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)

The SLP-76 (Src homology 2 domain-containing leukocyte protein of 76 kDa) adapter protein is expressed in T cells and myeloid cells, whereas its homologue BLNK (B cell linker protein) is expressed in B cells. SLP-76 and BLNK link immunoreceptor tyrosine-based activation motif-containing receptors to signaling molecules that include phospholipase C-gamma, mitogen-activated protein kinases, and the GTPases Ras and Rho. SLP-76 plays a critical role in T cell receptor, FcvarepsilonRI and gpVI collagen receptor signaling, and participates in signaling via FcgammaR and killer cell inhibitory receptors. BLNK plays a critical role in B cell receptor signaling. We show that murine bone marrow-derived macrophages express both SLP-76 and BLNK. Selective ligation of FcgammaRI and FcgammaRII/III resulted in tyrosine phosphorylation of both SLP-76 and BLNK. SLP-76(-/-) bone marrow-derived macrophages display FcgammaR-mediated tyrosine phosphorylation of Syk, phospholipase C-gamma2, and extracellular signal regulated kinases 1 and 2, and normal FcgammaR-dependent phagocytosis. These data suggest that both SLP-76 and BLNK are coupled to FcgammaR signaling in murine macrophages.
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PMID:Adapter proteins SLP-76 and BLNK both are expressed by murine macrophages and are linked to signaling via Fcgamma receptors I and II/III. 1067 25

Accumulating evidence indicates that the Cbl protein plays a negative role in immune receptor signaling; however, the mode of Cbl action in B cell receptor (BCR) signaling still remains unclear. DT40 B cells deficient in Cbl showed enhanced BCR-mediated phospholipase C (PLC)-gamma2 activation, thereby leading to increased apoptosis. A possible explanation for the involvement of Cbl in PLC-gamma2 activation was provided by findings that Cbl interacts via its Src homology 2 (SH2) domain with B cell linker protein (BLNK) after BCR ligation. BLNK is a critical adaptor molecule for PLC-gamma2 tyrosine phosphorylation through its binding to the PLC-gamma2 SH2 domains. As a consequence of the interaction between Cbl and BLNK, the BCR-induced recruitment of PLC-gamma2 to BLNK and the subsequent PLC-gamma2 tyrosine phosphorylation were inhibited. Thus, our data suggest that Cbl negatively regulates the PLC-gamma2 pathway by inhibiting the association of PLC-gamma2 with BLNK.
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PMID:Cbl suppresses B cell receptor-mediated phospholipase C (PLC)-gamma2 activation by regulating B cell linker protein-PLC-gamma2 binding. 1068 56

A soluble phospholipase C (PLC) from boar sperm generates InsP(3) and hence causes Ca(2+) release when added to sea urchin egg homogenate. This PLC activity is associated with the ability of sperm extracts to cause Ca(2+) oscillations in mammalian eggs following fractionation. A sperm PLC may, therefore, be responsible for causing the observed Ca(2+) oscillations at fertilization. In the present study we have further characterized this boar sperm PLC activity using sea urchin egg homogenate. Consistent with a sperm PLC acting on egg PtdIns(4,5)P(2), the ability of sperm extracts to release Ca(2+) was blocked by preincubation with the PLC inhibitor U73122 or by the addition of neomycin to the homogenate. The Ca(2+)-releasing activity was also detectable in sperm from other species and in whole testis extracts. However, activity was not observed in extracts from other tissues. Moreover recombinant PLCbeta1, -gamma1, -gamma2, -delta1, all of which had higher specific activities than boar sperm extracts, were not able to release Ca(2+) in the sea urchin egg homogenate. In addition these PLCs were not able to cause Ca(2+) oscillations following microinjection into mouse eggs. These results imply that the sperm PLC possesses distinct properties that allow it to hydrolyse PtdIns(4,5)P(2) in eggs.
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PMID:Different Ca2+-releasing abilities of sperm extracts compared with tissue extracts and phospholipase C isoforms in sea urchin egg homogenate and mouse eggs. 1069 2

