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)

Wiskott-Aldrich syndrome is an X-linked combined immunodeficiency affecting cells of several different hemopoietic lineages. The Wiskott-Aldrich syndrome protein (WASP), which has no homology with any other known protein families, is rich in proline motifs known to contribute to Src homology 3 binding sites. However, its function has not been determined. The Tec family of cytoplasmic tyrosine kinases, which include Btk (the X-linked agammaglobulinemia gene), Itk, and Tec, is thought to be involved in lymphoid cell signaling pathways. In this work, we show binding of WASP to the Src homology 3 domains of Btk, Itk, Tec, Grb2, and phospholipase C-gamma, which suggests a function for WASP in lymphoid cell signaling.
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PMID:Evidence that the Wiskott-Aldrich syndrome protein may be involved in lymphoid cell signaling pathways. 889 7

Protein tyrosine phosphorylation and other biochemical events have been shown to occur after cross-linking of Fc epsilonRI in rodent mast cells. To investigate the mechanism of Fc epsilonRI signal transduction in human mast cells, we used human cultured mast cells (HCMC) generated from cord blood cells in the presence of recombinant human stem cell factor and IL-6. We found that on cross-linking of Fc epsilonRI: 1) HCMC released histamine; 2) rapid tyrosine phosphorylation of multiple cellular substrates, including Syk, HS1, c-Cbl, ERK-1, and ERK-2, was observed; 3) intracellular Ca2+ and inositol phosphate production were increased within the first minute after Fc epsilonRI cross-linking; and 4) genistein, a tyrosine kinase inhibitor, inhibited both protein tyrosine phosphorylation and histamine release in a dose-dependent manner. These results were consistent with previous studies in rodent mast cells. In contrast, no tyrosine phosphorylation of phospholipase C gamma1 and Btk (Bruton's tyrosine kinase) were observed in our experimental conditions. These results suggest that the greater part of the early and late signaling events in HCMC is similar to those obtained with rodent mast cells and indicated that the requirement of tyrosine phosphorylation in the activation process of each of the signaling molecules might be different in HCMC and rodent mast cells. Our finding indicates that HCMC may be useful for analysis of Fc epsilonRI-mediated signal transduction in human mast cells.
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PMID:Early and late events in Fc epsilon RI signal transduction in human cultured mast cells. 955 Mar 84

In B lymphocytes, signaling through the B cell antigen receptor (BCR) contributes to cell fate decisions with different extents of receptor engagement leading to such outcomes as cell death, survival, or proliferation. During the past several years we have seen significant strides in our understanding of the signaling pathways that connect the BCR to the nucleus. Stimulation of the BCR leads to the activation of three types of intracellular protein tyrosine kinases Lyn, Syk, and Btk. Concerted action of these tyrosine kinases leads to the phosphorylation of multiple substrates and to activation of a variety of signaling pathways including phospholipase C-gamma, Ras, and phosphatidylinositol 3-kinase activation. The ability of B lymphocytes to react appropriately to a wide variety of environment stimuli requires a high degree of regulation on these multiple signaling pathways.
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PMID:Molecular dissection of B cell antigen receptor signaling (review). 985 57

Phospholipase D (PLD) has been proposed to play a key role in the signal transduction of cellular responses to various extracellular signals. Herein we provide biochemical and genetic evidence that cross-linking of the B cell receptor (BCR) induces rapid activation of PLD through a Syk-, Btk- and phospholipase C (PLC)-gamma2-dependent pathway in DT40 cells. Activation of PLD upon BCR engagement is completely blocked in Syk- or Btk-deficient cells, but unaffected in Lyn-deficient cells. Furthermore, in PLC-gamma2-deficient cells, BCR engagement failed to activate PLD. These results demonstrate that Syk, Btk and PLC-gamma2 are essential for BCR-induced PLD activation.
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PMID:Cross-linking of the B cell receptor induces activation of phospholipase D through Syk, Btk and phospholipase C-gamma2. 1009 92

