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)

Recombinant expression of a chimeric EGFR/ErbB-3 receptor in NIH 3T3 fibroblasts allowed us to investigate cytoplasmic events associated with ErbB-3 signal transduction upon ligand activation. An EGFR/ErbB-3 chimera was expressed on the surface of NIH 3T3 transfectants as two classes of receptors possessing epidermal growth factor (EGF) binding affinities comparable to those of the wild-type EGF receptor (EGFR). EGF induced autophosphorylation in vivo of the chimeric receptor and DNA synthesis of EGFR/ErbB-3 transfectants with a dose response similar to that of EGFR transfectants. However, the ErbB-3 and EGFR cytoplasmic domains exhibited striking differences in their interactions with several known tyrosine kinase substrates. We demonstrated strong association of phosphatidylinositol 3-kinase activity with the chimeric receptor upon ligand activation comparable in efficiency with that of the platelet-derived growth factor receptor, while the EGFR exhibited a 10- to 20-fold-lower efficiency in phosphatidylinositol 3-kinase recruitment. By contrast, both phospholipase C gamma and GTPase-activating protein failed to associate with or be phosphorylated by the ErbB-3 cytoplasmic domain under conditions in which they coupled with the EGFR. In addition, though certain signal transmitters, including Shc and GRB2, were recruited by both kinases, EGFR and ErbB-3 elicited tyrosine phosphorylation of distinct sets of intracellular substrates. Thus, our findings show that ligand activation of the ErbB-3 kinase triggers a cytoplasmic signaling pathway that hitherto is unique within this receptor subfamily.
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PMID:Efficient coupling with phosphatidylinositol 3-kinase, but not phospholipase C gamma or GTPase-activating protein, distinguishes ErbB-3 signaling from that of other ErbB/EGFR family members. 826 17

Multiple intracellular signal transduction pathways, including phospholipases A2 and D, can be activated by epidermal growth factor (EGF) in both a protein kinase C (PKC)-dependent and -independent manner. We investigated the activation of phospholipase D (PLD) by a PKC activator, phorbol myristate acetate (PMA) and by EGF in CHO cells transfected with the full-length EGF receptor. In cells labelled with arachidonic acid or linoleic acid, PMA activated a PLD, determined by formation of the transphosphatidylation product phosphatidylethanol in the presence of ethanol. A basal PLD activity was seen in linoleic acid-labelled cells but not in cells labelled with arachidonic acid. This basal activity was augmented by the protein phosphotyrosine phosphatase inhibitor vanadate and reduced by tyrosine kinase inhibition and was contributed to by PKC, as activity could not be elicited following prolonged exposure to phorbol ester, known to down-regulate some PKC isoforms. By contrast, EGF failed to stimulate formation of phosphatidylethanol in cells labelled with either fatty acid species. It is proposed that in the basal condition PKC-dependent PLD activation and protein tyrosine kinase phosphorylation are linked (possibly by a phospholipase C (PLC)-mediated formation of diacylglycerol); EGF which activated a phospholipase A2 (PLA2) but which failed to elicit PLC activation in these cells is without further effect on PLD.
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PMID:Activation of phospholipase D in CHO cells transfected with the human epidermal growth factor (EGF) receptor: differential effects of protein kinase C activation and EGF. 826 43

The mechanism(s) by which monoclonal antibodies (mAbs) against the epidermal growth factor (EGF) receptor regulate receptor function have been investigated with NIH3T3/HER14 fibroblasts expressing human EGF receptors. Bivalent 225 mAb or monovalent 225 Fab' inhibited transforming growth factor (TGF)-alpha-induced EGF receptor tyrosine phosphorylation and cell proliferation. Culture of HER14 cells with 225 mAb or 225 Fab' did not activate EGF receptor tyrosine kinase when assayed after lysis of cells in SDS sample buffer. However, when cells were cultured with bivalent 225 mAb, but not with monovalent 225 Fab', and were subsequently lysed and further incubated in Triton X-100 lysis buffer containing proteinase and phosphatase inhibitors, receptor phosphorylation was observed. Phosphorylation was confined to tyrosine residues and was inhibited by addition of genistein after lysis, indicating that it was due to the activation of protein tyrosine kinase. The activity of bivalent 225 mAb was unphysiologic, in contrast with TGF-alpha, in that receptor kinase activation occurred only after cell lysis and with delayed kinetics; serine and threonine phosphorylation did not occur; and down-regulation of EGF receptors was slower. Selective mAb-mediated phosphorylation of tyrosine residues on EGF receptors was sufficient to activate phosphorylation of a SH2 group-bearing substrate, phospholipase C-gamma, indicating that serine/threonine phosphorylation is not required for EGF receptor kinase activity. These studies provide novel insights into the capacity of bivalent mAb to modulate EGF receptor function.
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PMID:Regulation of epidermal growth factor receptor in NIH3T3/HER14 cells by antireceptor monoclonal antibodies. 840 44

