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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Short-term activated peripheral T lymphocytes are susceptible to apoptotic cell death triggered by CD2 mAbs. The aim of this study was to examine whether the CD2-mediated pathway of apoptosis is linked to the Fas death pathway, as this is the case for CD3/TCR-triggered apoptosis in several models of T cells. Using T lymphocytes from patients harboring Fas gene mutations and displaying a profound defect in Fas signaling of cell death, we show that CD2- (but not CD3-) mediated apoptosis still proceeds normally. In normal activated T cells, CD3-mediated apoptosis is prevented by reagents that block the Fas/Fas-ligand interaction, namely soluble M3 (an antagonistic anti-Fas mAb) and soluble human Fas.Fc, a fusion protein able to bind released Fas-ligand. In contrast, CD2 signaling of apoptosis resists these blocking agents. Neither new protein synthesis nor the activation of calcineurin was required for CD2- and Fas-mediated apoptosis, suggesting that latent cytoplasmic "death" molecules were activated upon stimulation of the cells. In both cases, protein tyrosine kinases were transiently activated, as is exemplified by the autophosphorylation and exokinase activity of p56lck, yielding overlapping yet nonidentical profiles of protein tyrosine phosphorylation. Pretreating the cells with herbimycin A, before the addition of the apoptotic stimuli, almost completely inhibited CD2 transmembrane signaling of apoptosis, but left intact Fas-induced apoptosis. Our data suggest that CD2 is a Fas-independent cell death pathway that might contribute directly to the elimination of T cells expanding during an immune reaction.
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PMID:CD2-induced apoptosis in activated human peripheral T cells: a Fas-independent pathway that requires early protein tyrosine phosphorylation. 861 39

The most evident immunosuppressive effect of cyclosporin A (CsA) on T cells is suppression of interleukin-2 (IL-2) production through the suppression of type-2B serine/threonine-specific phosphatase, calcineurin. To test whether suppression of IL-2 production is a major mechanism of CsA-mediated suppression of allograft rejection, we treated allogeneic skin-grafted mice with CsA and IL-2, and observed that IL-2 did not override the suppressive effect of CsA. Specific cytotoxic T lymphocyte (CTL) activity and natural killer (NK) activity of the spleens were increased by treatment with IL-2, and CsA significantly suppressed the killing activity. We also found that CsA-treatment decreased the expression of lck kinase of T cells and the production of IL-2 in response to concanavalin A (ConA), with minimum effect on IL-4 production. These results suggest that T cell dysfunctions other than decreased production of IL-2 are essential for suppressive effect of CsA on skin allograft rejection.
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PMID:Interleukin-2 does not overcome suppression of graft rejection by cyclosporin A: effect of cyclosporin A on T cell properties in vivo. 891 87

Recently, TAP42 was isolated as a high copy suppressor of sit4-, a yeast phosphatase related to protein phosphatase 2A (PP2A). TAP42 is related to the murine alpha4 protein, which was discovered independently by its association with Ig-alpha in the B cell receptor complex. Herein we show that a glutathione S-transferase (GST)-alpha4 fusion protein bound the catalytic subunit (C) of human PP2A from monomeric or multimeric preparations of PP2A in a "pull-down" assay. In an overlay assay, the GST-alpha4 protein bound to the phosphorylated and unphosphorylated forms of C that were separated in two-dimensional gels and immobilized on filters. The results show direct and exclusive binding of alpha4 to C. This is unusual because all known regulatory B subunits, or tumor virus antigens, bind stably only to the AC dimer of PP2A. The alpha4-C form of PP2A had an increased activity ratio compared with the AC form of PP2A when myelin basic protein phosphorylated by mitogen-activated protein kinase and phosphorylase a were used as substrates. Recombinant alpha4 cleaved from GST was phosphorylated by p56(lck) tyrosine kinase and protein kinase C. A FLAG-tagged alpha4 expressed in COS7 cells was recovered as a protein containing phosphoserine and coimmunoprecipitated with the C but not the A subunit of PP2A. Treatment of cells with rapamycin prevented the association of PP2A with FLAG-alpha4. The results reveal a novel heterodimer alpha4-C form of PP2A that may be involved in rapamycin-sensitive signaling pathways in mammalian cells.
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PMID:B cell receptor-associated protein alpha4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. 938 Jun 85

