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)

Chronic airway inflammation induces numerous structural changes of the airways involving hypertrophy and hyperplasia of airway smooth muscle (ASM). Thrombin has been identified in the bronchoalveolar lavage fluid of asthmatic subjects and displays potent bronchoconstrictor and mitogenic activity towards ASM. This study has addressed which proteinase-activated receptors (PARs) and signalling pathways are involved in mediating distinct effects of thrombin. Using cultured bovine tracheal smooth muscle (BTSM) cells as a model system, thrombin stimulated a marked increase in [3H]inositol phosphate ([3H]InsPs) accumulation, which was fully mimicked by a selective PAR1 activating peptide. In contrast, PAR1, PAR2, PAR3 and PAR4 activating peptides were unable to replicate the ability of thrombin to stimulate DNA synthesis as assessed by [3H]thymidine incorporation. Further investigation demonstrated that the mitogenic effect of thrombin did not involve stimulation of PDGF secretion but did involve activation of PDGF or EGF receptors and a G(i/o)-dependent activation of phosphoinositide 3-kinase. Thrombin, but not the PAR1, PAR2, PAR3 or PAR4 activating peptides was able to stimulate PtdIns(3,4,5)P3 mass accumulation. PAR3 antisense oligonucleotides substantially inhibit thrombin-stimulated [3H]thymidine incorporation and PtdIns(3,4,5)P3 generation but had no effect on thrombin-induced phosphoinositide hydrolysis. These data indicate that while PI hydrolysis and Ca2+ mobilisation induced by thrombin operates via PAR1-dependent activation of phospholipase C, phosphoinositide 3-kinase activation and DNA synthesis occurs via a distinct proteinase-activated receptor pathway, possibly involving PAR3.
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PMID:Thrombin induces DNA synthesis and phosphoinositide hydrolysis in airway smooth muscle by activation of distinct receptors. 1602 63

Aberrant epidermal growth factor receptor (EGFR) signaling is a major characteristic of many human malignancies including breast cancer. Since the discovery of EGF in 1960's and its receptor in 1980's, our understanding of the EGF/EGFR pathway has been significantly advanced and consequently, EGFR is considered as a major oncogenic factor and an attractive therapeutic target. The well-established traditional function of EGFR is known to transmit extra-cellular mitogenic signals, such as EGF and transforming growth factor-alpha (TGF-alpha), through activating a number of downstream signaling cascades. These include signaling modules that involve phospholipase C-gamma, Ras, and phosphatidylinositol-3 kinase (PI-3K). In cancer cells, the common outcomes following the activation of the EGFR-mediated downstream pathways are altered gene activities, leading to un-controlled tumor proliferation and apoptosis. Interestingly, emerging evidences suggest the existence of a direct mode of the EGFR pathway that is distinct from the traditional transduction pathway. This new mode of EGFR signaling involves cellular transport of EGFR from the cell-surface to the cell nucleus, association of nuclear EGFR complex with gene promoters, and transcriptional regulation of the target genes. Although the nature and pathological consequences of the nuclear EGFR pathway remain elusive, accumulating evidences suggest its association with increased tumor cell proliferation and poor survival rate in breast cancer patients. While several anti-EGFR agents are being tested in breast cancer patients clinically and others under pre-clinical development, a better understanding of the traditional and the nuclear EGFR pathways will facilitate the identification of patients that are likely to respond to these agents as well as future development of more effective anti-EGFR therapeutic interventions.
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PMID:EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization. 1626 6

