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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported the isolation of a cDNA encoding a T cell-specific adapter protein (TSAd). Its amino acid sequence contains an SH2 domain, tyrosines in protein binding motifs, and proline-rich regions. In this report we show that expression of TSAd is induced in normal peripheral blood T cells stimulated with anti-CD3 mAbs or anti-CD3 plus anti-CD28 mAbs. Overexpression of TSAd in Jurkat T cells interfered with TCR-mediated signaling by down-modulating anti-CD3/PMA-induced IL-2 promoter activity and anti-CD3 induced Ca2+ mobilization. The TCR-induced tyrosine phosphorylation of phospholipase C-gamma1, SH2-domain-containing leukocyte-specific phosphoprotein of 76kDa, and linker for activation of T cells was also reduced. Furthermore, TSAd inhibited Zap-70 recruitment to the CD3zeta-chains in a dose-dependent manner. Consistent with this, Lck kinase activity was reduced 3- to 4-fold in COS-7 cells transfected with both TSAd and Lck, indicating a regulatory effect of TSAd on Lck. In conclusion, our data strongly suggest an inhibitory role for TSAd in proximal T cell activation.
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PMID:T cell-specific adapter protein inhibits T cell activation by modulating Lck activity. 1097 97

The GTPase Rac controls signaling pathways often related to actin polymerization in various cell types. In T lymphocytes, Rac is activated by Vav, a major component of the multiprotein transduction complex associated to the TCR. Although profound signaling defects have been observed in Vav-deficient mice, a role of Rac in the corresponding early TCR signaling has not been tested directly. This question was investigated in Jurkat T cells transfected with either a dominant-negative (RacN17) or a constitutively active (RacV12) form of Rac. In T cells expressing either RacN17 or RacV12, the anti-CD3-induced Ca2+ response and production of inositol-1,4,5-trisphosphate were inhibited. The basal level of phosphatidylinositol-4,5-bisphosphate was not significantly diminished by Rac mutants. The major inhibitory effect of Rac mutants on Ca2+ signaling is exerted on the activity of phospholipase C-gamma and, before that, on the phosphorylation of ZAP-70 and of the linker molecule for activation of T cells, LAT. An anti-CD3-induced increase in actin polymerization was observed in control cells but not in cells transfected with a Rac mutant. In addition, latrunculin, which binds to monomeric actin, simultaneously inhibited basal and CD3-induced actin polymerization and Ca2+ signaling. These findings suggest a link between the effects exerted by Rac mutants on cortical actin polymerization and on TCR signaling. Rac cycling between its GTP- and GDP-bound states is necessary for this signaling. Alterations observed in early TCR-dependent signals suggest that Rac contributes to the assembly of the TCR-associated multiprotein transduction complex.
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PMID:Rac is involved in early TCR signaling. 1097 33

Peripheral T lymphocyte activation in response to TCR/CD3 stimulation is reduced in type 1 diabetic patients. To explore the basis of this deficiency, a comprehensive analysis of the signal transduction pathway downstream of the TCR/CD3 complex was performed for a cohort of patients (n = 38). The main result of the study shows that T cell hyporesponsiveness is positively correlated with a reduced amount of p56(lck) in resting T lymphocytes. Upon CD3-mediated activation, this defect leads to a hypophosphorylation of the CD3zeta-chain and few other polypeptides without affecting the recruitment of ZAP70. Other downstream effectors of the TCR/CD3 transduction machinery, such as phosphatidylinositol 3-kinase p85alpha, p59(fyn), linker for activation of T cells (LAT), and phospholipase C-gamma1, are not affected. In some patients, the severity of this phenotypic deficit could be linked to low levels of p56(lck) mRNA and resulted in the failure to efficiently induce the expression of the CD69 early activation marker. We propose that a primary deficiency in human type 1 diabetes is a defect in TCR/CD3-mediated T cell activation due to the abnormal expression of the p56(lck) tyrosine kinase.
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PMID:Specific deficiency of p56lck expression in T lymphocytes from type 1 diabetic patients. 1106 48

