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 have previously shown that T cells from rats exposed chronically to cigarette smoke or nicotine (NT) exhibit T cell anergy and decreased proliferation to T cell mitogens. Effects of chronic NT on T cell function persist for at least 2 weeks after the termination of NT treatment. Moreover, these effects of NT are causally related to the decreased Ca(2+) response to T cell receptor (TCR) ligation and constitutive activation of protein tyrosine kinase (PTK) and phospholipase C (PLC)-gamma1 activities. Acute NT treatment also suppresses the Con A-induced T cell proliferation; however, it is not known whether the mechanism(s) by which acute and chronic NT treatments inhibit T cell proliferation are identical. To evaluate this question, LEW rats were acutely treated with NT (1 mg/kg body wt) for 1, 2, or 24 h by an ip injection or implanted with constant-release miniosmotic pumps containing saline or NT (1 mg/kg body wt/day) for a 3-week chronic exposure. Inhibition of Con A-induced proliferation of peripheral blood cells (PBC) by both acute and chronic treatments was reversed by the inhibitor of nicotinic acetylcholine receptors, mecamylamine (MEC), indicating that these receptors are required for T cell proliferation. However, the effect of acute NT on the Con A response was short lived (i.e., observed at 1 and 2 h but not at 24 h after NT administration) and was seen in PBC but not in spleen cells. Unlike the chronic treatment, acute NT administration neither suppressed significantly the TCR-mediated [Ca(2+)](i) response nor did it cause the constitutive activation of PTK and PLC-gamma1 activities in blood lymphocytes. Acute, but not chronic, NT administration increased the plasma corticosterone concentration, and this increase was also inhibited by MEC. Moreover, adrenalectomy abrogated the acute but not chronic NT effects on the Con A response. Thus, the acute and chronic effects of NT on T lymphocytes are mechanistically distinct phenomena. Whereas chronic administration of NT causes T cell anergy, acute effects are primarily mediated via the activation of the hypothalamus-pituitary-adrenal axis.
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PMID:Acute and chronic nicotine exposures modulate the immune system through different pathways. 1073 45

To investigate the roles of various hematopoietic cell-specific adapter proteins in T cell receptor (TCR)-signaling leading to nuclear factor of activated T cell (NF-AT) and nuclear factor of kappaB (NF-kappaB) activation, we reconstituted TCR-signaling with CD8/zeta, various protein tyrosine kinases (PTKs), and adapter proteins in a non-lymphoid cell line, 293T. We show that SLP-76 and BLNK, but not LAT, effectively co-operated with Syk and Tec family PTKs to activate NF-AT and NF-kappaB. We also show that Tec family PTKs enhanced endogenous phospholipase C (PLC)-gamma1 phosphorylation induced by CD8/zeta and Syk in 293T cells. These results imply that PLC-gamma1 may play a critical role in a hematopoietic cell-specific adapter protein-mediated NF-AT and NF-kappaB activation in a non-lymphoid cell.
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PMID:Hematopoietic cell-specific adapter proteins, SLP-76 and BLNK, effectively activate NF-AT as well as NF-kappaB by Syk and Tec PTKs in non-lymphoid cell lines. 1124 Jan 41

The linker for activation of T cells (LAT) is essential for signaling through the T cell receptor (TCR). Following TCR stimulation, LAT becomes tyrosine-phosphorylated, creating docking sites for other signaling proteins such as phospholipase C-gamma(1) (PLC-gamma(1)), Grb2, and Gads. In this study, we have attempted to identify the critical tyrosine residues in LAT that mediate TCR activation-induced mobilization of intracellular Ca(2+) and activation of the MAP kinase Erk2. By using the LAT-deficient Jurkat derivative, J.CaM2, stable cell lines were established expressing various tyrosine mutants of LAT. We show that three specific tyrosine residues (Tyr(132), Tyr(171), and Tyr(191)) are necessary and sufficient to achieve a Ca(2+) flux following TCR stimulation. These tyrosine residues function by reconstituting PLC-gamma(1) phosphorylation and recruitment to LAT. However, these same tyrosines can only partially reconstitute Erk activation. Full reconstitution of Erk requires two additional tyrosine residues (Tyr(110) and Tyr(226)), both of which have the Grb2-binding motif YXN. This reconstitution of Erk activation requires that the critical tyrosine residues be on the same molecule of LAT, suggesting that a single LAT molecule nucleates multiple protein-protein interactions required for optimal signal transduction.
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PMID:Identification of the minimal tyrosine residues required for linker for activation of T cell function. 1139 91

