Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lymphocytes employ a complex assembly of signaling elements that have been organized on a spatiotemporal map to define their role in stimulating both proliferation and apoptosis. The antigen/major histocompatibility complex (MHC) initiates the sequence by organizing the assembly of an active T-cell receptor (TCR) complex responsible for transmitting information down various signaling cassettes (e.g., the IP3/Ca2+, DAG/PKC, ras/MAPK, and the PI 3-K pathways). It is proposed that CD28 may exert its costimulatory action by facilitating the assembly of an effective scaffold of signaling elements within the TCR complex. The absence of costimulation through CD28 seems to result in the assembly of a defective scaffold that reverses slowly and may thus account for the state of unresponsiveness responsible for peripheral T-cell tolerance. The signaling cassettes activated by the TCR and CD28 then engage cytosolic factors that transmit information into the nucleus to activate the genes that code for the IL-2 and Fas signaling pathways. The IL-2 and Fas receptors employ additional signaling cassettes (e.g., the JAK/STAT and the sphingomyelinase/ceramide pathways) to mediate their effects on proliferation and apoptosis, respectively. Information concerning these signaling systems is beginning to provide therapeutic strategies to manipulate the immune system to overcome human immunodeficiency virus (HIV) infection, autoimmune diseases, and graft rejection.
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PMID:Lymphocyte activation in health and disease. 909 51

Although dendritic cell (DC) activation is a critical event for the induction of immune responses, the signaling pathways involved in this process have not been characterized. In this report, we show that DC activation induced by lipopolysaccharide (LPS) can be separated into two distinct processes: first, maturation, leading to upregulation of MHC and costimulatory molecules, and second, rescue from immediate apoptosis after withdrawal of growth factors (survival). Using a DC culture system that allowed us to propagate immature growth factor-dependent DCs, we have investigated the signaling pathways activated by LPS. We found that LPS induced nuclear translocation of the nuclear factor (NF)-kappaB transcription factor. Inhibition of NF-kappaB activation blocked maturation of DCs in terms of upregulation of major histocompatibility complex and costimulatory molecules. In addition, we found that LPS activated the extracellular signal-regulated kinase (ERK), and that specific inhibition of MEK1, the kinase which activates ERK, abrogated the ability of LPS to prevent apoptosis but did not inhibit DC maturation or NF-kappaB nuclear translocation. These results indicate that ERK and NF-kappaB regulate different aspects of LPS-induced DC activation: ERK regulates DC survival whereas NF-kappaB is responsible for DC maturation.
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PMID:Dendritic cell survival and maturation are regulated by different signaling pathways. 984 30

Cbl is the product of the protooncogene c-cbl and is involved in T cell antigen receptor (TCR)-mediated signaling. To understand the role of Cbl for immune system development and function, we generated a Cbl-deficient mouse strain. In Cbl-deficient mice, positive selection of the thymocytes expressing major histocompatibility complex class II-restricted transgenic TCR was significantly enhanced. Two factors may have contributed to the altered thymic selection. First, Cbl deficiency markedly up-regulated the activity of ZAP-70 and mitogen-activated protein kinases. The mitogen-activated protein kinase pathway was shown previously to be involved in thymic positive selection. Second, Cbl-deficient thymocytes expressed CD3 and CD4 molecules at higher levels, which consequently may increase the avidity of TCR/major histocompatibility complex/coreceptor interaction. Thus, Cbl plays a novel role in modulating TCR-mediated multiple signaling pathways and fine-tunes the signaling threshold for thymic selection.
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PMID:Altered thymic positive selection and intracellular signals in Cbl-deficient mice. 986 Oct 6

Abnormal expression of major histocompatibility complex (MHC) class I and class II in various tissues is associated with autoimmune disease. Autoimmune responses can be triggered by viral infections or tissue injuries. We show that the ability of a virus or a tissue injury to increase MHC gene expression is duplicated by any fragment of double-stranded (ds) DNA or dsRNA introduced into the cytoplasm of nonimmune cells. Activation is sequence-independent, is induced by ds polynucleotides as small as 25 bp in length, and is not duplicated by single-stranded polynucleotides. In addition to causing abnormal MHC expression, the ds nucleic acids increase the expression of genes necessary for antigen processing and presentation: proteasome proteins (e.g., LMP2), transporters of antigen peptides; invariant chain, HLA-DM, and the costimulatory molecule B7.1. The mechanism is different from and additive to that of gamma-interferon (gammaIFN), i.e., ds polynucleotides increase class I much more than class II, whereas gammaIFN increases class II more than class I. The ds nucleic acids also induce or activate Stat1, Stat3, mitogen-activated protein kinase, NF-kappaB, the class II transactivator, RFX5, and the IFN regulatory factor 1 differently from gammaIFN. CpG residues are not responsible for this effect, and the action of the ds polynucleotides could be shown in a variety of cell types in addition to thyrocytes. We suggest that this phenomenon is a plausible mechanism that might explain how viral infection of tissues or tissue injury triggers autoimmune disease; it is potentially relevant to host immune responses induced during gene therapy.
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PMID:Activation of target-tissue immune-recognition molecules by double-stranded polynucleotides. 1005 33