TCR- but not CD2-triggered IL-2 production is p56(lck) dependent. To test the hypothesis that p59(fyn), a second src-family protein tyrosine kinase (PTK) expressed in T lymphocytes, might be an essential upstream component of the CD2 signaling pathway, we generated human (h) CD2 transgenic (tg) fyn(+/+) and fyn(-/-) mice. Clustering of hCD2 molecules on resting peripheral T lymphocytes results in Ca(2+) mobilization, activation of MAPK and cellular proliferation. In contrast, in the absence of p59(fyn), these CD2-initiated activities are markedly reduced, while TCR-triggered proliferation is unaffected. Several CD2 pathway components regulated by p59(fyn) have been identified including phospholipase C-gamma1 (PLC-gamma1), Vav, protein kinase C-theta isoform (PKC-theta), docking protein (Dok), focal adhesion kinase (FAK) and Pyk2. Decreased inducible PKC-theta catalytic activity and Vav phosphorylation likely account for diminished p38 and JNK activation in hCD2tg fyn(-/-) mice. Moreover, deficiency in fyn-dependent PLC-gamma1 catalytic activity may contribute to reduced PKC-alpha-dependent ERK activation. Of note, CD2-dependent Dok but not linker from activated T cells (LAT) tyrosine phosphorylation requires p59(fyn). Furthermore, that FAK and Pyk2 are target substrates implies that p59(fyn) may be an important regulator of T cell adhesion as well. Collectively, these data identify p59(fyn) as a key PTK in CD2-mediated activation of mature T lymphocytes.
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PMID:A critical role for p59(fyn) in CD2-based signal transduction. 1109 70

Rheumatoid arthritis (RA) synovial fluid (SF)-T lymphocytes appear relatively inactive in situ and respond only weakly to diverse stimuli ex vivo. To characterize the molecular defects underlying this hyporesponsiveness we analyzed the expression level of several proteins involved in TCR-proximal signal transduction. As compared to peripheral blood (PB)-T lymphocytes, SF-T cells from some (but not all) of the patients analyzed expressed lower levels of TCRalphabeta, CD3epsilon, TCRzeta, p56(lck) and LAT, while p59(fyn), phospholipase C-gamma1 and ZAP-70 expression was unaltered. Semi-quantitative analysis of T cells from several patients revealed that the degree of TCRzeta chain and p56(lck) modulation correlated statistically significantly with the level of SF-T cell hyporesponsiveness. The differential reactivity of p56(lck) specific monoclonal and polyclonal antibodies in SF-T but not PB-T lymphocytes indicated that p56(lck) modulation consists of a conformational change rather than loss of expression. Our results indicate that multiple signaling molecules can be modulated in RA SF-T cells and show for the first time a direct quantitative correlation between T cell hyporesponsiveness and modulation of TCRzeta and of p56(lck), a critical protein tyrosine kinase required for T cell activation.
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PMID:A potential role for protein tyrosine kinase p56(lck) in rheumatoid arthritis synovial fluid T lymphocyte hyporesponsiveness. 1122 99

The cytotoxic activity of NK cells is regulated by class I MHC proteins. Although much has been learned about NK recognition of class I autologous targets, the mechanisms of NK self-tolerance are poorly understood. To examine the role of a nonpolymorphic, ubiquitously expressed class Ib Ag, Q9, we expressed it on class I-deficient and NK-sensitive B78H1 melanoma. Presence of this Qa-2 family member on tumor cells partially protected targets from lysis by bulk lymphokine-activated killer (LAK) cells. H-2K(b)-expressing B78H1 targets also reduced LAK cell activity, while H-2D(b) offered no protection. Importantly, blocking with F(ab')(2) specific for Q9 or removal of this GPI-attached molecule by phospholipase C cleavage restored killing to the level of vector-transfected cells. Experiments with LAK cells derived from H2(b) SCID and B6 mice established that NK1.1(+)TCR(-) NK and NK1.1(+)TCR(+) LAK cells were the prevalent cytolytic populations inhibitable by Q9. Treatment of mice with poly(I:C) also resulted in generation of Q9-regulated splenic cytotoxicity. LAK cells from different mouse strains responded to Q9, suggesting that the protective effect of this molecule is not detectably influenced by Ly49 polymorphisms or the presence/absence of Q9 in NK-harboring hosts. We propose that Q9 expressed on melanoma cells serves as a ligand for yet unidentified NK inhibitory receptor(s) expressed on NK1.1(+) NK/T cells.
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PMID:The nonclassical major histocompatibility complex molecule Qa-2 protects tumor cells from NK cell- and lymphokine-activated killer cell-mediated cytolysis. 1185 6

The Tec family tyrosine kinase Itk is critical for efficient signaling downstream of the TCR. Biochemically, Itk is directly phosphorylated and activated by Lck. Subsequently, Itk activates phospholipase C-gamma1, leading to calcium mobilization and extracellular signal-regulated kinase/mitogen-activated protein kinase activation. These observations suggested that Itk might play an important role in positive selection and CD4/CD8 lineage commitment during T cell development in the thymus. To test this, we crossed Itk-deficient mice to three lines of TCR transgenics and analyzed progeny on three different MHC backgrounds. Analysis of these mice revealed that fewer TCR transgenic T cells develop in the absence of Itk. In addition, examination of multiple T cell development markers indicates that multiple stages of positive selection are affected by the absence of Itk, but the T cells that do develop appear normal. In contrast to the defects in positive selection, CD4/CD8 lineage commitment seems to be intact in all the TCR transgenic itk(-/-) lines tested. Overall, these data indicate that altering TCR signals by the removal of Itk does not affect the appropriate differentiation of thymocytes based on their MHC specificity, but does impact the efficiency with which thymocytes complete their maturation process.
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PMID:The absence of Itk inhibits positive selection without changing lineage commitment. 1205 26