Carbocisteine is a mucoregulatory drug normalizing sialic acid and fucose contents in mucins through the regulation of glycosyltransferase activities. Tumor necrosis factor (TNF)-alpha-induced overexpression of sialyl-Lewis x epitopes, containing sialic acid and fucose, in mucins were previously reported to be regulated by glycosyltransferase mRNAs expression through phosphatidyl inositol-specific phospholipase C (PI-PLC) signaling pathways [Ishibashi, Y., Inouye, Y., Okano, T., Taniguchi, A., 2005. Regulation of sialyl-Lewis x epitope expression by TNF-alpha and EGF in an airway carcinoma cell line. Glycoconj. J. 22, 53-62]. To investigate the mechanism behind the mucoregulatory action of carbocisteine, the present study evaluated the effects of carbocisteine on TNF-alpha-induced overexpression of sialyl-Lewis x epitopes in NCI-H292 cells. 100 mug/ml of carbocisteine was able to inhibit the TNF-alpha-induced expression of hST3GallV mRNA, FUT3 mRNA, C2/4GnT mRNA and sialyl-Lewis x epitopes as well as the TNF-alpha-induced activity of PI-PLC in NCI-H292 cells. These findings suggest that carbocisteine may normalize the sialyl-Lewis x epitopes expression in mucins through the inhibition of cellular PI-PLC activity in vivo.
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PMID:Effects of carbocisteine on sialyl-Lewis x expression in an airway carcinoma cell line stimulated with tumor necrosis factor-alpha. 1638 97

In non-excitable cells, the inositol 1,4,5-trisphosphate receptor (IP3R) is an intracellular Ca2+ channel which plays a major role in Ca2+ signalling. Three isoforms of IP3R have been identified (IP3R-1, IP3R-2 and IP3R-3) and most cell types express different proportions of each isoform. The differences between the pharmacological and functional properties of the various isoforms of IP3R are poorly known. RINm5F cells who express almost exclusively (approximately 90%) the IP3R-3, represent an interesting model to study this particular isoform. Here, we investigated a regulatory mechanism by which protein kinase C (PKC) may influence IP3R-3-mediated Ca2+ release. With an immunoprecipitation approach we confirmed that RINm5F cells express almost exclusively the IP3R-3 isoform. With an in vitro phosphorylation approach, we showed that the immunopurified IP3R-3 was efficiently phosphorylated by exogenous PKC. With a direct in cellulo approach and an indirect in cellulo back-phosphorylation approach we showed that phorbol-12-myristate-13-acetate (PMA) causes the phosphorylation of IP3R-3 in intact RINm5F cells. In saponin-permeabilized RINm5F cells, 3-induced Ca2+ release was reduced after a pre-treatment with PMA. PMA also reduced the Ca2+ response of intact RINm5F cells stimulated with carbachol and EGF, two agonists that use different receptor types to activate phospholipase C. These results suggest the existence of a negative feedback mechanism involving two components of the Ca2+ signalling cascade, whereby activated PKC dampens IP3R-3 activity.
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PMID:Protein kinase C decreases the apparent affinity of the inositol 1,4,5-trisphosphate receptor type 3 in RINm5F cells. 1732 Sep 50

The 14th EGFL-repeat (Ten14) of human tenascin cytotactin activates the epidermal growth factor receptor (EGFR) with micromolar affinity; however, unlike EGF, Ten14-mediated activation of EGFR does not lead to receptor internalization. As the divergent signaling pathways downstream of EGFR have been shown to be triggered from plasma membrane and cytosolic locales, we investigated whether Ten14-mediated surface restriction of EGFR resulted in altered biochemical and cellular responses as compared to EGF. Molecules associated with migratory cascades were activated to a relatively greater extent in response to Ten14, with very weak activation of proliferation-associated cascades. Activation of phospholipase C gamma (PLCgamma) and m-calpain, associated with lamellipod protrusion and tail retraction, respectively, were noted at even at sub-saturating doses of Ten14. However, activation of ERK/MAPK, p90RSK, and Elk1, factors affecting proliferation, remained low even at high Ten14 concentrations. Similar activation profiles were observed for EGF-treated cells at 4 degrees C, a maneuver that limits receptor internalization. We demonstrate a concurrent effect of such altered signaling on biophysical responses-sustained migration was observed at levels of Ten14 that activated PLCgamma, but did not stimulate proliferation significantly. Here, we present a novel class of EGFR ligands that can potentially signal as a part of the extracellular matrix, triggering specific intracellular signaling cascades leading to a directed cellular response from an otherwise pleiotropic receptor. This work extends the signaling paradigm of EGFL repeat being presented in a restricted fashion as part of the extracellular matrix.
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PMID:Cell surface restriction of EGFR by a tenascin cytotactin-encoded EGF-like repeat is preferential for motility-related signaling. 1770 41