We investigated the effect of extracellular ATP on the interaction of epidermal growth factor (EGF) with its receptor in cultured renal epithelial cells, LLC-PK1. Pretreatment with ATP, but not adenosine, inhibited the binding of 125I-labeled EGF. The inhibition demonstrated by ATP resulted from a decrease in the affinity of EGF receptors for its ligand, with no change in the number of EGF receptors. Incubation of phorbol 12-myristate 13-acetate (PMA) for 30 min mimicked the ATP-mediated inhibition. On the other hand, prolonged pretreatment with PMA, which leads to disappearance of protein kinase C activity, reversed the inhibition. In addition, pretreatment with the protein kinase C inhibitor 1-(5-isoquinoline sulfonyl)-2-methylpiperazine prevented the ATP-mediated inhibition. ATP triggered an increase in inositol 1,4,5-trisphosphate levels and translocation of protein kinase C from cytosol to membranes, consist with the stimulation of phospholipase C and the activation of protein kinase C. These results demonstrate that extracellular ATP attenuates the ligand binding affinity of EGF receptor via the stimulation of phospholipase C, leading to the activation of protein kinase C in the LLC-PK1 cells.
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PMID:Extracellular ATP-induced regulation of epidermal growth factor signaling in cultured renal LLC-PK1 cells. 847 24

Both epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) produce a dose-dependent stimulation in the rate of cell division in a rat clonal dental pulp-cell line (RDP 4-1). To elucidate the initial mitogen-induced cellular events that may mediate mitogenic action, the effects of EGF and IGF-I on cellular protein tyrosine phosphorylation were examined. In a dose-dependent manner, EGF (1-100 ng/ml) transiently stimulated tyrosine phosphorylation in four major proteins with apparent molecular weights of 220, 180, 140 and 120 kDa, and in five other more minor proteins (90, 80, 65, 55 and 44 kDa). IGF-I (1-100 ng/ml) dose-dependently stimulated the tyrosine phosphorylation of 160- and 140-kDa proteins, and had a smaller effect on the 80-, 65- and 44 kDa proteins. In contrast to the action of EGF, IGF-I-induced tyrosine phosphorylation was sustained for more than 60 min, particularly that of the 160-kDa phosphoprotein. From the results of specific immunoprecipitation/Western-blot analyses, the 180-kDa EGF-sensitive protein could be identified as the EGF receptor (EGF-R). Among the IGF-I-sensitive pulp cell proteins, the 160-kDa protein was identified as insulin-receptor substrate-1. Both mitogenic treatments stimulated the tyrosine phosphorylation of a weak, 44-kDa protein, which we have identified as the extracellular signal-regulated kinase-1. Despite the presence of phosphoproteins of the correct size, neither the IGF-I receptor (IGF-I-R) nor the phospholipase C gamma-isoform could be identified as tyrosine kinase substrates in either treatment. Pretreatment with the tyrosine kinase inhibitor genistein (20 micrograms/ml) significantly inhibited EGF- and IGF-I-induced tyrosine phosphorylation in permeabilized RDP 4-1 cells, and the tyrosine phosphatase inhibitor orthovanadate (1 mM) significantly prolonged the duration of the mitogen-stimulated tyrosine phosphorylation in both intact or permeabilized cells. Phorbol 12-myristate 13-acetate (100 nM), which activates protein kinase C (PKC), inhibited the tyrosine phosphorylation induced by either growth factor. This action was blocked by pretreatment with staurosporine (200 nM, 15 min), a selective PKC inhibitor. However, neither removing external Ca2+ with EGTA (1 mM) nor inducing Ca2+ influx with A23187 ionophore (2 microM) significantly altered EGF- or IGF-I-induced phosphorylation. These findings strongly suggest that authentic EGF-R and IGF-I-R on RDP 4-1 cells are coupled to complex, tyrosine kinase-mediated, intracellular signalling systems that are sensitive to a PKC-dependent mechanism. EGF- and IGF-I-induced tyrosine phosphorylation cascades may have important roles in vivo in the regulation of dental pulp-cell proliferation and ultimately may affect dentine formation.
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PMID:Protein tyrosine phosphorylation induced by epidermal growth factor and insulin-like growth factor-I in a rat clonal dental pulp-cell line. 852 2