Natural killer (NK) cells participate in both innate and adaptive immunity through the prompt secretion of cytokines and ability to lyse virally infected cells or tumor cells. Although it has been well understood that lipid rafts (rafts) and a raft-associated linker for activation of T cells (LAT) plays a central role in TCR signal transduction, there are still great gaps in our knowledge of the molecular events involved in NK cell activation. We show here that CD2 and rafts became polarized to the site of NK cell activation by CD2 cross-linking or target cell binding using confocal microscopy, and LAT and a significant amount of CD2 colocalized in raft fractions of sucrose-density gradient from an NK cell line, NK3.3. CD2 cross-linking strongly induced tyrosine phosphorylation of LAT, resulting in increased association with phosphatidylinositol 3-kinase (PI 3-K) and phospholipase C-gamma1 (PLC-gamma1). In vitro binding studies using glutathione S-transferase fusion proteins demonstrated that a large portion of the association between LAT and PI 3-K or PLC-gamma1 was mediated through their SH2 domains in tyrosine phosphorylation-dependent manner. Furthermore, disruption of lipid rafts by cholesterol depletion from cell membranes using methyl-beta-cyclodextrin markedly reduced LAT tyrosine phosphorylation and NK cell functions, including cytotoxicity and granule exocytosis. These results document that modulation of raft integrity by aggregation of NK cell activating receptors, which leads to the formation of complexes of LAT with PI 3-K and PLC-gamma1, is essential for the NK cell lytic mechanisms.
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PMID:Lipid rafts as the signaling scaffold for NK cell activation: tyrosine phosphorylation and association of LAT with phosphatidylinositol 3-kinase and phospholipase C-gamma following CD2 stimulation. 1220 31

Linker for activation of T cells (LAT) is a membrane-associated adaptor protein that is phosphorylated on multiple tyrosines upon TCR cross-linking. Previous studies show that LAT is essential for TCR-mediated signaling and thymocyte development. In this study, we expressed a series of LAT Tyr to Phe mutants in LAT-deficient J.CaM2.5 cells and examined their tyrosine phosphorylation; association with Grb2, Gads, and phospholipase C (PLC)-gamma1; and function in T cell activation. Our results showed that the five membrane-distal tyrosines were phosphorylated upon T cell activation. Grb2, Gads, and PLC-gamma1 associated with LAT preferentially via different sets of tyrosine residues; however, they failed to interact with LAT mutants containing only one tyrosine. We also determined the minimal requirement of LAT tyrosine residues in T cell activation and thymocyte development. Our results showed that a minimum of three tyrosines is required for LAT to function in T cell activation and thymocyte development. LAT mutants that were capable of binding Grb2 and PLC-gamma1 could reconstitute T cell activation in LAT-deficient cells and thymocyte development in LAT-deficient mice.
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PMID:Minimal requirement of tyrosine residues of linker for activation of T cells in TCR signaling and thymocyte development. 1249 16

Ag receptor engagement without costimulation induces a tolerant state in CD4(+) T cells termed anergy. Anergic CD4(+) T cells are primarily characterized by the inability to produce IL-2, but the biochemical basis for this functional defect is not completely understood. We demonstrate that primary CD4(+) T cells anergized by costimulatory blockade exhibit impaired TCR-coupled phospholipase C (PLC)gamma-1 activation. This defect is associated with the marked reduction of multiple downstream signaling events required for IL-2 transcription, including mobilization of intracellular Ca(2+) and activation of the mitogen-activated protein kinase cascade. We also found that primary anergic CD4(+) T cells fail entirely to modulate their integrin binding avidity in response to TCR stimulation. Integrin avidity modulation is required for full T cell activation and effector function, and as we show in this study, is completely dependent upon PLCgamma-1 activity. Finally, analogs that mimic the actions of diacylglycerol and inositol 1,4,5-triphosphate, the immediate products of PLCgamma-1 activity, restored integrin avidity modulation and IL-2 production by anergic T cells. Thus, deficient coupling of PLCgamma-1 to the TCR appears to be a central biochemical defect that could potentially account for the failure of multiple functional responses in primary anergic CD4(+) T cells.
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PMID:Regulation of T cell activation and tolerance by phospholipase C gamma-1-dependent integrin avidity modulation. 1268 43


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