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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TRK-fused gene (TFG) was first identified as a partner of NTRK1 in generating the thyroid TRK-T3 oncogene, and is also involved in oncogenic rearrangements with ALK in anaplastic lymphoma and NOR1 in mixoid chondrosarcoma. The TFG physiological role is still unknown, but the presence of a number of motifs involved in protein interactions suggests that it may function by associating with other proteins. We have recently demonstrated that TFG associates and regulates the activity of the tyrosine phosphatase SHP-1. In this study by yeast two-hybrid screening we identified NEMO and TANK, two proteins modulating the NF-kappaB pathway, as novel TFG-interacting proteins. These interactions were further characterized in vitro and in vivo. We provide evidence that TFG and NEMO may be part of the same high molecular weight complex. TFG enhances the effect of TNF-alpha, TANK, TNF receptor-associated factor (TRAF)2, and TRAF6 in inducing NF-kappaB activity. We suggest that TFG is a novel member of the NF-kappaB pathway.
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PMID:The TFG protein, involved in oncogenic rearrangements, interacts with TANK and NEMO, two proteins involved in the NF-kappaB pathway. 1654 66

TGF-beta signaling is critical for controlling naive T cell homeostasis and differentiation; however, the biological and biochemical changes induced by TGF-beta in effector/memory T cells are poorly defined. We show that although TGF-beta inhibits effector/memory peripheral blood T lymphoblast proliferation and IL-2 production, the intensity and kinetics for TCR-induced global tyrosine phosphorylation are markedly increased compared with that in untreated cells or naive T cells. After TCR ligation, tyrosine phosphorylation of proximal tyrosine kinases and docking proteins like linker for activation of T cells is maintained for >30 min in TGF-beta-primed cells compared with untreated cells where phosphorylation of these targets returned to basal levels by 10 min. Extended phosphorylation of linker for activation of T cells in treated peripheral blood T selectively prolongs ERK 1/2 signaling and phospholipase C-gamma1 activation leading to increased Ca(2+) flux. A kinase/phosphatase imbalance could not account for extended phosphorylation as CD45R, SHP-1, and SHP-2 expression remains unaltered. The contradiction between prolonged signal transduction and inhibition of proliferation is partially explained by the observation that TGF-beta priming results in ERK 1/2-independent p21 induction and decreased cyclin D1 expression leading to accumulation of T cells in G(0)/G(1) phases of the cell cycle and cell cycle arrest. Despite inhibition of T cell function by TGF-beta priming, TCR and cytokine signaling pathways are intact and selectively extended, suggesting that suppression in the effector/memory T cell is mediated by reprogramming signal transduction, rather than its inhibition as in the naive T cell.
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PMID:TGF-beta inhibits IL-2 production and promotes cell cycle arrest in TCR-activated effector/memory T cells in the presence of sustained TCR signal transduction. 1820 44

Nonclassical major histocompatibility complex (MHC) class I molecule human leukocyte antigen (HLA)-G is normally expressed on the placental cells, especially fetal endothelial cells and invasive cytotrophoblast cells at the maternal-fetal interface. This antigen meditates immune tolerance in pregnancy through interaction with immune cells including natural killer (NK) cells. In this study, we investigated the mechanisms underlying HLA-G1-mediated inhibition of NK cytotoxicity using HLA-G1-transfected K562 cells and NK92 cells. We found that inhibition of NK cytotoxicity by HLA-G1 was associated with decreased formation of NK-target cell conjugates and defective formation of immunologic synapse, as characterized by actin depolarization and perforin immobilization in nonactive NK cells. HLA-G1 engagement induced dephosphorylation of Vav by tyrosine phosphatase-1 (SHP-1), and thus blocked the Syk-->MEK/ERK activating signaling pathway in activating NK cells. These results indicate that HLA-G1 inhibits NK cytotoxicity by blocking activating signal transduction pathway, which is required for the formation of activating immunologic synapse.
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PMID:Human leukocyte antigen-G1 inhibits natural killer cytotoxicity through blocking the activating signal transduction pathway and formation of activating immunologic synapse. 1829 71

Lymphocyte activation gene-3 (LAG-3) is a CD4-related transmembrane protein expressed by regulatory T cells that binds MHC II on APCs. It is shown in this study that during Treg:DC interactions, LAG-3 engagement with MHC class II inhibits DC activation. MHC II cross-linking by agonistic Abs induces an ITAM-mediated inhibitory signaling pathway, involving FcgammaRgamma and ERK-mediated recruitment of SHP-1 that suppresses dendritic cell maturation and immunostimulatory capacity. These data reveal a novel ITAM-mediated inhibitory signaling pathway in DCs triggered by MHC II engagement of LAG-3, providing a molecular mechanism in which regulatory T cells may suppress via modulating DC function.
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PMID:Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. 1842 11