The entry of B lymphocytes into secondary lymphoid organs is a critical step in the development of an immune response, providing a site for repertoire shaping, antigen-induced activation and selection. These events are controlled by signals generated through the B cell antigen receptor (BCR) and are associated with changes in the migration properties of B cells in response to chemokine gradients. The chemokine stromal cell-derived factor (SDF)-1alpha is thought to be one of the driving forces during those processes, as it is produced inside secondary lymphoid organs and induces B lymphocyte migration that arrests upon BCR engagement. The signaling pathway that mediates this arrest was genetically dissected using B cells deficient in specific BCR-coupled signaling components. BCR-induced inhibition of SDF-1alpha chemotaxis was dependent on Syk, BLNK, Btk, and phospholipase C (Plc)gamma2 but independent of Ca2+ mobilization, suggesting that the target of BCR stimulation was a protein kinase C (PKC)-dependent substrate. This target was identified as the SDF-1alpha receptor, CXCR4, which undergoes PKC- dependent internalization upon BCR stimulation. Mutation of the internalization motif SSXXIL in the COOH terminus of CXCR4 resulted in B cells that constitutively expressed this receptor upon BCR engagement. These studies suggest that one pathway by which BCR stimulation results in inhibition of SDF-1alpha migration is through PKC-dependent downregulation of CXCR4.
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PMID:B cell antigen receptor engagement inhibits stromal cell-derived factor (SDF)-1alpha chemotaxis and promotes protein kinase C (PKC)-induced internalization of CXCR4. 1022 86

Coligation of paired immunoglobulin-like receptor B (PIR-B) with B cell antigen receptor (BCR) blocks antigen-induced B cell activation. This inhibition is mediated in part by recruitment of SHP-1 and SHP-2 to the phosphorylated ITIMs in the cytoplasmic domain of PIR-B; however the molecular target(s) of these phosphatases remain elusive. Here we show that PIR-B ligation inhibits the BCR-induced tyrosine phosphorylation of Igalpha/Igbeta, Syk, Btk and phospholipase C (PLC)-gamma2. Overexpression of a catalytically inactive form of SHP-1 prevents the PIR-B-mediated inhibition of tyrosine phosphorylation of Syk, Btk, and PLC-gamma2. Dephosphorylation of Syk and Btk mediated by SHP-1 leads to a decrease of their kinase activity, which in turn inhibits tyrosine phosphorylation of PLC-gamma2. Furthermore, we define a requirement for Lyn in mediating tyrosine phosphorylation of PIR-B. Based on these results, we propose a model of PIR-B-mediated inhibitory signaling in which coligation of PIR-B and BCR results in phosphorylation of ITIMs by Lyn, subsequent recruitment of SHP-1, and a resulting inhibition of the BCR-induced inositol 1,4,5-trisphosphate generation by dephosphorylation of Syk and Btk.
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PMID:Paired immunoglobulin-like receptor B (PIR-B) inhibits BCR-induced activation of Syk and Btk by SHP-1. 1032 49

Activation of Akt by multiple stimuli including B cell antigen receptor (BCR) engagement requires phosphatidylinositol 3-kinase and regulates processes including cell survival, proliferation, and metabolism. BCR cross-linking activates three families of non-receptor protein tyrosine kinases (PTKs) and these are transducers of signaling events including phospholipase C and mitogen-activated protein kinase activation; however, the relative roles of PTKs in BCR-mediated Akt activation are unknown. We examined Akt activation in Lyn-, Syk- and Btk-deficient DT40 cells and B cells from Lyn(-/-) mice. BCR-mediated Akt activation required Syk and was partially dependent upon Btk. Increased BCR-induced Akt phosphorylation was observed in Lyn-deficient DT40 cells and Lyn(-/-) mice compared with wild-type cells suggesting that Lyn may negatively regulate Akt function. BCR-induced tyrosine phosphorylation of the phosphatidylinositol 3-kinase catalytic subunit was abolished in Syk-deficient cells consistent with a receptor-proximal role for Syk in BCR-mediated phosphatidylinositol 3-kinase activation; in contrast, it was maintained in Btk-deficient cells, suggesting Btk functions downstream of phosphatidylinositol 3-kinase. Calcium depletion did not influence BCR-induced Akt phosphorylation/activation, showing that neither Syk nor Btk mediates its effects via changes in calcium levels. Thus, BCR-mediated Akt stimulation is regulated by multiple non-receptor PTK families which regulate Akt both proximal and distal to phosphatidylinositol 3-kinase activation.
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PMID:Syk and Bruton's tyrosine kinase are required for B cell antigen receptor-mediated activation of the kinase Akt. 1052 50