Calcium signaling was observed in murine T cells over time, starting at a precise moment of contact with a layer of fibroblasts expressing a stimulatory major histocompatibility class II-peptide complex. The contact was controlled by a film-thinning apparatus. Intracellular calcium levels were followed with the ratiometric dye, Fura-2. The calcium response was highly synchronized and well fitted by a mathematical model. The model includes three components: a sequence of reactions occurring after T cell receptor (TCR) triggering; InsP3-mediated calcium release from intracellular stores (Meyer and Stryer, Proc. Natl. Acad. Sci. USA 85: 5051-5055, 1988); and slow changes in levels phospholipase C-gammal (PLCgammal) reflecting a decrease in receptor triggering rate. Each component in the model controls a different part of the response-the initial delay, the sharp rise, and the slow decay, respectively. Kinetic parameters determined from curve fitting were the initial delay in calcium signaling defined as the time when [PLCgammal] reached its half of its maximum (76 s), the coefficient characterizing calcium efflux from endoplasmic reticulum (ER) (2.86 microM s(-1), expressed per liter of cell volume), and a rate constant characterizing the diminishing yield of production of PLCgammal (0.00046 s(-1)) by active TCR. Only the parameter representing PLCgammal production varied much from cell to cell.
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PMID:Modeling of early events in T cell signal transduction after controlled T cell activation by peptide major histocompatibility complex. 1140 Jul 19

In Jurkat T lymphocytes, hydrogen peroxide (H(2)O(2)) potentiates the phosphorylation level of extracellular signal-regulated kinase 1 and 2 (ERK1/2) caused by T cell receptor (TCR) stimulation with anti-CD3 and anti-CD28 or anti-CD3 alone. Submillimolar concentrations of H(2)O(2)-induced phosphorylation of ERK1/2 and MAP/ERK kinase 1 and 2 (MEK1/2) without antigenic stimulation. H(2)O(2) also induced the electrophoretic mobility shift of Lck from 56 to 60 kDa. The MEK inhibitor, PD98059 attenuated ERK1/2 and MEK1/2 phosphorylation, as well as the migration shift of Lck induced by H(2)O(2). The phospholipase C (PLC) inhibitor, U73122, and EGTA reduced the phosphorylation of both ERK1/2 and MEK1/2 induced by H(2)O(2). Interestingly, an increase of intracellular cAMP level with forskolin or 8-(4-chlorophenylthio)-cAMP augmented ERK1/2 phosphorylation by H(2)O(2), while inhibiting MEK1/2 phosphorylation by H(2)O(2). These results demonstrate an alternative pathway that results in augmentation of ERK1/2 phosphorylation without concomitant MEK1/2 phosphorylation in T cells.
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PMID:cAMP potentiates H(2)O(2)-induced ERK1/2 phosphorylation without the requirement for MEK1/2 phosphorylation. 1149 22

Adaptor proteins lack catalytic activity and contain only protein-protein interaction domains. They have been shown to interact with an ever-growing number of signaling proteins and to play essential roles in many signaling pathways. SLP-76 and LAT are cell-type-specific adaptor proteins expressed in T cells, NK cells, platelets, and mast cells. In these cell types, SLP-76 and LAT are required for signaling by immunoreceptor tyrosine-based activation motif(ITAM)-containing receptors, including the T cell receptor (TCR), the pre-TCR, the high-affinity Fc epsilon receptor, and the platelet GPVI collagen receptor. In B cells, an analogous adaptor, BLNK/SLP-65, is required for signaling by the ITAM-containing B cell receptor. This review summarizes recent research on SLP-76, LAT, and BLNK. A major challenge in understanding adaptor protein function has been to sort out the many interactions mediated by adaptor proteins and to define the mechanisms by which adaptors mediate critical signaling events. In the case of LAT, SLP-76, and BLNK, the availability of tractable genetic systems, deficient in expression of each of these adaptor proteins, has facilitated in-depth investigation of their signaling functions and mechanisms of action. The picture that has emerged is one in which multiple adaptor proteins cooperate to bring about the formation of a large signaling complex, localized to specialized lipid microdomains within the cell membrane and known as GEMs. Adaptors not only recruit signaling proteins, but also play an active role in regulating the conformation and activation of many of the proteins recruited to the complex. In particular, recent research has shed light on the mechanisms by which multiple adaptor proteins cooperate to bring about the recruitment and activation of phospholipase C gamma in response to the activation of ITAM-containing receptors.
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PMID:Mechanisms of signaling by the hematopoietic-specific adaptor proteins, SLP-76 and LAT and their B cell counterpart, BLNK/SLP-65. 1168 12

