Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The angiogenesis inhibitor AGM-1470 has recently been reported to inhibit collagen-induced arthritis in rats. To determine if the anti-arthritic effects of AGM-1470 might be due to T cell inhibition, we have studied its effects on T cell responses in vitro. Responses of human cells to tetanus toxoid (TT), and those of murine splenocytes to staphylococcal enterotoxin (SE), mitogens or a mls difference were inhibited by AGM-1470. Responses of human cells to SE, OKT3 and PHA were all partially inhibited on day 2 (d2) but not d3, and in fact were augmented on d6-8. The amount of IL-2 in SEA cultures was augmented on d4 and d5. There were no differences in the expression of CD3, CD4, CD8, CD25, CD45RA, CD45RO, LFA-1, VLA-4 or VLA-6 in inhibited cultures, except for slight decreases in CD25 and CD45RO in TT cultures. These results indicated that the angiogenesis inhibitor AGM-1470 also modulates human and murine lymphocyte function.
 ...
PMID:Modulation of T lymphocyte function by the angiogenesis inhibitor AGM-1470. 827 96

The in vitro T cell nonresponsiveness or anergy to restimulation with staphylococcal enterotoxin B (SEB) following the in vivo injection of the superantigen is well characterized. Here we use mice transgenic for a V beta 8.2+ T cell receptor (TcR) (reactive with SEB) to establish a large population of anergic T cells in vivo. As expected, peripheral T cells from the SEB injected transgenic mice failed to proliferate or produce interleukin (IL)-2 following restimulation with the superantigen in vitro. However, in this system superantigen reactivity could be restored by either addition of exogenous IL-2, or stimulation with immobilized anti-TcR antibody. To evaluate the effects of superantigen-induced anergy in vivo, SEB-injected or noninjected control transgenic mice were immunized and boosted with the T cell-dependent antigen tetanus toxin (TT). SEB injection of the V beta 8.2+ transgenic mice 5 days prior to the TT immunization inhibited the anti-TT antibody response as measured over a 100-day period, whereas injection of a superantigen which does not interact with the V beta 8.2% TcR (such as SEA) did not. Furthermore, SEB injection of control nontransgenic mice did not interfere with the induction of a high titer anti-TT antibody response. In contrast to the inhibition seen when SEB was given prior to TT immunization, injection of transgenics with SEB either after the priming TT immunization or after the recall booster injection did not significantly influence the titers of anti-TT antibodies produced. These results demonstrate that the establishment of peripheral T cell anergy to superantigens inhibits the specific antigenic priming of helper T cells in vivo, but does not prevent primed T cells from helping B cells to mount an effective antibody response.
 ...
PMID:Differential effects of superantigen-induced "anergy" on priming and effector stages of a T cell-dependent antibody response. 829 94

CD6 is a 130 000 MW T-cell surface glycoprotein that can deliver coactivating signals to mature T lymphocytes. Studies using monoclonal antibodies (mAb) have defined at least four epitopes on CD6, and distinct functional responses are elicited by mAb to the different epitopes. The function of CD6 is unknown. Multiple CD6 ligands are predicted, based on data that a soluble CD6 fusion protein precipitates at least three peptides. A cDNA clone for one of these ligands, termed activated leucocyte-cell adhesion molecule (ALCAM) has recently been isolated. In order to further characterize the role of CD6 in cell-cell interactions, we have examined the role of CD6 in a variety of responses by tetanus toxoid (TT) specific human T-cell clones. Anti-CD6 mAb UMCD6 (epitope 3) inhibits antigen-specific responses of such clones to TT, but not to the superantigen SEA. Responses of clones to nominal antigen are CD6-dependent using either peripheral blood mononuclear cells (PBMC) or macrophage-depleted E rosette negative cells as the antigen-presenting cell (APC) population. Furthermore, these clones made autoreactive with DNA methyltransferase inhibitors express increased CD6, and autoreactivity is inhibited by UMCD6. Taken together, the data suggests the existence of a functional CD6 ligand in peripheral blood which is expressed by APC, including cells other than macrophages. Interactions between CD6 and CD6 ligands may regulate both antigen specific and autoreactive responses of human T lymphocytes.
 ...
PMID:Role of the CD6 glycoprotein in antigen-specific and autoreactive responses of cloned human T lymphocytes. 888 54

Peripheral blood mononuclear cells from 16 children with atopic disease (range of IgE levels: 33 - 2892 kU/l) and 12 age matched controls were stimulated either with mAbs specific for CD3, CD2, CD3 plus CD28, CD2 plus CD28, with Tetanus Toxoid, SEA, or PHA plus PMA and their cell proliferation was determined. In addition, their cytokine production (IL2, IL4, IL10, IFN gamma) following selected stimuli was measured. We found that the cells from atopics proliferated significantly better in response to CD2 stimulation than control cells, with no difference in response to CD3 or SEA stimulation. Furthermore, cells from atopics produced significantly higher amounts of IL4 than cells from controls, a difference most pronounced following CD2 plus CD28 stimulation. No differential production was found for IL10 and IFN gamma. We conclude that in atopic children with moderately elevated IgE a hyperreactivity of the CD2 pathway of stimulation and a clear elevation of IL4 but not of IL10 or IFN gamma production can be demonstrated.
 ...
PMID:Enhanced production of IL4 but not of IFN gamma and IL 10 by peripheral blood mononuclear cells from atopic children in response to CD2 plus CD28 stimulation. 890 57

