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)

Insulin is known to control a number of anabolic metabolic processes in a variety of target tissues through activation of cell surface receptors. It is clear that insulin receptor activation provokes increases in tyrosine kinase activity and autophosphorylation of the insulin receptor, but subsequent events have not been elucidated. Recently, it has become clear that insulin provokes the following rapid changes in phospholipid metabolism, which result in the generation of several intercellular signaling substances (or mediators): (1) hydrolysis of a phosphatidylinositol-glycan; (2) stimulation of de novo synthesis of phosphatidic acid; and (3) hydrolysis of phosphatidylcholine by a phospholipase C and/or D. Hydrolysis of the phosphatidylinositol-glycan leads to the release of polar headgroups, which serve as mediators to activate phosphatases, and may thereby account for a number of insulin effects on carbohydrate metabolism, lipid metabolism, and regulation of cyclic nucleotide metabolism. All three phospholipid effects of insulin also generate diacylglycerol, which activates protein kinase C, and this may contribute to insulin effects on glucose transport, ion and amino acid transport, protein synthesis, and gene expression (messenger RNA synthesis). Combined, the headgroup mediators and diacylglycerol-protein kinase C signaling systems may account for many, or perhaps most, of insulin's actions. Moreover, the three phospholipid effects of insulin appear to be coordinated, and may function as an integrated cycle to ensure the continued synthesis of lipids, which are the sources of the signaling substances during insulin action.
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PMID:Phospholipid signaling systems in insulin action. 305 93

The effects of tumour-promoting phorbol esters on the receptor-mediated endocytosis of insulin were investigated in the human hepatoma cell line HepG2. Treatment of these cells with the biologically active phorbol 12-O-tetradecanoylphorbol 13-acetate (TPA), but not with the non-tumour-promoting analogue 4 alpha-phorbol 12,13-didecanoate, resulted in dramatic morphological changes, which were accompanied by a 1.5-2.5-fold increase in specific 125I-insulin association with the cells at 37 degrees C. This increase in insulin binding was not observed when the binding reaction was performed at 4 degrees C. The potentiation of 125I-insulin association with TPA-treated cells at 37 degrees C could be completely accounted for by an increase in the intracellular pool of internalized insulin; there was no concomitant increase in cell-surface insulin binding. Dissociation studies showed that the enhanced internalization of insulin by cells after treatment with TPA resulted from a decrease in the rate of intracellular processing of the insulin after receptor-mediated endocytosis. The phorbol-ester-induced enhancement of internalized insulin in HepG2 cells was additive with the potentiation of endocytosed insulin induced by both the lysosomotropic reagent chloroquine and the ionophore monensin; this indicates that TPA affects the intracellular processing of the insulin receptor at a point other than those disrupted by either of these two reagents. The potentiation of insulin receptor internalization by tumour-promoting phorbol esters could be completely mimicked by treatment with phospholipase C, but not with phospholipase A, and partially mimicked by treatment with the synthetic diacylglycerol 1-oleoyl-2-acetylglycerol. By these criteria, the effects of phorbol esters on the insulin receptor in HepG2 cells appear to be mediated through protein kinase C. These results support the concept that the activation of protein kinase C by treatment with phorbol esters causes a perturbation of the insulin-receptor-mediated endocytotic pathway in HepG2 cells, reflected in a long-term decreased rate of dissociation of internalized insulin by the phorbol-ester-treated cells.
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PMID:Potentiation of specific association of insulin with HepG2 cells by phorbol esters. 353 1

The effect of alterations to the insulin receptor on the insulin sensitivity of isolated adipocytes was studied. Receptor changes were induced by treatment of adipocytes with either phospholipase C or trypsin. After enzyme treatment, binding of insulin to insulin receptors and insulin-mediated glucose metabolism were examined. Exposure of adipocytes to phospholipase C (2 units/ml) significantly increased insulin binding to the cells, but destroyed the ability of the cells to oxidize glucose. After treatment with trypsin (500 micrograms/ml) for 5 min, insulin binding to the adipocytes was significantly increased. This was shown to be due to an increase in insulin-receptor affinity. Metabolic studies showed that trypsin treatment led to an increase in basal glucose transport but markedly decreased the response to insulin at all concentrations tested. Adipocytes treated with trypsin showed no significant difference in basal glucose oxidation rates when compared with controls, but were less sensitive to insulin at low insulin concentrations, and showed a decreased maximum response at high insulin concentrations. In conclusion, these findings indicate a dissociation between induced changes in binding of insulin to insulin receptors and subsequent hormone action. The importance of post-receptor events in the biological action of insulin is highlighted.
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PMID:The effects of trypsin and phospholipase C on insulin binding and action in the isolated adipocyte. 699 Sep 21