The Tec kinases Rlk and Itk are critical for full T cell receptor (TCR)-induced activation of phospholipase C-gamma and mitogen-activated protein kinase. We show here that the mutation of Rlk and Itk impaired activation of the transcription factors NFAT and AP-1 and production of both T helper type 1 (TH1) and TH2 cytokines. Consistent with these biochemical defects, Itk-/- mice did not generate effective TH2 responses when challenged with Schistosoma mansoni eggs. Paradoxically, the more severely impaired Rlk-/-Itk-/- mice were able to mount a TH2 response and produced TH2 cytokines in response to this challenge. In addition, Rlk-/-Itk-/- cells showed impaired TCR-induced repression of the TH2-inducing transcription factor GATA-3, suggesting a potential mechanism for TH2 development in these hyporesponsive cells. Thus, mutations that affect Tec kinases lead to complex alterations in CD4+ TH cell differentiation.
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PMID:Mutation of Tec family kinases alters T helper cell differentiation. 1170 66

Oxidative stress plays an important role in the induction of T lymphocyte hyporesponsiveness observed in several human pathologies including cancer, rheumatoid arthritis, leprosy, and AIDS. To investigate the molecular basis of oxidative stress-induced T cell hyporesponsiveness, we have developed an in vitro system in which T lymphocytes are rendered hyporesponsive by co-culture with oxygen radical-producing activated neutrophils. We have observed a direct correlation between the level of T cell hyporesponsiveness induced and the concentration of reactive oxygen species produced. Moreover, induction of T cell hyporesponsiveness is blocked by addition of N-acetyl cysteine, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride, and catalase, confirming the critical role of oxidative stress in this system. The pattern of tyrosine-phosphorylated proteins was profoundly altered in hyporesponsive as compared with normal T cells. In hyporesponsive T cells, T cell receptor (TCR) ligation no longer induced phospholipase C-gamma1 activation and caused reduced Ca(2+) flux. In contrast, despite increased levels of ERK1/2 phosphorylation, TCR-dependent activation of mitogen-activated protein kinase ERK1/2 was unaltered in hyporesponsive T lymphocytes. A late TCR-signaling event such as caspase 3 activation was as well unaffected in hyporesponsive T lymphocytes. Our data indicate that TCR-signaling pathways are differentially affected by physiological levels of oxidative stress and would suggest that although "hyporesponsive" T cells have lost certain effector functions, they may have maintained or gained others.
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PMID:Reactive oxygen species differentially affect T cell receptor-signaling pathways. 1191 64

Vav1 is a signal transducing protein required for T cell receptor (TCR) signals that drive positive and negative selection in the thymus. Furthermore, Vav1-deficient thymocytes show greatly reduced TCR-induced intracellular calcium flux. Using a novel genetic system which allows the study of signaling in highly enriched populations of CD4(+)CD8(+) double positive thymocytes, we have studied the mechanism by which Vav1 regulates TCR-induced calcium flux. We show that in Vav1-deficient double positive thymocytes, phosphorylation, and activation of phospholipase C-gamma1 (PLCgamma1) is defective. Furthermore, we demonstrate that Vav1 regulates PLCgamma1 phosphorylation by at least two distinct pathways. First, in the absence of Vav1 the Tec-family kinases Itk and Tec are no longer activated, most likely as a result of a defect in phosphoinositide 3-kinase (PI3K) activation. Second, Vav1-deficient thymocytes show defective assembly of a signaling complex containing PLCgamma1 and the adaptor molecule Src homology 2 domain-containing leukocyte phosphoprotein 76. We show that this latter function is independent of PI3K.
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PMID:Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma1 via phosphoinositide 3-kinase-dependent and -independent pathways. 1199 16

Three members of the Tec family kinases, Itk, Rlk and Tec, have been implicated in signaling downstream of the T cell receptor (TCR). The activity of these kinases in T cells has been shown to be important for the full activation of phospholipase C-gamma1 (PLC-gamma1). Disruption of Tec family signaling in Itk-/- and Rlk-/-Itk-/- mice has multiple effects on T cell development, cytokine production and T-helper cell differentiation. Furthermore, mice possessing mutations in signaling molecules upstream of PLC-gamma1, such as Src homology 2 (SH2) domain-containing phosphoprotein of 76 kDa (SLP-76), linker for activation of T cells (LAT) and Vav1, or in members of the nuclear factor for activated T cells (NFAT) family of transcription factors, which are downstream of PLC-gamma1, have been found to have similar phenotypes to Tec family-deficient mice, emphasizing the importance of this pathway in regulating T cell activation, differentiation and homeostasis.
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PMID:The role of Tec family kinases in T cell development and function. 1261 56


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