Membrane metalloendopeptidase EC 3.4.24.11 (Enkephalinase, neutral endopeptidase, NEP) is a cellular ectoenzyme, immunophenotypically identified as the leukocyte cluster of differentiation CD10 or CALLA (common acute lymphoblastic leukemia antigen). Immunological, biochemical and molecular biology techniques have identified tis cell membrane feature in various organs: brain, cardiovascular system, lung, placenta, kidney etc. The CD10 immunophenotype is a common feature of lymphoblasts in acute lymphoid leukemia not expressing the T- or B-markers. The enzymatic activity of CD10/NEP possibly influences normal lymphocyte ontogeny by proteolytic cleavage of the regulatory peptides. The substrates of CD10/NEP in the kidneys are (see the list of abbreviations) ANP, adrenomedullin and PAMP; in the brain, the substrates are enkephalins and oxytocin; in the lung, bombesin, BLP, GRP, neuromedin C, substance P and neurokinin A; in the cardiovascular system, angiotenisin II, bradykinin and CGRP; in the gut, VIP; on the neutrophil membrane, fMLP etc. Some substrates are not strictly tissue-specific, e.g. substance P. Preclinical and clinical trials explore possibilities of therapeutic application of the inhibitors of neutral endopeptidase, such as thiorphan in the management of pain, diarrhoea, depression, arterial hypertension and asthma. Other possibilities of application include the treatment of hyalinomembranous disease and prevention of neurotoxicosis in tetanus and botulism.
 ...
PMID:[Membrane metalloendopeptidase (CD10/CALLA): distribution, physiologic and pathophysiologic functions and its inhibitors]. 974 92

We used confocal microscopy, patch-clamp, and biotin-labeling techniques to examine the role of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in mediating the effect of inhibition of PTK on ROMK1 trafficking in HEK-293 cells transfected with c-Src and green fluorescent protein (GFP)-ROMK1. Inhibition of c-Src with herbimycin A significantly decreased the tyrosine phosphorylation level of ROMK1. Patch-clamp studies demonstrated that addition of herbimycin A increased the activity of ROMK1 in cell-attached patches. Confocal microscopic imaging showed that herbimycin A decreased the intracellular intensity of GFP-ROMK1. The biotin-labeling technique demonstrated that the inhibition of c-Src increased surface ROMK1 by 110%. In contrast, inhibition of c-Src did not increase the K channel number in HEK cells transfected with R1Y337A, a ROMK1 mutant in which tyrosine residue 337 was mutated to alanine. This suggests that tyrosine residue 337 is essential for the herbimycin A-induced increase in surface ROMK1 channels. To determine whether SNARE proteins are involved in mediating exocytosis of ROMK1 induced by the inhibition of c-Src, we examined the effect of herbimycin A on ROMK1 trafficking in cells treated with tetanus toxin. The incubation of cells in a medium containing tetanus toxin abolished the herbimycin A-induced increase in the number of surface ROMK1. In contrast, inhibition of c-Src still increased the numbers of surface ROMK1 in cells treated with boiled tetanus toxin. We conclude that tyrosine dephosphorylation enhances the exocytosis of ROMK1 and that SNARE proteins are required for exocytosis induced by inhibition of PTK.
 ...
PMID:Tetanus toxin abolishes exocytosis of ROMK1 induced by inhibition of protein tyrosine kinase. 1255 63