The role of somatostatin (SST) and epidermal growth factor (EGF) in breast cancer is undisputed; however, the molecular mechanisms underlying their antiproliferative or proliferative effects are not well understood. We initially confirmed that breast tumour tissues express all five somatostatin receptors (SSTR1-5) and four epidermal growth factor receptors (ErbB1-4). Subsequently, to gain insight into the function of SSTRs and ErbBs in oestrogen receptor (ER)-positive (MCF-7) or ERalpha-negative (MDA-MB-231) breast cancer cells, we defined SSTR1, SSTR5 and ErbB1 mRNA and protein expression in these two tumour cell lines. Consistent with previous studies showing SSTR1/SSTR5 heterodimerization and having seen cell-specific and ligand-selective alterations in receptor expression, we next elucidated whether SSTR1 and SSTR5 functionally interact with ErbB1 using pbFRET analysis. We subsequently determined the effects of SST and EGF either alone, or in combination, on selected downstream signalling molecules such as erk1/2, p38 and JNK. Here, we showed that both SST and EGF influenced erk1/2 phosphorylation and that SST modulated the effects of EGF in a cell-specific manner. We also demonstrated agonist-, time and cell-dependent regulation of p38 phosphorylation. We further investigated modulation of Grb2, SOS, Shc, SH-PTP1 and SH-PTP2. ErbB1 adaptor proteins known to play a role in MAPK activation, Shc, Grb2 and SOS, changed in an agonist- and cell-specific manner whereas, SH-PTP1 and SH-PTP2, adaptor proteins reported to interact with SSTRs, translocated from the cytosol to membrane in a cell-specific manner following SST and/or EGF treatment. Although several previous studies have shown crosstalk between RTKs and GPCRs, there are no reports describing SSTR (GPCR) modulation of ErbBs (RTK) in breast cancer. To the best of our knowledge, this is the first report describing crosstalk/interactions between SSTRs and ErbBs.
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PMID:Somatostatin receptors 1 and 5 heterodimerize with epidermal growth factor receptor: agonist-dependent modulation of the downstream MAPK signalling pathway in breast cancer cells. 1907 Jun 59

One mechanism viruses use to subvert immune surveillance is through mutation of MHC contact residues of antigenic epitopes that weaken T cell recognition to the point that the immune system is ignorant of the infection. However, in contrast to ignorance, results presented herein demonstrate that intracellular signaling does occur upon stimulation with a lymphocytic choriomeningitis virus-derived escape mutant as demonstrated by the sustained activation of Src homology 2 domain-containing protein tyrosine phosphatase (SHP-1). In addition to the increased SHP-1 activity, we found that the mutated epitope failed to induce oxidation of SHP-1, further enhancing enzymatic activity. Sustained activation of SHP-1 in a reduced form correlated with ERK and early growth response gene 1 activation and failure of T cells to commit to the effector lineage. Thus, instead of immune ignorance, these studies demonstrate the activation of a negative signaling pathway that actively suppresses T cell responses and limits recognition of viral escape mutants.
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PMID:CD8+ T cell responses to a viral escape mutant epitope: active suppression via altered SHP-1 activity. 1920 34

Among the many oncogenic variants of the anaplastic lymphoma kinase (ALK), nucleophosmin 1 (NPM)/ALK fusion protein expressed in the subset of T-cell lymphoma (ALK(+)TCL) is currently the best characterized. NPM/ALK activates several signal transduction pathways, including PI3K/AKT, MEK/ERK, mTORC1, STAT3, and STAT5b. In turn, the pathways modulate expression and function of many genes and proteins involved in the key cellular functions such as proliferation, growth, survival, metabolism, and angiogenesis. Recent data indicate that NPM/ALK also promotes immune evasion of the ALK(+)TCL by inducing through STAT3 activation the expression of immunosuppressive cytokines interleukin-10 (IL-10) and transforming growth factor-beta (TGFss) and cell surface protein CD274 (PD-L1, B7-H1). In addition, NPM/ALK protects its own expression by mediating via STAT3 and at least one member of the DNA methyltransferase family DNMT1 epigenetic silencing of the SHP-1 and STAT5a genes. In ALK+TCL cells, SHP-1 and STAT5a proteins act as potent tumor suppressors by promoting degradation of the NPM/ALK protein and inhibiting expression of the NPM/ALK gene, respectively. These findings provide further rationale to therapeutically target ALK and its effector proteins, foremost STAT3. They also suggest that immunotherapeutic approaches to ALK(+)TCL and, possibly, other ALK-driven malignancies may require inhibition of ALK and STAT3 to achieve the optimal clinical efficacy.
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PMID:Anaplastic lymphoma kinase (ALK)-induced malignancies: novel mechanisms of cell transformation and potential therapeutic approaches. 1939 33