CD19 is a coreceptor on B cells that enhances the increase in cytoplasmic calcium and ERK2 activation when coligated with the B cell Ag receptor. Constructs containing point mutations and truncations were expressed in Daudi human B lymphoblastoid cells to systematically determine the requirement for individual CD19 cytoplasmic tyrosines in these responses. Evidence for activity was found for Y330, Y360, and Y421 as well as that previously published for Y391. Precipitates formed with phosphopeptides consisting of CD19 sequences flanking these residues were used to screen for cytoplasmic proteins that mediate signaling. Phosphopeptide Y330 precipitated Grb2 and Sos, whereas phosphopeptides Y391 and Y421 both precipitated Vav and phospholipase C-gamma2. These molecules also were found associated with native CD19. In mapping studies with altered constructs, CD19 Y330 and/or Y360 were necessary for binding Grb2 and Sos. Vav associated with CD19 constitutively in unstimulated cells by a tyrosine-independent mechanism requiring the portion of CD19 encoded by exons 9-12. After B cell Ag receptor stimulation, Vav association was tyrosine-dependent, but binding was influenced by multiple residues. However, when maximally phosphorylated by pervanadate, Y391 and, to a lesser extent, Y421 were sufficient. CD19 Y391 was also both necessary and sufficient for binding phospholipase C-gamma2. Thus, different tyrosines along the CD19 cytoplasmic domain provide scaffolding for the formation of complexes of different signaling molecules.
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PMID:Systematic analysis of the role of CD19 cytoplasmic tyrosines in enhancement of activation in Daudi human B cells: clustering of phospholipase C and Vav and of Grb2 and Sos with different CD19 tyrosines. 1070 2

Syk plays a crucial role in the transduction of oxidative stress signaling. In this paper, we investigated the roles of Src homology 2 (SH2) domains of Syk in oxidative stress signaling, using Syk-negative DT40 cells expressing the N- or C-terminal SH2 domain mutant [mSH2(N) or mSH2(C)] of Syk. Tyrosine phosphorylation of Syk in cells expressing mSH2(N) Syk after H(2)O(2) treatment was higher than that in cells expressing wild-type Syk or mSH2(C) Syk. The tyrosine phosphorylation of wild-type Syk and mSH2(C) Syk, but not that of mSH2(N), was sensitive to PP2, a specific inhibitor of Src-family protein-tyrosine kinase. In oxidative stress, the C-terminal SH2 domain of Syk was demonstrated to be required for induction of tyrosine phosphorylation of cellular proteins, phospholipase C (PLC)-gamma2 phosphorylation, inositol 1,4, 5-triphosphate (IP(3)) generation, Ca(2)(+) release from intracellular stores, and c-Jun N-terminal kinase activation. In contrast, in mSH2(N) Syk-expressing cells, tyrosine phosphorylation of intracellular proteins including PLC-gamma2 was markedly induced in oxidative stress. The enhanced phosphorylation of mSH2(N) Syk and PLC-gamma2, however, did not link to Ca(2)(+) mobilization from intracellular pools and IP(3) generation. Thus, the N- and C-terminal SH2 domains of Syk possess distinctive functions in oxidative stress signaling.
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PMID:Distinctive functions of Syk N-terminal and C-terminal SH2 domains in the signaling cascade elicited by oxidative stress in B cells. 1078 87