The epidermal growth factor receptor (EGFR)/ErbB receptor tyrosine kinases regulate several aspects of development, including the development of the mammalian nervous system. ErbB signaling also has physiological effects on neuronal function, with influences on synaptic plasticity and daily cycles of activity. However, little is known about the effectors of EGFR activation in neurons. Here we show that EGF signaling has a nondevelopmental effect on behavior in Caenorhabditis elegans. Ectopic expression of the EGF-like ligand LIN-3 at any stage induces a reversible cessation of feeding and locomotion. These effects are mediated by neuronal EGFR (also called LET-23) and phospholipase C-gamma (PLC-gamma), diacylglycerol-binding proteins, and regulators of synaptic vesicle release. Activation of EGFR within a single neuron, ALA, is sufficient to induce a quiescent state. This pathway modulates the cessation of pharyngeal pumping and locomotion that normally occurs during the lethargus period that precedes larval molting. Our results reveal an evolutionarily conserved role for EGF signaling in the regulation of behavioral quiescence.
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PMID:Epidermal growth factor signaling induces behavioral quiescence in Caenorhabditis elegans. 1789 Nov 42

G-protein coupled receptor (GPCR) kinase-2 interacting protein 1 (GIT1) is a multifunctional scaffolding protein that regulates epidermal growth factor receptor (EGFR) signaling pathways. We demonstrate that GIT1 interacts with sorting nexin 6 (SNX6), a member of the SNX family that increases EGFR trafficking between endosomes and lysosomes, thereby enhancing EGFR degradation. The GIT1-SNX6 interaction is increased 3-fold after treatment with EGF for 60 min. The second coiled-coil domain (CC2; aa 424-474) of GIT1 mediates binding to SNX6. Subcellular fractionation and confocal microscopy data indicate that GIT1 and SNX6 interact in endosomes. Knockdown of GIT1 expression by small interfering RNA decreased the rate of EGF-induced EGFR degradation. Expression of exogenous GIT1 or SNX6 alone did not alter EGFR degradation; however, coexpression of GIT1 and SNX6 decreased EGFR levels both basally and in response to EGF. In contrast, expression of GIT1(CC2 deleted) and SNX6 did not reduce EGFR levels, demonstrating that the interaction between GIT1 and SNX6 was required to regulate EGFR trafficking. Phosphorylation of the EGFR substrate phospholipase C-gamma was decreased by coexpression of GIT1 and SNX6. These data demonstrate an endosomal, EGF-regulated interaction between SNX6 and GIT1 that enhances degradation of the EGFR, and thereby alters EGFR signaling. Our findings suggest a new role for GIT1 in tyrosine kinase receptor trafficking.
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PMID:An epidermal growth factor (EGF) -dependent interaction between GIT1 and sorting nexin 6 promotes degradation of the EGF receptor. 1852 62

Benzo[a]pyrene (BaP) is activated by xenobiotic-metabolizing enzymes to highly mutagenic and carcinogenic metabolites. Previous studies in this laboratory have shown that benzo[a]pyrene quinones (BPQs), 1,6-BPQ and 3,6-BPQ, are able to induce epidermal growth factor receptor (EGFR) cell signaling through the production of reactive oxygen species. Recently, we have reported that BPQs have the potential to induce the expression of genes involved in numerous pathways associated with cell proliferation and survival in human mammary epithelial cells. In the present study we demonstrated that BPQs not only induced EGFR tyrosine autophosphorylation, but also induced EGFR-dependent tyrosine phosphorylation of phospholipase C-gamma1 and several signal transducers and activators of transcription (STATs). The effects of BPQs were evaluated in a model of EGF withdrawal in MCF10-A cells. We found that BPQs (1 muM), induced EGFR tyrosine phosphorylation at positions Y845, Y992, Y1068, and Y1086. PLC-gamma1 phosphorylation correlated with the phosphorylation of tyrosine-Y992, a proposed docking site for PLC-gamma1 on the EGFR. Additionally, we found that BPQs induced the activation of STAT-1, STAT-3, STAT-5a and STAT-5b. STAT5 was shown to translocate to the nucleus following 3,6-BPQ and 1,6-BPQ exposures. Although the patterns of phosphorylation at EGFR, PLC-gamma1 and STATs were quite similar to those induced by EGF, an important difference between BPQ-mediated signaling of the EGFR was observed. Signaling produced by EGF ligand produced a rapid disappearance of EGFR from the cell surface, whereas BPQ signaling maintained EGFR receptors on the cell membrane. Thus, the results of these studies show that 1,6-BPQ and 3,6-BPQ can produce early events as evidenced by EGFR expression, and a prolonged transactivation of EGFR leading to downstream cell signaling pathways.
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PMID:EGF-receptor phosphorylation and downstream signaling are activated by benzo[a]pyrene 3,6-quinone and benzo[a]pyrene 1,6-quinone in human mammary epithelial cells. 1916 69