Exposing normal human breast epithelia (HBE) cells, which were growth arrested by a 3-day culture in EGF-deprived medium, to the microtubule disrupting agent, demecolcin (N-deacetyl-N-methyl-colchicine), for 2 hr significantly stimulated the initiation of DNA synthesis 22 hr later. The demecolcin-induced DNA synthesis was not accompanied by activation of the EGF receptor and it was inhibited by calphostin C, an inhibitor of protein kinase C (PKC), and U-73122, an inhibitor of phospholipase C (PLC). Contrary to this, the EGF-induced DNA synthesis was inhibited by tyrphostin A25, a specific inhibitor of the EGF receptor tyrosine kinase, and calphostin C. The results suggested that the involvement of PLC and PKC in the demecolcin-induced signal transduction pathway leads to the initiation of DNA synthesis.
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PMID:Inhibition of demecolcin-induced DNA synthesis by inhibitors of phospholipase C and protein kinase C. 861 1

Recent evidence indicates that reactive oxygen species (ROS) may function as intracellular messengers in receptor signaling pathways. The possible role of ROS in epidermal growth factor (EGF) signaling was therefore investigated. Stimulation of A431 human epidermoid carcinoma cells with EGF resulted in a transient increase in the intracellular concentration of ROS, measured with the oxidation-sensitive fluorescent probe 2',7'-dichlorofluorescin diacetate and laser-scanning confocal microscopy. The predominant ROS produced appeared to be H2O2, because the EGF-induced increase in fluorescence was completely abolished by incorporation of catalase into the cells by electroporation. The elimination of H2O2 by catalase also inhibited the EGF-induced tyrosine phosphorylation of various cellular proteins including the EGF receptor and phospholipase C-gamma1. The dependence of H2O2 production on the intrinsic tyrosine kinase activity of the EGF receptor and the autophosphorylation sites located in its COOH-terminal tail was investigated. EGF failed to induce H2O2 generation in cells expressing a kinase-inactive EGF receptor. However, normal H2O2 generation was observed in cells expressing a mutant receptor from which the 126 COOH-terminal amino acids had been deleted to remove four (out of the total of five) autophosphorylation sites. These results suggest that EGF-induced H2O2 formation requires the kinase activity but probably not the autophosphorylation sites of the EGF receptor and that inhibition of protein tyrosine phosphatase activity by H2O2 may be required for EGF-induced protein tyrosine phosphorylation to be manifested.
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PMID:Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. 899 50

Mutation of the autophosphorylation sites of receptor protein-tyrosine kinases alters ligand dependent internalization and down-regulation, indicating a critical role for these sites in receptor processing. Currently, no differences in receptor processing based on an individual autophosphorylation site have been defined. By using a glutathione S-transferase fusion protein containing the src homology 2 domains of phospholipase C-gamma1 to specifically recognize tyrosine 992 on the EGF receptor (Tyr(P)992), we have found differences in this subpopulation of receptors. Following EGF stimulation, the number of Tyr(P)992 receptors increased 2-fold over receptors identified by an antibody that recognizes activated EGF receptors (alpha-Act. EGFR) in A431 cells. Confocal fluorescence microscopy showed that Tyr(P)992 receptors underwent endocytosis at a slower rate and did not rapidly concentrate in juxtanuclear bodies. Tyr(P)992 receptors were associated with more SOS, Ras-GTPase activating protein, phosphatidylinositol 3-kinase, and SHPTP2/syp, but less Grb2, than receptors in the general population, and these receptors were more heavily phosphorylated than the general population of active receptors. These findings suggest that autophosphorylation status is relevant to the endocytosis, degradation, and effector molecule interaction of individual EGF receptors. Further investigations based on phosphorylation status should provide new insights into how receptor protein-tyrosine kinase signaling is regulated.
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PMID:Subsets of epidermal growth factor receptors during activation and endocytosis. 902 Jan 17