Immature thymocytes that are positively selected based upon their response to self-peptide-MHC complexes develop into mature T cells that are not overtly reactive to those same complexes. Developmental tuning is the active process through which TCR-associated signaling pathways of single-positive thymocytes are attenuated to respond appropriately to the peptide-MHC molecules that will be encountered in the periphery. In this study, we explore the mechanisms that regulate the tuning of CD4(+) single-positive T cells to MHC class II encountered in the thymic medulla. Experiments with murine BM chimeras demonstrate that tuning can be mediated by MHC class II expressed by either thymic medullary epithelial cells or thymic dendritic cells. Tuning does not require the engagement of CD4 by MHC class II on stromal cells. Rather, it is mediated by interactions between MHC class II and the TCR. To understand the molecular changes that distinguish immature hyperactive T cells from tuned mature CD4(+) T cells, we compared their responses to TCR stimulation. The altered response of mature CD4 single-positive thymocytes is characterized by the inhibition of ERK activation by low-affinity self-ligands and increased expression of the inhibitory tyrosine phosphatase SHP-1. Thus, persistent TCR engagement by peptide-MHC class II on thymic medullary stroma inhibits reactivity to self-Ags and prevents autoreactivity in the mature repertoire.
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PMID:The activation threshold of CD4+ T cells is defined by TCR/peptide-MHC class II interactions in the thymic medulla. 1984 39

Immune responses to citrullinated neoantigens and clinical efficacy of costimulation blockade indicate a general defect in maintaining T cell tolerance in rheumatoid arthritis (RA). To examine whether TCR threshold calibration contributes to disease pathogenesis, signaling in RA T cells was quantified. RA patients had a selective increase in ERK phosphorylation compared with demographically matched controls due to a mechanism distal of Ras activation. Increased ERK responses included naive and memory CD4 and CD8 T cells and did not correlate with disease activity. The augmented ERK activity delayed SHP-1 recruitment to the TCR synapse and sustained TCR-induced Zap70 and NF-kappaB signaling, facilitating responses to suboptimal stimulation. Increased responsiveness of the ERK pathway was also a characteristic finding in the SKG mouse model of RA where it preceded clinical symptoms. Treatment with subtherapeutic doses of a MEK-1/2 inhibitor delayed arthritis onset and reduced severity, suggesting that increased ERK phosphorylation predisposes for autoimmunity and can be targeted to prevent disease.
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PMID:ERK-dependent T cell receptor threshold calibration in rheumatoid arthritis. 2000 89

SHP-1 plays an important role for the regulation of signaling from various hematopoietic cell receptors. In this study, we examined IL-3-induced cell proliferation and IL-3 depletion-induced apoptosis in bone marrow-derived mast cells (BMMC) established from motheaten (me) that lack SHP-1 expression, viable motheaten (me(v)) expressing phosphatase-deficient SHP-1, and wild-type (WT) mice. When BMMC were stimulated with IL-3, increased ERK activation was evident in resting state and sustained in me-BMMC relative to WT-BMMC. ERK is known to be involved in the regulation of cell proliferation and apoptosis in some cells. In accordance with sustained ERK activation, apoptosis was decreased in me- and me(v)-BMMC compared with WT-BMMC. In contrast to the predicted role of ERK as a pro-survival molecule, IL-3-induced cell proliferation was much lower in me- and me(v)-BMMC than WT-BMMC. Stimulation with lower concentration of IL-3 or addition of PD98059, a MEK inhibitor, to the culture resulted in the suppression of decreased apoptosis and cell proliferation in me- and me(v)-BMMC. Collectively, these results suggest that SHP-1 positively regulates IL-3-dependent mast cell proliferation and apoptosis by inhibiting ERK activity through its phosphatase activity. Furthermore, our results indicate that ERK would act as a negative regulator for cell proliferation and induce apoptosis when its activity is highly increased.
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PMID:Deficiency of SHP1 leads to sustained and increased ERK activation in mast cells, thereby inhibiting IL-3-dependent proliferation and cell death. 2104


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