Rho family GTPases are important cellular switches and control a number of physiological functions. Understanding the molecular basis of interaction of these GTPases with their effectors is crucial in understanding their functions in the cell. Here we present the crystal structure of the complex of Rac2 bound to the split pleckstrin homology (spPH) domain of phospholipase C-gamma(2) (PLCgamma(2)). Based on this structure, we illustrate distinct requirements for PLCgamma(2) activation by Rac and EGF and generate Rac effector mutants that specifically block activation of PLCgamma(2), but not the related PLCbeta(2) isoform. Furthermore, in addition to the complex, we report the crystal structures of free spPH and Rac2 bound to GDP and GTPgammaS. These structures illustrate a mechanism of conformational switches that accompany formation of signaling active complexes and highlight the role of effector binding as a common feature of Rac and Cdc42 interactions with a variety of effectors.
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PMID:Structural insights into formation of an active signaling complex between Rac and phospholipase C gamma 2. 1939 99

Phosphorylation of phospholipase C-delta(1) (PLC-delta(1)) in vitro and in vivo was investigated. Of the serine/threonine kinases tested, protein kinase C (PKC) phosphorylated the serine residue(s) of bacterially expressed PLC-delta(1) most potently. It was also demonstrated that PLC-delta(1) directly bound PKC-alpha via its pleckstrin homology (PH) domain. Using deletion mutants of PLC-delta(1) and synthetic peptides, Ser35 in the PH domain was defined as the PKC mediated in vitro phosphorylation site of PLC-delta(1). In vitro phosphorylation of PLC-delta(1) by PKC stimulated [(3)H]PtdIns(4,5)P(2) hydrolyzing activity and [(3)H]Ins(1,4,5)P(3)-binding of the PLC-delta(1). On the other hand, endogenous PLC-delta(1) was constitutively phosphorylated and phosphoamino acid analysis revealed that major phosphorylation sites were threonine residues in quiescent cells. The phosphorylation level and the species of phosphoamino acid were not changed by various stimuli such as PMA, EGF, NGF, and forskolin. Using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, we determined that Thr209 of PLC-delta(1) is one of the constitutively phosphorylated sites in quiescent cells. The PLC activity was potentiated when constitutively phosphorylated PLC-delta(1) was dephosphorylated by endogenous phosphatase(s) in vitro. Additionally, coexpression with PKC-alpha reduced serine phosphorylation of PLC-delta(1) detected by an anti-phosphoserine antibody and PLC-delta(1)-dependent basal production of inositol phosphates in NIH-3T3 cells, suggesting PKC-alpha activates phosphatase or inactivates another kinase involved in PLC-delta(1) serine phosphorylation to modulate the PLC-delta(1) activity in vivo. Taken together, these results suggest that PLC-delta(1) has multiple phosphorylation sites and phosphorylation status of PLC-delta(1) regulates its activity positively or negatively depends on the phosphorylation sites.
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PMID:Phosphorylation of phospholipase C-delta 1 regulates its enzymatic activity. 1968 Oct 39


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