TCR down-regulation plays an important role in modulating T cell responses both during T cell development and in mature T cells. Down-regulation of the TCR is induced by engagement of the TCR by specific ligands and/or by activation of protein kinase C (PKC). We report here that ligand- and PKC-induced TCR down-regulation is mediated by two distinct, independent mechanisms. Ligand-induced TCR down-regulation is dependent on the protein tyrosine kinases p56(lck) and p59(fyn) but independent of PKC and the CD3gamma leucine-based (L-based) internalization motif. In contrast, PKC-induced TCR down-regulation is dependent on the CD3gamma L-based internalization motif but independent of p56(lck) and p59(fyn). Finally, our data indicate that in the absence of TCR ligation, TCR expression levels can be finely regulated via the CD3gamma L-based motif by the balance between PKC and serine/threonine protein phosphatase activities. Such a TCR ligation-independent regulation of TCR expression levels could probably be important in determining the activation threshold of T cells in their encounter with APC.
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PMID:Two distinct pathways exist for down-regulation of the TCR. 964 32

This study investigates the second messengers involved in NF-kappaB activation by the bisperoxovanadium (bpV) phosphotyrosyl phosphatase inhibitors. We first initiated a time course analysis of bpV-mediated activation of the human immunodeficiency virus type-1 long terminal repeat- and NF-kappaB-driven reporter gene. Our results showed a slower and more transient activation of both kappaB-regulated luciferase-encoding vectors by bpV compounds when compared with the action of tumor necrosis factor-alpha (TNF). Time course analyses of NF-kappaB translocation by shift assay experiments further confirmed these results, hence implying distinct pathways of NF-kappaB activation for bpV compounds and TNF. Attempts to characterize the bpV-dependent signaling cascade revealed that the src family protein tyrosine kinase p56(lck) was critical for NF-kappaB induction by bpV. Furthermore, p56(lck) interaction with the intracytoplasmic tail of CD4 markedly enhanced such induction. Optimal activation of NF-kappaB following bpV treatment necessitated downstream effectors of p56(lck) such as the syk family protein tyrosine kinase ZAP-70 and the molecular adaptor SLP-76. Importantly, reduced NF-kappaB activation was observed when capacitative calcium entry was deficient but also upon pharmacological inhibition of calmodulin and calcineurin. Altogether, these results suggest that induction of NF-kappaB by phosphotyrosyl phosphatase bpV inhibitors necessitates both proximal and distal effectors of T cell activation.
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PMID:p56(lck), ZAP-70, SLP-76, and calcium-regulated effectors are involved in NF-kappaB activation by bisperoxovanadium phosphotyrosyl phosphatase inhibitors in human T cells. 1057 81

Exposure to type I interferons (IFN) increased estrogen receptor (ER) ligand binding and induced protein kinase C (PKC) translocation within 30 min but had no effect on net incorporation of [32P] into ER in Madin Darby bovine kidney (MDBK) cells. Ligand binding was also increased within 30 min by phorbol ester and the protein phosphatase inhibitor okadaic acid. Mitogen-activated protein (MAP) kinase phosphorylation was initially inhibited between 2 and 30 min and subsequently activated between 30 and 60 min after treatment with IFN. The activatory response was blocked by the PKC inhibitor Ro 31-8220. Following transient transfection with an ERE-CAT reporter construct, IFN increased CAT expression after 6 h but decreased ER ligand binding, transcriptional activity and phosphorylation after 48 h, probably as a result of decreased ER concentrations. The results rule out rapid activation of ER ligand binding through phosphorylation at Ser118 by MAP kinase because (1) the increase in ligand binding preceded activation of MAP kinase, and (2) IFN had no short-term effect on [32P]incorporation or ER transcriptional activity. The rapid effect of IFN on ER ligand binding is postulated to reflect phosphorylation of the receptor at Tyr537 by p56lck, a member of the Src family of PKC-activated tyrosine kinases.
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PMID:Acute effects of interferon on estrogen receptor function do not involve the extracellular signal-regulated kinases p42mapk and p44mapk. 1071 59