In the present study, isolated pancreatic acinar membranes were used to investigate the mechanism of epidermal growth factor (EGF)-induced activation of phospholipase C (PLC). The data show that EGF caused a rapid and strong increase in tyrosine phosphorylation of the EGF receptor, with a maximum 5-15 s after the beginning of the incubation followed by a decline. With use of [3H]phosphatidylinositol 4,5-bisphosphate as an exogenous substrate, PLC activity increased fourfold on exposure of the membranes to EGF (85 nM). In contrast, EGF-induced tyrosine phosphorylation of PLC-gamma 1 was rather small, indicating that tyrosine phosphorylation of PLC-gamma 1 is not proportional to changes in PLC activity. EGF-induced activation of PLC was strongly inhibited by pretreatment of the membranes with pertussis toxin, by an antibody raised against a COOH-terminal sequence shared by alpha-subunits of the inhibitory G proteins G(i)1 and G(i)2, and by an anti-PLC-gamma 1 antibody, whereas anti-G(i) alpha 3, anti-Gq/11 alpha, and anti-PLC-beta 1 antibodies had no effect. In contrast, pertussis toxin or the anti-G(i) alpha 1-2 antibody had no effect on EGF-induced tyrosine phosphorylation of PLC-gamma 1. EGF promoted association of G(i) proteins with both the EGF receptor and PLC-gamma 1 with similar kinetics as EGF-receptor autophosphorylation. All EGF-induced responses were abolished by the specific tyrosine kinase inhibitor pp60v-arc (137-157), suggesting that EGF-receptor tyrosine kinase activity is essential for G(i)1-2-mediated activation of PLC-gamma 1. However, there was no evidence of tyrosine phosphorylation of G(i) alpha 1-2. Taken together, these data show that EGF causes activation of PLC-gamma 1 by a mechanism requiring activation of G(i)1-2 and only a small increase in tyrosine phosphorylation of PLC-gamma 1.
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PMID:Epidermal growth factor activates phospholipase C-gamma 1 via G(i)1-2 proteins in isolated pancreatic acinar membranes. 917 40

Epidermal growth factor (EGF)-induced autophosphorylation of the EGF receptor results in high-affinity binding of the adaptor protein GRB2, which serves as a convergence point for multiple signaling pathways. Present studies demonstrate that EGF induces the co-immunoprecipitation of phospholipase C (PLC)-gamma1 with the adaptor protein GRB2 and the guanine nucleotide exchange factor Sos, but not with the adaptor protein SHC, in WB cells. Inhibition of PLC-gamma1 tyrosine phosphorylation by phenylarsine oxide reduces the co-immunoprecipitation of PLC-gamma1 with GRB2. Furthermore, angiotensin II, a G protein-coupled receptor agonist, also induces the tyrosine phosphorylation of PLC-gamma1 and its co-immunoprecipitation with GRB2 in WB cells. Interestingly, angiotensin II stimulation also causes tyrosine phosphorylation of the EGF receptor, suggesting that angiotensin II-induced PLC-gamma1 tyrosine phosphorylation in WB cells may be via EGF receptor tyrosine kinase activation. In addition, there is some level of association between PLC-gamma1 and GRB2 that is independent of the tyrosine phosphorylation of PLC-gamma1 in both in vivo and in vitro studies. In vitro studies further demonstrate that the Tyr771 and Tyr783 region of PLC-gamma1 and the SH2 domain of GRB2 are potentially involved in the tyrosine phosphorylation-dependent association between PLC-gamma1 and GRB2. The association of PLC-gamma1 with GRB2 and Sos suggests that PLC-gamma1 may be directly involved in the Ras signaling pathway and that GRB2 may be involved in the translocation of PLC-gamma1 from cytosol to the plasma membrane as a necessary step for its effect on inositol lipid hydrolysis.
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PMID:A new function for phospholipase C-gamma1: coupling to the adaptor protein GRB2. 928 17


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