TNF-alpha induced a dose- and time-dependent increase in cyclooxygenase-2 (COX-2) expression and PGE2 formation in human NCI-H292 epithelial cells. Immunofluorescence staining demonstrated that COX-2 was expressed in cytosol and nuclear envelope. Tyrosine kinase inhibitors (genistein or herbimycin) or phosphoinositide-specific phospholipase C inhibitor (U73122) blocked TNF-alpha-induced COX-2 expression. TNF-alpha also stimulated phosphatidylinositol hydrolysis and protein kinase C (PKC) activity, and both were abolished by genistein or U73122. The PKC inhibitor, staurosporine, also inhibited TNF-alpha-induced response. The 12-O-tetradecanoylphorbol 13-acetate (TPA), a PKC activator, also stimulated COX-2 expression, this effect being inhibited by genistein or herbimycin. NF-kappaB DNA-protein binding and COX-2 promoter activity were enhanced by TNF-alpha, and these effects were inhibited by genistein, U73122, staurosporine, or pyrolidine dithiocarbamate. TPA stimulated both NF-kappaB DNA-protein binding and COX-2 promoter activity, these effects being inhibited by genistein, herbimycin, or pyrolidine dithiocarbamate. The TNF-alpha-induced, but not the TPA-induced, COX-2 promoter activity was inhibited by phospholipase C-gamma2 mutants, and the COX-2 promoter activity induced by either agent was attenuated by dominant-negative mutants of PKC-alpha, NF-kappaB-inducing kinase, or I-kappaB (inhibitory protein that dissociates from NF-kappaB) kinase (IKK)1 or 2. IKK activity was stimulated by both TNF-alpha and TPA, and these effects were inhibited by staurosporine or herbimycin. These results suggest that, in NCI-H292 epithelial cells, TNF-alpha might activate phospholipase C-gamma2 via an upstream tyrosine kinase to induce activation of PKC-alpha and protein tyrosine kinase, resulting in the activation of NF-kappaB-inducing kinase and IKK1/2, and NF-kappaB in the COX-2 promoter, then initiation of COX-2 expression and PGE2 release.
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PMID:TNF-alpha-induced cyclooxygenase-2 expression in human lung epithelial cells: involvement of the phospholipase C-gamma 2, protein kinase C-alpha, tyrosine kinase, NF-kappa B-inducing kinase, and I-kappa B kinase 1/2 pathway. 1094 3

Garlic has been used in herbal medicine for thousands of years. Some reports have shown that garlic has protective effects against atherosclerosis and inhibits platelet function. In this study, we investigated the mechanism by which diallyl trisulfide (DT), a component of garlic, inhibits platelet function. DT inhibited platelet aggregation and Ca(2+) mobilization in a concentration-dependent manner without increasing intracellular cyclic AMP and cyclic GMP. DT also had no inhibitory effects on thromboxane A(2) (TXA(2)) production in cell-free systems. Collagen-related peptide (CRP)-induced Ca(2+) mobilization is regulated by phospholipase C-gamma2 (PLC-gamma2) activation. We evaluated the effect of DT on tyrosine phosphorylation of PLC-gamma2 and the production of inositol-1,4,5-trisphosphate (IP(3)). DT at concentrations that inhibited platelet aggregation and Ca(2+) mobilization had no effects on tyrosine phosphorylation of PLC-gamma2 or on the formation of IP(3) induced by CRP. Similar results were obtained with thrombin-induced platelet activation. DT inhibited platelet aggregation and Ca(2+) mobilization induced by thrombin without affecting the production of IP(3.) We then evaluated the effect of DT on the binding of IP(3) to its receptor. DT at high concentrations partially blocked the binding of IP(3) to its receptor. Taken together, our findings suggest that the agent suppresses Ca(2+) mobilization at a step distal to IP(3) formation. DT may provide a good tool for investigating Ca(2+) mobilization.
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PMID:Inhibition by diallyl trisulfide, a garlic component, of intracellular Ca(2+) mobilization without affecting inositol-1,4, 5-trisphosphate (IP(3)) formation in activated platelets. 1102 Apr 49

Mutations in the gene encoding Bruton's tyrosine kinase (BTK) interfere with B cell proliferation and lead to an X-linked immunodeficiency in mice characterized by reduced B cell numbers. Recent studies have established that BTK transmits signals from the B cell antigen receptor (BCR) to transcription factor NF-kappaB, which in turn reprograms a set of genes required for normal B cell growth. We now demonstrate that induction of NF-kappaB via this pathway requires the intermediate action of the -gamma2 isoform of phospholipase C (PLC-gamma2), a potential phosphorylation substrate of BTK. Specifically, pharmacologic agents that block the action of either PLC-gamma2 or its second messengers prevent BCR-induced activation of IkappaB kinase. Moreover, activation of NF-kappaB in response to BCR signaling is completely abolished in B cells deficient for PLC-gamma2. Taken together, these findings strongly suggest that PLC-gamma2 functions as an integral component of the BTK/NF-kappaB axis following BCR ligation. Interference with this NF-kappaB cascade may account for some of the B cell defects reported for plc-gamma2(-/-) mice, which develop an X-linked immunodeficiency-like phenotype.
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PMID:Phospholipase C-gamma 2 couples Bruton's tyrosine kinase to the NF-kappaB signaling pathway in B lymphocytes. 1104 93