Activation of lymphocytes through their antigen receptors leads to mobilization of intracellular Ca(2+) ions. This process requires expression of SLP adaptors and involves phosphorylation of phospholipase C-gamma isoforms by the Tec-related protein tyrosine kinase Btk in B cells and Itk in T cells. The SH2 domain of Btk and Itk is essential for phospholipase C-gamma phosphorylation and mutations in this domain lead to the X-linked agammaglobulinemia immuno deficiency in humans. Here we show that, in contrast to SH2 domains from other signaling proteins, the Btk and Itk SH2 domains exhibit a restricted binding specificity. They bind selectively to tyrosine-phosphorylated SLP-65 and SLP-76 in activated B and T cells, respectively. Our findings suggest that Btk/Itk and phospholipase C-gamma both bind via their SH2 domain to phosphorylated SLP adaptors, and that this association is required for the activation of phospholipase C-gamma.
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PMID:Interaction of SLP adaptors with the SH2 domain of Tec family kinases. 1055 26

The Tec family has emerged recently as a subfamily among nonreceptor type protein-tyrosine kinases, consisting of Tec, Btk, Itk/Tsk/Emt, Bmx, and Txk/Rlk. Because many members of this family have been shown to be activated in response to growth and differentiation stimuli in hematopoietic tissues, they are presumed to function in vivo as important signaling mediators. Although that hypothesis was further strengthened by the knowledge that mutations in Btk cause agammaglobulinemia in humans, we have only limited information concerning the molecular interaction through which Tec kinases exert their effects. One characteristic feature of Tec family members is the presence of a pleckstrin homology domain in their protein structure, suggesting a physical and functional interaction with the phospholipid-dependent signaling pathways. Recent data have revealed that Tec kinases regulate phospholipase C isoforms. This review summarizes current knowledge concerning the in vivo roles of the Tec family proteins.
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PMID:The Tec family protein-tyrosine kinases: a subset of kinases for a subset of signalings. 1064 36

Pleckstrin homology (PH) domain binding to D3-phosphorylated phosphatidylinositides (PI) provides a reversible means of recruiting proteins to the plasma membrane, with the resultant change in subcellular localization playing a key role in the activation of multiple intracellular signaling pathways. Previously we found that the T-cell-specific PH domain-containing kinase Itk is constitutively membrane associated in Jurkat T cells. This distribution was unexpected given that the closely related B-cell kinase, Btk, is almost exclusively cytosolic. In addition to constitutive membrane association of Itk, unstimulated JTAg T cells also exhibited constitutive phosphorylation of Akt on Ser-473, an indication of elevated basal levels of the phosphatidylinositol 3-kinase (PI3K) products PI-3,4-P(2) and PI-3,4,5-P(3) in the plasma membrane. Here we describe a defect in expression of the D3 phosphoinositide phosphatase, PTEN, in Jurkat and JTAg T cells that leads to unregulated PH domain interactions with the plasma membrane. Inhibition of D3 phosphorylation by PI3K inhibitors, or by expression of PTEN, blocked constitutive phosphorylation of Akt on Ser-473 and caused Itk to redistribute to the cytosol. The PTEN-deficient cells were also hyperresponsive to T-cell receptor (TCR) stimulation, as measured by Itk kinase activity, tyrosine phosphorylation of phospholipase C-gamma1, and activation of Erk compared to those in PTEN-replete cells. These data support the idea that PH domain-mediated association with the plasma membrane is required for Itk activation, provide evidence for a negative regulatory role of PTEN in TCR stimulation, and suggest that signaling models based on results from Jurkat T-cell lines may underestimate the role of PI3K in TCR signaling.
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PMID:Deficiency of PTEN in Jurkat T cells causes constitutive localization of Itk to the plasma membrane and hyperresponsiveness to CD3 stimulation. 1095 90


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