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)

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

Engagement of the T-cell receptor (TCR) triggers a series of signaling events that lead to the activation of T cells. HIP-55 (SH3P7 or mAbp1), an actin-binding adaptor protein, interacts with and is tyrosine phosphorylated by ZAP-70, which is a crucial proximal protein tyrosine kinase for TCR signaling. HIP-55 is important for JNK and HPK1 activation induced by TCR signaling. In this study, we report the generation and characterization of HIP-55 knockout mice. We found that HIP-55 knockout mice were viable and fertile but showed decreased body weight and increased occurrence of death within the first 4 weeks after birth. The lymphoid organs in HIP-55 knockout mice showed cellularity and T-cell development comparable to that of the wild-type mice. HIP-55 knockout T cells displayed defective T-cell proliferation, decreased cytokine production, and decreased up-regulation of the activation markers induced by TCR stimulation. TCR internalization was slightly increased in HIP-55 knockout T cells. These phenotypes were accompanied by reduced immune responses, including antigen-specific antibody production and T-cell proliferation in HIP-55 knockout mice. The TCR-induced signaling events, including LAT/phospholipase Cgamma1 phosphorylation and HPK1/JNK activation, were partially defective in HIP-55 knockout T cells. These results demonstrate the importance of HIP-55 as an adaptor protein in the TCR signaling and immune system.
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PMID:HIP-55 is important for T-cell proliferation, cytokine production, and immune responses. 1605 1

T-cell receptor (TCR) stimulation results in the recruitment and activation of the proteins ZAP70 and Lck. These two proteins have been implicated in signalling derived from interferon receptors, although their precise role in this independent pathway has not been determined fully. These observations raise a fundamental question of how a given protein in a cell can be involved in more than one signalling pathway, yet each pathway is able to produce a highly specific downstream response to its own stimulant. To maintain exclusivity of response, each pathway must isolate its component molecules chemically, spatially or dynamically from other prevailing pathways. To address this question, the proteins ZAP70 and Lck were investigated following stimulation of the interferon-alpha receptor and the TCR in T cells by two different extracellular stimulants: interferon-alpha and the anti-CD3 antibody, OKT3, respectively. We first demonstrate that ZAP70 plays a pivotal role in interferon-stimulated MAPK activation, and that the tyrosine residue at position 319 of ZAP70 is important for interferon-stimulated ERK activation. Translocation of both ZAP70 and Lck to the nucleus following interferon receptor stimulation is demonstrated for the first time. Fluorescence resonance energy transfer microscopy revealed a high degree of spatial localization of the ZAP70/Lck complex within the cell following IFNalpha stimulation, in contrast to a diffuse presence following the application of OKT3. The difference in the spatio-temporal localization of these proteins following stimulation may eliminate signal crosstalk, and could explain the differentiation of the specific downstream responses of these pathways.
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PMID:Distinct spatial and temporal distribution of ZAP70 and Lck following stimulation of interferon and T-cell receptors. 1621 25

Little is known as to the molecular mechanisms involved with mercury intoxication at very low levels. Although the mechanism is not known, animal studies have nevertheless shown that low levels of mercury may target the immune system. Inorganic mercury (Hg2+) at very low (but non-toxic) levels can disrupt immune system homeostasis, in that genetically susceptible rodents develop idiosyncratic autoimmune disease, which is associated with defective T-cell function. T lymphocyte function is intimately coupled to the T-cell receptor. We have previously reported that on a molecular level, low concentrations of Hg2+ disrupt signaling from the T-cell receptor by interfering with activation of Ras and ERK MAP kinase. In this report we expand upon those results by showing that in T lymphocytes exposed to low concentration of Hg2+, Ras fails to become properly activated because upstream of Ras in the T cell signal transduction pathway, the important scaffolding element Linker for Activation of T Cells (LAT) fails to become properly phosphorylated. Hypo-phosphorylation of LAT occurs, because upstream of LAT, the LAT reactive tyrosine kinase ZAP-70 is also not properly activated in Hg2+ treated cells.
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PMID:Inorganic mercury inhibits the activation of LAT in T-cell receptor-mediated signal transduction. 1625 84