The T cell hybridoma "171", which lacks CD4 but expresses T cell receptor (TCR) for hen egg white lysozyme, requires introduction of wild-type CD4 for antigen-mediated induction and secretion of interleukin-2 (IL-2). Mutant CD4, which fails to associate with the tyrosine kinase p56lck does not support IL-2 secretion, suggesting that a role of CD4 is to bring cytoplasmic p56lck into alignment for signal transduction to the IL-2 promotor. Using 171, 171-CD4 (wild-type) and 171-CD4 (mutant), we found that IL-2 secretion was inhibited by FK 506 and cyclosporin but not by rapamycin. However, this inhibition was not associated with calcium fluxes since no change in cytoplasmic free calcium levels ([Ca]i; resting level 80 nM) was detectable during antigen stimulation of the 171 or 171-CD4 cells. Thus, although FK 506 and cyclosporin inhibited calcium-dependent signalling to the IL-2 promoter via inhibition of the protein phosphatase calcineurin, it is possible that IL-2 induction via TCR/CD4 requires an FK 506 (and cyclosporin) sensitive step which is independent of cytoplasmic calcium changes.
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PMID:FK 506 and cyclosporin each block antigen-induced T cell receptor signalling that is dependent on CD4 co-receptor and operates in the absence of detectable cytoplasmic calcium fluxes. 1127 4

Selectins are mediating transient contacts of leukocytes with endothelium during inflammatory processes and in the development of the immune system. L-selectin expressed on almost all leukocytes also functions as a signaling receptor. Recently, we have identified different signaling pathways in T lymphocytes by L-selectin. One signaling cascade leads via the tyrosine kinase p56lck to the small G-proteins Ras and Rac and to MAP-kinases. A second independent pathway results in ceramide release. In this study, an L-selectin-induced translocation of the transcription factor NFAT to the nucleus was identified. Using genetically modified JCaM1.6 cells, pharmacological inhibitors, and antisense molecules, it was shown that L-selectin-induced NFAT activation depends on src-tyrosine kinases, calcineurin and small G-proteins. MAP-kinases and actin filaments were identified as Ras effectors involved in NFAT translocation. We conclude that L-selectin cross-linking results in activation of NFAT by different signaling pathways. The activation of NFAT might modulate the immune response of leukocytes interacting with endothelial cells.
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PMID:Mechanisms of L-selectin-induced activation of the nuclear factor of activated T lymphocytes (NFAT). 1184 96