Engagement of the T cell receptor (TCR) by peptide antigen bound to the major histocompatibility complex molecules initiates a biochemical cascade involving protein tyrosine kinases (PTKs) such as Lck, ZAP70 and Csk, and protein tyrosine phosphatases (PTPases) such as CD45, SHP-1 and SHP-2. In the process of T cell activation, immune tyrosine-based activation motifs (ITAMs) and immune tyrosine-based inhibitory motifs(ITIMs) within the cytoplasmic region of CD3 and CD152 molecules play a key role in the activation of PTKs and PTPases. Consequently, Ras/MAP kinase and PLC gamma 1 pathways are activated to induce IL-2 gene transcription through AP-1 and NF-AT generation. Recent biochemical and genetic evidence has suggested that dysfunction in these TCR-related molecules resulted in immuno-deficiency, breakdown of tolerance and abnormal T cell development.
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PMID:[T cell receptor and its related molecules in signal transduction]. 1007 90

It has been widely accepted that T cell activation requires two signals; one from the binding of the antigen/major histocompatibility complex to the T-cell receptor (TCR)/CD3 complex and the other from the interaction between a surface molecule on antigen presenting cells and its receptor on T cells. The second signal is considered as co-stimulatory and the B7/CD28 pair has been well studied as a prototype. Recently 4-1BB (CD137) has been characterized as another co-stimulatory molecule for T cell activation. However, unlike the CD28/B7 pair, 4-1BB and its ligand 4-1BBL constitute a member of the tumor necrosis factor (TNF) receptor/TNF pair superfamily. The signaling mechanism of 4-1BB has not been revealed in detail. To investigate whether 4-1BB takes the signaling pathways analogous to those for TNF receptors, we generated polyclonal antibodies against human 4-1BB and 4-1BBL and established stable transfectants of the receptor and the ligand with a high level of cell surface expression. Over-expression of h4-1BB was found to result in the activation of c-Jun N-terminal kinase (JNK) in the human embryonic kidney cell line 293. In T cells, it has been previously demonstrated that JNK activation requires dual signals such as the ligation of TCR/CD3 complex plus CD28 co-stimulation or PMA plus ionomycin. The JNK activation by 4-1BB in Jurkat T cells was also found to require stimulation of the TCR/CD3 complex, consistent with the notion that 4-1BB functions as a co-stimulatory molecule for T cell activation.
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PMID:Activation of c-jun N-terminal kinase by 4-1BB (CD137), a T cell co-stimulatory molecule. 1090 Nov 61

Positive selection allows thymocytes that recognize an individual's own major histocompatibility complex (self-MHC) molecules to survive and differentiate, whereas negative selection removes overtly self-reactive thymocytes. Although both forms of thymic selection are mediated by the alphabeta T-cell receptor (TCR) and require self-MHC recognition, an important question is whether they are controlled by distinct signalling cascades. We have shown that mutation of an essential motif within the TCR alpha-chain-connecting peptide domain (alpha-CPM) profoundly affects positive but not negative selection. Using transgenic mice expressing a mutant alpha-CPM TCR we examined the contribution of several mitogen-activated protein kinase (MAPK) cascades to thymic selection. Here we show that in thymocytes expressing a mutant alpha-CPM receptor, a positively selecting peptide failed to activate the extracellular signal-regulated kinase (ERK), although other MAPK cascades were induced normally. The defect in ERK activation was associated with impaired recruitment of the activated tyrosine kinases Lck and ZAP-70, phosphorylated forms of the TCR component CD3zeta and the adaptor protein LAT to detergent-insoluble glycolipid-enriched microdomains (DIGs). Therefore, an intact DIG-associated signalosome is essential for sustained ERK activation, which leads to positive selection.
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PMID:A motif in the alphabeta T-cell receptor controls positive selection by modulating ERK activity. 1093 40

