CD28, is frequently lost. Instead, CD4(+)CD28(null) T cells express killer immunoglobulin-like receptors (KIRs) with a preferential expression of the stimulatory receptor, CD158j. The frequency of CD4(+)CD28(null) T cells in rheumatoid arthritis (RA) correlates with the risk for more severe disease. Moreover, the KIR2DS2 gene, which encodes for CD158j, is a genetic risk factor for rheumatoid vasculitis. CD158j signals through the adaptor molecule, KARAP/DAP12, to positively regulate cytotoxic activity in NK cells. However, the majority of CD4(+)CD28(null) T cell clones lacked the expression of KARAP/DAP12. Despite the absence of KARAP/DAP12, CD158j was functional and augmented interferon-gamma production after T cell receptor stimulation. Cross-linking of CD158j resulted in selective phosphorylation of c-Jun NH(2)-terminal protein kinase (JNK) and its upstream kinase, MKK4 that led to the expression of ATF-2 and c-Jun, all in the absence of extracellular signal-regulated kinase (ERK)1/2 phosphorylation. Mutation of the lysine residue within the transmembrane domain of CD158j abolished JNK activation, suggesting that an alternate adaptor molecule was being used. CD4(+)CD28(null) T cells expressed DAP10 and inhibition of phosphatidylinositol 3-kinase, which acts downstream of DAP10, inhibited JNK activation; however, no interaction of DAP10 with CD158j could be detected. Our data suggest that CD158j in T cells functions as a costimulatory molecule through the JNK pathway independent of KARAP/DAP12 and DAP10. Costimulation by CD158j may contribute to the autoreactivity of CD4(+)CD28(null) T cells in RA.
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PMID:Selective activation of the c-Jun NH2-terminal protein kinase signaling pathway by stimulatory KIR in the absence of KARAP/DAP12 in CD4+ T cells. 1259 2

beta 3 integrins mediate fibronectin binding and enhanced activation of cytotoxic T lymphocytes (CTL). The intracellular signals initiated by beta 3 integrins in lymphocytes are not well characterized, but in many cell types, beta 1 integrin ligation activates mitogen-activated protein (MAP) kinases. In the present study, we find that fibronectin can synergize with very low levels of CD3 stimulation to activate the extracellular signal-regulated kinase (ERK)1 and ERK2 MAP kinases but that fibronectin alone induces no detectable MAP kinase activation in CTL. Surprisingly, antibodies to beta1 or beta 3 integrins were also unable to stimulate MAP kinase activation, suggesting that although beta 1 integrins are capable of stimulating MAP kinase activation in other cells, they cannot do so in CTL. In CTL, phosphorylation of proline-rich tyrosine kinase 2 downstream of integrin stimulation did not result in recruitment of the adaptor protein Grb2. Additionally, we examined the role of MAP kinases in regulating integrin-mediated adhesion. Anti-CD3-triggered adhesion to fibronectin was largely insensitive to the MAP kinase kinase inhibitor PD98059. Triggered cell-spreading on fibronectin was inhibited by PD98059 but not by U0126. In summary, ligation of beta 3 integrin by antibodies or fibronectin or of beta1 integrin by monoclonal antibodies fails to activate ERK MAP kinases, but integrin ligation synergizes with T cell receptor stimulation upstream of MAP kinases.
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PMID:Beta 1/beta 3 integrin ligation is uncoupled from ERK1/ERK2 activation in cytotoxic T lymphocytes. 1262 53

4-1BB(CD137) is a member of the tumor necrosis factor receptor superfamily and provides a costimulatory signal by interaction with 4-1BB ligand expressed on antigen-presenting cells. The expression of 4-1BB is known to be activation-dependent. Here, we investigated the transcriptional machinery required for T cell receptor (TCR) activation-dependent induction of 4-1BB expression in CD3-CEM cells treated with phorbol myristate acetate and ionomycin. Using 5'-deletion constructs of 4-1BB promoter in luciferase reporter assays, we demonstrated that the transcriptional elements mediating 4-1BB upregulation were located in the region between approximately 0.9 and approximately 1.1 kb from the translational start site. Characterization of these sites by electrophoretic mobility shift assay and site-directed mutagenesis revealed that nuclear factor kappaB (NF-kappaB) and activating protein-1 (AP-1) are involved. MEK and c-Jun N-terminal kinase-1 activity was required for activation-dependent 4-1BB upregulation. Thus, NF-kappaB and AP-1 are involved in the TCR stimulation-dependent transcriptional regulation of the 4-1BB promoter.
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PMID:NF-kappaB and AP-1 regulate activation-dependent CD137 (4-1BB) expression in T cells. 1270 38

Vav1 is a signaling protein required for both positive and negative selection of CD4(+)CD8(+) double positive thymocytes. Activation of the ERK MAPK pathway is also required for positive selection. Previous work has shown that Vav1 transduces T cell receptor (TCR) signals leading to an intracellular calcium flux. We now show that in double positive thymocytes Vav1 is required for TCR-induced activation of the ERK1 and ERK2 kinases via a pathway involving the Ras GTPase, and B-Raf, MEK1, and MEK2 kinases. Furthermore, we show that Vav1 transduces TCR signals to Ras by controlling the membrane recruitment of two guanine nucleotide exchange factors. First, Vav1 transduces signals via phospholipase Cgamma1 leading to the membrane recruitment of RasGRP1. Second, Vav1 is required for recruitment of Sos1 and -2 to the transmembrane adapter protein LAT. Finally, we show that Vav1 is required for TCR-induced LAT phosphorylation, a key event for the activation of both phospholipase Cgamma1 and Sos1/2. We propose that reduced LAT phosphorylation is the key reason for defective TCR-induced calcium flux and ERK activation in Vav1-deficient cells.
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PMID:Vav1 transduces T cell receptor signals to the activation of the Ras/ERK pathway via LAT, Sos, and RasGRP1. 1476 85


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