The receptors for insulin and PDGF are tyrosine kinases that mediate distinct effects in identical cellular backgrounds. Each receptor must therefore engage a unique subset of the available signaling elements--at least partly through the selection of proteins with src-homology 2 domains (SH2 proteins). Autophosphorylation sites in the PDGFr directly bind SH2 proteins, whereas activation of the insulin receptor leads to phosphorylation of IRS-1, which in turn binds SH2 proteins. In HIR 3.5 cells, which contain similar numbers of PDGF and insulin receptors, insulin, but not PDGF, stimulated tyrosyl phosphorylation of IRS-1. Similarly, insulin, but not PDGF, treatment of HIR 3.5 stimulated the association of IRS-1 with PtdIns 3'-kinase, although PDGF stimulated the association of PtdIns 3'-kinase with the tyrosine-phosphorylated PDGFr. Association with IRS-1 activated PtdIns 3'-kinase more effectively than association with the PDGFr. Whereas the PDGFr associated with PtdIns 3'-kinase, ras-GAP, GRB-2, and phospholipase C gamma, only GRB-2 and PtdIns 3'-kinase associated with IRS-1. Moreover, PDGF, but not insulin, caused tyrosine phosphorylation of phospholipase C gamma in HIR 3.5 cells. Thus, the insulin signal differs from that of PDGF by the insertion of a cytosolic, nonreceptor SH2 domain docking protein (IRS-1). Furthermore, IRS-1 binds a different subset of SH2 domain-containing proteins than does the PDGFr and regulates at least one common element (PtdIns 3'-kinase) differently than the PDGFr. These results support the hypothesis that IRS-1 differentiates the signals generated by the insulin receptor and PDGFr tyrosine kinases by binding and regulating a specific subset of SH2 domain-containing signaling molecules.
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PMID:Common and distinct elements in insulin and PDGF signaling. 748 83

There is a 3-aa insertion in the transmembrane (TM) domain of the p68gag-ros protein-tyrosine kinase encoded by avian sarcoma virus UR2 v-ros as compared with that of the protooncogene c-ros. The effect of this insertion on biological function and biochemical properties of v-Ros protein was investigated by deleting these 3 aa to generate the mutant TM1. This mutant has greatly reduced transforming, mitogenic, and tumorigenic activities despite the fact that the protein-tyrosine kinase activity and cell-surface localization of TM1 protein are unaffected. However, unlike UR2 protein, mutant TM1 protein becomes glycosylated, is differentially phosphorylated, and fails to induce tyrosine phosphorylation of a 88-kDa protein and a major substrate of insulin receptor, insulin receptor substrate 1. The TM1 protein is unable to associate with phosphatidylinositol 3-kinase and fails to promote association of insulin receptor substrate 1 with phosphatidylinositol 3-kinase. By contrast, tyrosine phosphorylation of Shc protein and phospholipase C gamma as well as interaction of Grb2 protein with Shc and SOS protein signaling components are unaltered in the TM1 infected cells. Our results show that the TM-domain sequence of p68gag-ros profoundly affects its function and substrate interaction. The mutant defines a signaling pathway including phosphatidylinositol 3-kinase, insulin receptor substrate 1, and possibly an 88-kDa protein that does not overlap the Ras pathway and is important for full transforming and mitogenic potency of v-ros protein-tyrosine kinase.
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PMID:Modulatory effect of the transmembrane domain of the protein-tyrosine kinase encoded by oncogene ros: biological function and substrate interaction. 752 86