Dendritic cells (DC) are highly specialized antigen-presenting cells that on activation by inflammatory stimuli (eg, tumor necrosis factor alpha [TNF-alpha] and interleukin-1beta [IL-1beta]) or infectious agents (eg, lipopolysaccharide [LPS]), mature and migrate into lymphoid organs. During maturation, DC acquire the capacity to prime and polarize resting naive T lymphocytes. Maturation of monocyte-derived DC (MDDC) is inhibited by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. This study found that in the presence of the mitogen-activated protein kinase kinase 1-extracellular signal-regulated kinase (ERK) inhibitors PD98059 or U0126, TNF-alpha- and LPS-induced phenotypic and functional maturation is enhanced. ERK pathway inhibitors increased expression of major histocompatibility complex and costimulatory molecules; loss of mannose-receptor-mediated endocytic activity; nuclear factor-kappaB DNA-binding activity; release of IL-12 p40; and allogeneic T-cell proliferation induced by LPS or TNF-alpha. Moreover, PD98059 and U0126 enhanced LPS-triggered production of IL-12 p70. In agreement with the effect of ERK inhibitors, maturation of MDDC was delayed in the presence of serum, an effect that was reversed by U0126. These results indicate that the ERK and p38 MAPK signaling pathways differentially regulate maturation of MDDC and suggest that their relative levels of activation might modulate the initial commitment of naive T-helper (Th) cells toward Th1 or Th2 subsets. The findings also suggest that maturation of MDDC might be pharmacologically modified by altering the relative levels of activation of both intracellular signaling routes.
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PMID:Extracellular signal-regulated protein kinase signaling pathway negatively regulates the phenotypic and functional maturation of monocyte-derived human dendritic cells. 1156 5

Suppressor of cytokine signaling-1 (SOCS-1) is a negative regulator of the Jak-STAT (signal transducer and activator of transcription cytokine) signaling pathway but may also regulate other pathways. At least in vitro, SOCS-1 inhibits the action of multiple cytokines. By studying the effects of SOCS-1 deficiency, we investigated whether SOCS-1 is involved in preventing cytokine-induced death of pancreatic islet cells, a potential mechanism of insulin deficiency in autoimmune diabetes. Tumor necrosis factor (TNF) + interferon-gamma (IFNgamma) was more potent at inducing cell death in SOCS-1-/- islets than in wild type. Individually, these cytokines did not induce cell death. The titration of the two cytokines suggested that this increased cell death was because of hypersensitivity to TNF. Interleukin-1 + IFNgamma induced the same level of cell death in SOCS-1-/- and wild-type islets, suggesting that the sensitivity of islets to IFNgamma or interleukin-1-mediated cytotoxicity is not affected by SOCS-1 deficiency. Additionally, SOCS-1-/- beta cells were responsive to lower concentrations of TNF measured by class I major histocompatibility complex up-regulation. The TNF + IFNgamma damage of islets was mediated by inducible nitric-oxide synthase (iNOS), and increased iNOS expression and nitric oxide production were found in SOCS-1-/- islets following cytokine treatment. A further analysis revealed that SOCS-1 deficiency results in augmented TNF signaling via the p38 mitogen-activated protein kinase pathway but not NFkappaB or c-Jun N-terminal kinase pathways. Increased p38 signaling may be responsible for the increased iNOS expression in SOCS-1-/- islets. Therefore, these findings provide evidence that physiological levels of SOCS-1 negatively regulate TNF signaling.
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PMID:Suppressor of cytokine signaling-1 regulates the sensitivity of pancreatic beta cells to tumor necrosis factor. 1203 39

The highly polymorphic human major histocompatibility complex (HLA) class II molecules are acknowledged as signaling receptors although their coupling to signaling pathways is not yet fully elucidated. In this study, we investigated how HLA class II can be coupled to protein tyrosine kinase (PTK) signaling pathway in B cells and whether there might be differences depending on HLA class II isotype. Using the human B cell line Ramos, we demonstrate that CD19 and CD20 are two HLA class II-associated receptors that couple HLA class II to PTK signaling pathway where CD20 appears to be amajor component of HLA class II-mediated activation of Src kinases. Both HLA-DR and HLA-DP co-immunoprecipitate tyrosine-phosphorylated proteins (p-Tyr) whereas only activation through HLA-DR increases the tyrosine phosphorylation of these proteins. Indeed, in contrast to HLA-DR, cross-linking HLA-DP induces neither tyrosine phosphorylation nor homotypic adhesion, and induces ERK1/2 activation. Differential association of these isotypes with CD20 appears to be one of the mechanisms underlying their differential signaling. We provide an experimental evidence for a mechanism by which HLA class II molecules can be coupled to PTK signaling pathway and, underscores their isotypes differential signaling. Further investigation of these mechanisms is likely to provide new insights into how isotype specific MHC class II signaling can contribute to the regulation of the immune response.
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PMID:MHC class II isotype-specific signaling complex on human B cells. 1220 41


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