Extracellular signal-regulated kinase 1c (ERK1c) is an alternatively spliced form of ERK1 that is regulated differently than other ERK isoforms. We studied the Golgi functions of ERK1c and found that it plays a role in MEK-induced mitotic Golgi fragmentation. Thus, in late G2 and mitosis of synchronized cells, the expression and activity of ERK1c was increased and it colocalized mainly with Golgi markers. Small interfering RNA of ERK1c significantly attenuated, whereas ERK1c overexpression facilitated, mitotic Golgi fragmentation. These effects were also reflected in mitotic progression, indicating that ERK1c is involved in cell cycle regulation via modulation of Golgi fragmentation. Although ERK1 was activated in mitosis as well, it could not replace ERK1c in regulating Golgi fragmentation. Therefore, MEKs regulate mitosis via all three ERK isoforms, where ERK1c acts specifically in the Golgi, whereas ERK1 and 2 regulate other mitosis-related processes. Thus, ERK1c extends the specificity of the Ras-MEK cascade by activating ERK1/2-independent processes.
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PMID:ERK1c regulates Golgi fragmentation during mitosis. 1653 48

Tributyltin (TBT), a toxic and widespread environmental contaminant, has been shown to inhibit natural killer (NK) cell cytotoxic function significantly. Inhibition of NK cell cytotoxic function has the potential to increase viral infections and tumor growth. Upon NK cell binding to lysis-sensitive tumor cells, an intracellular pathway is activated, which generally begins with activation of non-receptor protein tyrosine kinases (PTKs) and ends with mitogen-activated protein kinase (MAPK)-mediated release of lytic granules toward the contacted target cell. In the current studies, we used a cytotoxicity assay to examine how low doses (200nM or lower) of TBT affect cytotoxic function. Additionally, we investigated how low doses of TBT modulate the signaling pathway that dictates lytic granule exocytosis. A 1h exposure to 200, 100, 50 and 25nM TBT significantly decreased cytotoxic function 6d later. We also saw significant activation of p38 and p44/42 by as low as 50nM TBT within ten minutes of exposure. The observed activation of MAPKs, p38 and p44/42, implicated their upstream activators MAPK kinases (MAP2Ks). On examining MAP2Ks, MKK3/6 and MEK1/2, activation was seen within ten minutes. However, when the most upstream signaling molecules in this pathway, non-receptor protein tyrosine kinases (PTKs) such as Syk, ZAP-70, Pyk2 and Src were examined, no significant activation was seen. These data imply that upstream activators of MAP2Ks, MAP2K kinases (MAP3Ks), are activated by TBT exposures and/or that MAP2K phosphatases are being inhibited by TBT. Taken together, these data suggest that TBT-induced activation of MAPKs, p38 and p44/42, is caused by their upstream activators MAP2Ks, MKK3/6 and MEK1/2, respectively.
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PMID:Alteration of an essential NK cell signaling pathway by low doses of tributyltin in human natural killer cells. 1678 Oct 40

The interactions between peptide/MHC complexes and their cognate TCR are essential for various T cell responses. However, the relationship between the avidity of TCR ligand and the subsequent intracellular signaling through the TCR is still unclear. To investigate the effects of TCR ligand avidity on TCR-mediated signaling, we established L cells expressing HLA-DR4 molecules covalently linked with agonistic peptide (high-affinity ligand) or altered peptide ligand (APL; low-affinity ligand) at various densities as APC for a cognate human CD4(+) T cell clone. Using this system, we demonstrated that the T cell clone stimulated with APL/HLA-DR4 complexes presented at an excessive density provoked the up-regulation of CD69, IL-2 production and proliferation, but no detectable phosphorylation of ZAP-70/LAT/SLP-76. Furthermore, in contrast to the high-affinity stimulation, the low-affinity stimulation evoked delayed and sustained activation of the B-Raf/extracellular signal-regulated kinase (ERK) pathway without Raf-1 activation. The strength and duration of B-Raf/ERK activations closely correlated with the density of the TCR ligand. A knockdown approach confirmed that B-Raf activation was indispensable for the APL-induced T cell responses. These observations suggest that the differences in TCR-peptide/MHC interactions reflect the strength and duration of B-Raf/Raf-1/ERK activation in the human CD4(+) T cells.
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PMID:TCR ligand avidity determines the mode of B-Raf/Raf-1/ERK activation leading to the activation of human CD4+ T cell clone. 1679 76