In B lymphocytes, a signaling complex that contributes to cell fate decisions is the B-cell antigen receptor (BCR), with different extents of receptor engagement leading to such outcomes as cell death, survival, or proliferation. Here, based upon the available genetic and biochemical data of the BCR signal components, we discuss several mechanisms by which BCR signals are propagated and modified, with specific emphasis on the phospholipase C (PLC)-gamma2-calcium pathway Gene-targeting experiments in DT40 chicken B cells highlighted the importance of the intracellular protein tyrosine kinases Syk and Btk in PLC-gamma2 activation. Until recently, the molecular mechanism underlying the double requirement for Syk and Btk in PLC-gamma2 activation remained unclear, but new data suggest that an adapter molecule, B-cell linker protein (alternatively named SLP-65 or BASH), phosphorylated by Syk, provides docking sites for Btk SH2 domain as well as PLC-gamma2 SH2 domains, thus bringing Btk into close proximity with PLC-gamma2. The activated Btk then phosphorylates PLC-gamma2, leading to its activation. The activated PLC-gamma2 converts phosphatidylinositol 4,5-bisphosphate into the second messenger inositol 1,4,5-trisphosphate (IP3), which in turn binds to IP3 receptors located on the endoplasmic reticulum (ER). Binding of IP3 to the IP3 receptors is essential for triggering a calcium release from the ER and subsequent entry of extracellular calcium. Balancing these activation signals in the PLC-gamma2-calcium pathway are the inhibitory receptors expressed on B cells, FcyRII and paired immunoglobin-like receptor (PIR)-B. Although both FcyRII and PIR-B inhibits the BCR-mediated [Ca2+]i increase, the inhibitory mechanisms of these receptors are distinct. The FcyRII-mediated inhibitory signal is dependent on lipid phosphatase SHIP, whereas the PIR-B requires redundant functions of protein phosphatases SHP-1 and SHP-2. Thus, PIR-B and FcgammaRII inhibit calcium signals by utilizing two distinct signaling molecules, thereby contributing to setting threshold levels for activation signals as well as terminating activation responses.
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PMID:Regulation of the phospholipase C-gamma2 pathway in B cells. 1104 65

B lymphocytes lacking the adaptor protein B cell linker (BLNK) do not proliferate in response to B cell antigen receptor (BCR) engagement. We demonstrate here that BCR-activated BLNK(-)/- B cells fail to enter the cell cycle, and this is due to their inability to induce the expression of the cell cycle regulatory proteins such as cyclin D2 and cyclin-dependent kinase 4. BCR-stimulated BLNK(-)/- B cells also do not up-regulate the cell survival protein Bcl-x(L), which may be necessary for the cells to complete the cell cycle. In addition, BLNK(-)/- B cells exhibit a high rate of spontaneous apoptosis in culture. Examination of the various BCR-activated signaling pathways in mouse BLNK(-)/- B cells reveals the intact activation of Akt and mitogen-activated protein kinases but the impaired activation of nuclear factor (NF)-kappaB that is known to regulate genes involved in cell proliferation and survival. The inability to activate NF-kappaB in BCR-stimulated BLNK(-)/- B cells is due to a failure to induce the degradation of the inhibitory kappaB protein. In all these aspects, BLNK(-)/- B cells resemble xid B cells that have a mutation in Bruton's tyrosine kinase (Btk). Recently, phospholipase C (PLC)-gamma2 has also been demonstrated to be essential for NF-kappaB activation. Since BLNK has been shown separately to interact with both Btk and PLC-gamma2, our finding of normal Btk but impaired PLC-gamma2 activation in BCR-stimulated BLNK(-)/- B cells strongly suggests that BLNK orchestrates the formation of a Btk-PLC-gamma2 signaling axis that regulates NF-kappaB activation. Taken together, the NF-kappaB activation defect may be sufficient to explain the similar defects in BCR-induced B cell proliferation and T cell-independent immune responses in BLNK(-)/-, Btk(-)/-, and PLC-gamma2(-)/- mice.
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PMID:The adaptor protein BLNK is required for b cell antigen receptor-induced activation of nuclear factor-kappa B and cell cycle entry and survival of B lymphocytes. 1127 46


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