Previous publications from our group [Gil, Chaib, Pelliccioni and Aguilera (2000) FEBS Lett. 481, 177-182; Gil, Chaib, Blasi and Aguilera (2001) Biochem. J. 356, 97-103] have reported the activation, in rat brain synaptosomes, of several phosphoproteins, such as neurotrophin tyrosine kinase (Trk) A receptor, phospholipase Cgamma-1, protein kinase C (PKC) isoforms and extracellular-signal-regulated kinases 1 and 2 (ERK-1/2). In the present study, we examined, by means of phospho-specific antibodies, the activation of the signalling cascades involving neurotrophin Trk receptor, Akt kinase and ERK pathway, in cultured cortical neurons from foetal rat brain, by tetanus toxin (TeTx) as well as by the C-terminal part of its heavy chain (H(C)-TeTx). TeTx and H(C)-TeTx induce fast and transient phosphorylation of Trk receptor at Tyr(674) and Tyr(675), but not at Tyr(490), although the potency of TeTx in this action was higher when compared with H(C)-TeTx action. Moreover, H(C)-TeTx and TeTx also induced phosphorylation of Akt (at Ser(473) and Thr(308)) and of ERK-1/2 (Thr(202)/Tyr(204)), in a time- and concentration-dependent manner. The detection of TeTx- and H(C)-TeTx-induced phosphorylation at Ser(9) of glycogen synthase kinase 3beta confirms Akt activation. In the extended analysis of the ERK pathway, phosphorylation of the Raf, mitogen-activated protein kinase kinase (MEK)-1/2 and p90Rsk kinases and phosphorylation of the transcription factor cAMP-response-element-binding protein were detected. The use of tyrphostin AG879, an inhibitor of Trk receptors, demonstrates their necessary participation in the H(C)-TeTx-induced activation of Akt and ERK pathways, as well as in the phosphorylation of phospholipase Cgamma-1. Furthermore, both pathways are totally dependent on phosphatidylinositol 3-kinase action, and they are independent of PKC action, as assessed using wortmannin and Ro-31-8220 as inhibitors. The activation of PKC isoforms was determined by their translocation from the cytosolic compartment to the membranous compartment, showing a clear H(C)-TeTx-induced translocation of PKC-alpha and -beta, but not of PKC- epsilon.
 ...
PMID:C-terminal fragment of tetanus toxin heavy chain activates Akt and MEK/ERK signalling pathways in a Trk receptor-dependent manner in cultured cortical neurons. 1271 Aug 87

Numerous studies have suggested that sexual dimorphism may exist in learning and memory, particularly in types involving the hippocampus. In the present study, we examined the effects of two different tetani on the induction of long-term potentiation in the CA1 region of hippocampal slices from adult female and male rats to determine the sexual differences in their responses to tetanizing stimulation. We found that the induction of LTP is sex-dependent, and that there were clear sexual differences in the responses to different tetanus patterns, but not impulse number or stimulation frequency. Multiple trains of tetani were more effective in the indution of LTP in male rats than in female ones. These findings suggest that male rats can react to a broader range of tetanizing stimulation compared with female rats. Based on our results and the findings of other studies, we propose that the interaction of gonadal hormones with Ca2+/NMDAR and the subsequent regulation of the ERK/MAP kinase pathway are critical mechanisms for sexual dimorphism in the induction of LTP.
 ...
PMID:Sexual dimorphism in the induction of LTP: critical role of tetanizing stimulation. 1510 26

Gastrodia elata (G. elata) is a traditional Chinese herbal medicine for treating headaches, dizziness, tetanus, and epilepsy. In this study, differential methanol (MeOH) extracts of G. elata were found to prevent serum-deprived rat pheochromocytoma (PC12) cell apoptosis by the MTT assay and Hoechst staining. A serine/threonine kinase inhibitor attenuated this protection. G. elata resulted in phosphorylation and dephosphorylation of ERK1/2 and JNK1/2-p38 MAPKs (members of the serine/threonine kinase family), respectively, as revealed by Western blot analysis. An upstream ERK inhibitor attenuated G. elata-induced ERK phosphorylation but not protective effect. Although JNK and p38 inhibitors attenuated their related enzyme activities during serum deprivation, only JNK inhibitor prevented serum-deprived apoptosis. Thus, G. elata prevents serum-deprived apoptosis through activation of the serine/threonine kinase-dependent pathway and suppression of JNK activity.
 ...
PMID:Gastrodia elata prevents rat pheochromocytoma cells from serum-deprived apoptosis: the role of the MAPK family. 1526 68

When cultured cerebellar granule neurones are transferred from a medium containing high extracellular potassium concentration ([K+]e) (25 mm) to one with lower [K+]e (5 mm), caspase-3 activity is induced and cells die apoptotically. In contrast, if cells in non-depolarizing conditions are treated with brain-derived neurotrophic factor (BDNF), caspase-3 activity, chromatin condensation and cell death are markedly diminished. In this study, we show that the C-terminal domain of the tetanus toxin heavy-chain (Hc-TeTx) is able to produce the same neuroprotective effect, as assessed by reduction of tetrazolium salts and by chromatin condensation. Hc-TeTx-conferred neuroprotection appears to depend on phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase, as is demonstrated by the selective inhibitors Wortmannin and PD98059, respectively. Hc-TeTx also induces phosphorylation of the tyrosine kinase BDNF receptor, activation of p21Ras in its GTP-bound form, and phosphorylation of the cascade including extracellular-signal-regulated kinases-1/2 (ERK-1/2), p90 ribosomal S6 kinase (p90rsk) and CREB (cAMP-response-element-binding protein). On the other hand, activation of the Akt pathway is also detected, as well as inhibition of the active form of caspase-3. These results point to an implication of both PI3K- and ERK-dependent pathways in the promotion of cerebellar granule cell survival by Hc-TeTx.
 ...
PMID:The C-terminal domain of the heavy chain of tetanus toxin rescues cerebellar granule neurones from apoptotic death: involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. 1531 77


1 2 Next >>