The human major histocompatibility complex (HLA) encodes two sets of HLA class I molecules, which have been termed class Ia (or classical) and class Ib (or nonclassical) molecules. The class Ia molecules include the gene products of HLA-A, HLA-B, and HLA-C loci and are characterized by broad tissue expression and by a high degree of polymorphism. The class Ib molecules include the gene products of HLA-E, HLA-F, and HLA-G loci and are characterized by a restricted tissue distribution and by limited polymorphism. Besides being expressed on nucleated cells, classical and nonclassical HLA class I molecules are present in serum in soluble form (sHLA-I). The serum level of sHLA-I molecules is significantly increased in a variety of physiological and pathological conditions such as pregnancy, acute rejection episodes following organ allografts, acute graft-versus-host-disease (GVHD) following bone marrow transplantation, autoimmune diseases, viral infections, and malignant melanoma. Because of the statistically significant association with clinical parameters, the level of sHLA-I antigens has been suggested to represent a useful marker to predict the evolution of viral infections and to monitor the clinical course of allografts. Moreover, elevated levels of functional sHLA-I and soluble Fas-ligand molecules have been detected by our group in blood components and might play a role in the immunomodulatory effect of autologous and allogeneic transfusions. Several lines of evidence suggest that sHLA-I molecules are immunologically functional and may play an immunoregulatory role. In fact, they have been shown to elicit antibodies in both allogeneic and xenogeneic combinations, to inhibit the activity of alloreactive cytotoxic T lymphocytes (CTL), and to induce apoptosis in alloreactive and virus-specific CTL, in activated autologous and allogeneic CD8+ T cells, and in CD8+ NK cells. There is general agreement about the mechanism underlying the inhibition of CTL activity by sHLA antigens. This inhibition appears to be mediated by interactions of sHLA-I antigens a1 and a2 domains with T cell receptor (TCR). By contrast, there is conflicting information about the mechanism underlying induction of apoptosis of activated T cells by sHLA-I antigens. Several authors reported that sHLA-I molecules induced apoptosis of alloreactive CD8+ cytotoxic T lymphocytes through interaction with their TCR. However, our own data and those other groups indicate that classical and nonclassical sHLA-I molecules trigger Fas/Fas-ligand mediated apoptosis of phytohemoagglutinin (PHA)-activated and virus-specific CD8+ T lymphocytes as well as of CD8+ NK cells by interacting with CD8 coreceptor. Recently, we performed a series of experiments in our laboratory to clarify the intracellular mechanism(s) leading to Fas-ligand upregulation and secretion. These unpublished data indicate that sHLA-I/CD8 ligation elicits the phosphorylation of p56lck protein thyrosin kinase (PTK) associated with CD8 cytoplasmic domain in the absence of any other TCR-derived signal, the activation of syk-like ZAP-70 PTK and protein kinase C, and extracellular calcium influx. Then, activation and nuclear translocation of NF-kB and NF-AT occurs, leading to Fas-ligand mRNA transcription and soluble Fas-ligand secretion, which delivers the death signal. Interestingly, soluble Fas-ligand secretion and CD8+ cell apoptosis, but not CD8+ cell cytolitic activity, are completely inhibited by Cyclosporin A, which specifically blocks the activation of the calcineurin/calmodulin pathway. Taken together, these data suggest that sHLA-I molecules are involved in a signal-transduction pathway leading to Fas-ligand expression, soluble Fas-ligand secretion, and CD8+ cells apoptosis.
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PMID:Soluble HLA class I molecules/CD8 ligation trigger apoptosis of CD8+ cells by Fas/Fas-ligand interaction. 1280 26

Interactions of membrane proteins are important in various aspects of cell function. However, weak membrane protein-protein interactions are difficult to study using techniques such as co-immunoprecipitations. CD4 is a cell surface protein involved in T cell activation and the binding of the human immunodeficiency virus to HIV target cells. Here we report the use of cross-linking followed by affinity purification of CD4 in combination with mass spectrometry for identification of proteins that are in the proximity of CD4. Besides the components of the CD4 receptor complex, CD4 and lck, we have identified by tandem mass spectrometry 17 tryptic peptides from transferrin receptor CD71, three peptides from protein phosphatase CD45, and one peptide from 4F2 lymphocyte activation antigen CD98. The efficiency of the cross-linking did not correlate with the level of cell surface expression of the detected molecules, excluding a possible bias of the cross-linking toward the most abundant cell surface molecules. Whereas the association of CD4 with CD45 has been reported, the associations with CD71 and CD98 have not been previously described. We used small-scale immunoprecipitation after cross-linking in combination with fluorescence resonance energy transfer (FRET) measurements to investigate the association between CD4 and CD71. Our data show that CD71 self-associates on the cell surface, that a small fraction of CD4 can be detected by copurifying it with CD71 after cross-linking, and that the level of association between CD4 and CD71 significantly increases after phorbol 12-myristate 13-acetate-induced endocytosis of CD4. This suggests that a small fraction of CD4 associates with clusters of CD71. As both molecules undergo endocytic recycling, the association and cross-linking result from their clustering in the same pit and/or vesicle. The CD4-CD98 association probably results from nonspecific cross-linking.
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PMID:Lateral membrane protein associations of CD4 in lymphoid cells detected by cross-linking and mass spectrometry. 1470 53


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