SDF-1alpha (CXCL12) signaling via its receptor, CXCR4, stimulates T cell chemotaxis and gene expression. The ZAP-70 tyrosine kinase critically mediates SDF-1alpha-dependent migration and prolonged ERK mitogen-activated protein (MAP) kinase activation in T cells. However, the molecular mechanism by which CXCR4 or other G protein-coupled receptors activate ZAP-70 has not been characterized. Here we show that SDF-1alpha stimulates the physical association of CXCR4 and the T cell receptor (TCR) and utilizes the ZAP-70 binding ITAM domains of the TCR for signal transduction. This pathway is responsible for several of the effects of SDF-1alpha on T cells, including prolonged ERK MAP kinase activity, increased intracellular calcium ion concentrations, robust AP-1 transcriptional activity, and SDF-1alpha costimulation of cytokine secretion. These results suggest new paradigms for understanding the effects of SDF-1alpha and other chemokines on immunity.
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PMID:CXCR4 physically associates with the T cell receptor to signal in T cells. 1691 88

The protein Daxx promotes Fas-mediated cell death through activation of apoptosis signal-regulating kinase 1, leading to the activation of the MAPKs JNK and p38. Owing to the in utero lethality of daxx-deficient mice, the in vivo role of Daxx has been so far difficult to analyze. We have generated transgenic mice expressing a dominant-negative form of Daxx (Daxx-DN) in the T-cell lineage. We show that Daxx is recruited to the Fas receptor upon FasL engagement and that Daxx-DN expression protects activated T cells from Fas-induced cell death, by preventing the death-inducing signal complex to be properly formed. Normal lymphocyte development and homeostasis are nevertheless observed. Interestingly, we report that both in vitro and in vivo stimulation of Daxx-DN T-lymphocytes leads to increased proliferative T-cell responses. This increased proliferation is associated with a marked increase in tyrosine phosphorylation of LAT and ZAP70 as Daxx-DN favor their recruitment to the T-cell receptor (TCR) complex. These findings identify Daxx as a critical regulator of T-lymphocyte homeostasis by decreasing TCR-induced cell proliferation and by promoting Fas-mediated cell death.
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PMID:Requirement for Daxx in mature T-cell proliferation and activation. 1708 15

ShcA is an important mediator of Ras/MAPK activation in PTK-regulated pathways triggered by surface receptors. This function is subserved by the constitutively expressed p52-kDa isoform. Besides activating Ras, p52Shc couples the TCR to Rho GTPases, and thereby participates in actin cytoskeleton remodeling in T cells. Here we have addressed the potential involvement of p52Shc in T-cell chemotaxis and the role of the phosphorylatable tyrosine residues, YY239/240 and Y317, in this process. We show that CXCR4 engagement by the homeostatic chemokine, SDF-1alpha, results in p52Shc phosphorylation and its assembly into a complex that includes Lck, ZAP-70, and Vav. This process was found to be both Lck and Gi dependent. Expression of p52Shc mutants lacking YY239/240 or Y317, or p52Shc deficiency, resulted in a profound impairment in CXCR4 signaling and SDF-1alpha-dependent chemotaxis, underscoring a crucial role of p52Shc as an early component of the CXCR4 signaling cascade. p52Shc was also found to be required for ligand-dependent CXCR4 internalization independently of tyrosine phosphorylation. Remarkably, CXCR4 engagement promoted phosphorylation of the zeta chain of the TCR/CD3 complex, which was found to be essential for CXCR4 signaling, as well as for SDF-1alpha-dependent receptor endocytosis and chemotaxis, indicating that CXCR4 signals by transactivating the TCR.
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PMID:p52Shc is required for CXCR4-dependent signaling and chemotaxis in T cells. 1753 90


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