The initiation of saliva formation by parotid acinar cells, which comprise the majority of cells in this salivary gland, is initiated by the release of neurotransmitters (acetylcholine, substance P) from parasympathetic nerves. In response to substance P and the muscarinic agonist carbachol, two ligands that activate phospholipase C-linked receptors, which stimulate fluid secretion, PKC delta was phosphorylated on tyrosine residues. The maximal agonist-dependent tyrosine phosphorylation occurred within seconds of the addition of either agonist and then returned rapidly to a smaller increased level. Phorbol ester also caused a rapid increase in tyrosine phosphorylation, which reached a maximal level 5 min after the addition of phorbol 12-myristate 13-acetate. The increase in tyrosine phosphorylation of PKC delta was blocked by tyrosine kinase inhibitors genistein and staurosporine. Ionophore-mediated elevation of [Ca2+]i or activation of the beta-adrenergic receptor, epidermal growth factor receptor, or insulin receptor did not promote the tyrosine phosphorylation of PKC delta. These results indicate that tyrosine phosphorylation plays a role in early signal transduction events promoted by the activation of muscarinic and substance P receptors and suggests that the tyrosine phosphorylation of PKC delta has a role in the activation of fluid secretion by neurotransmitters binding to phospholipase C-linked receptors.
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PMID:Carbachol, substance P, and phorbol ester promote the tyrosine phosphorylation of protein kinase C delta in salivary gland epithelial cells. 753 27

Rapid and long term effects of protein kinase C alpha activation on receptor tyrosine kinase signaling parameters were investigated in human 293 embryonic fibroblasts and mouse NIH 3T3 cells. Within minutes of phorbol 12-myristate 13-acetate treatment, epidermal growth factor receptor and HER2 tyrosine phosphorylation was decreased, while platelet-derived growth factor receptor and insulin receptor autophosphorylation was upregulated. These effects are not mediated by protein kinase C-dependent receptor tyrosine kinase phosphorylation but apparently by activation or inactivation of receptor tyrosine kinase-specific phosphatases, as indicated by neutralization of these phenomena upon treatment of cells with sodium orthovanadate. In contrast to these short term effects, sustained activation of protein kinase C alpha by phorbol 12-myristate 13-acetate results in translocation of protein kinase C from the cytosol to the membrane fraction where it forms stable complexes with all receptor tyrosine kinases investigated. Ligand-induced receptor tyrosine kinase/protein kinase C association in NIH 3T3 fibroblasts is accompanied by a mobility shift of the receptor, indicating phosphorylation by activated protein kinase C. This phenomenon correlates with the disappearance of receptor tyrosine kinases from the cell surface, implying that this interaction plays a role in the process of receptor internalization and degradation. Interestingly, ligand-stimulated receptor down-regulation is also enhanced by overexpression of phospholipase C gamma, which strongly indicates a role for this common receptor tyrosine kinase substrate in negative regulation of growth factor signals.
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PMID:Rapid and long-term effects on protein kinase C on receptor tyrosine kinase phosphorylation and degradation. 764 54

We have previously demonstrated that mechanical unweighting of the soleus muscle by hindlimb suspension leads to increases in insulin receptor binding, muscle/fat-specific glucose transporter (GLUT-4) protein levels, and insulin-stimulated glucose transport activity. The present study used a novel approach to further evaluate the potential role of postreceptor binding mechanisms in this enhanced insulin effect after unweighting. Insulin-like growth factor I (IGF-I), vanadate, and phospholipase C were used to stimulate glucose transport activity independently of insulin receptor binding. Soleus glucose transport activity (assessed by 2-deoxyglucose uptake) was evaluated in vitro with soleus strips (approximately 18 mg). Progressively increased responses to maximally effective doses of insulin or IGF-I were observed after 3 and 6 days of unweighting compared with weight-matched control strips. Enhanced maximal responses to vanadate (6 days only) and phospholipase C (3 and 6 days) for 2-deoxyglucose uptake were also observed. The results of this study 1) provide evidence that post-insulin receptor binding mechanisms also play a role in the enhanced response of the insulin-dependent pathway for stimulation of glucose transport in unweighted skeletal muscle and 2) indicate that IGF-I action on glucose transport is included in this enhanced response in unweighted muscle.
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PMID:Effect of insulin-like factors on glucose transport activity in unweighted rat skeletal muscle. 822 87

An inositol phosphoglycan that is the polar head group of a glycosyl phosphatidylinositol has been considered as a putative mediator of insulin action. To gain insight into the functions of this hormone during development, the relationships between insulin, insulin receptors, glycosyl phosphatidylinositol, and inositol phosphoglycan were studied. Glycosyl phosphatidylinositol was isolated and characterized in fetal liver as early as day 15 of intrauterine life. In isolated hepatocytes from fetal and adult rats labeled with [3H]glucosamine, [3H]galactose, or [3H]myo-inositol, these molecules were incorporated into glycosyl phosphatidylinositol. In hepatocytes labeled with [3H]glucosamine and then allowed to react with [1-14C]IAI, the [3H]glycosyl phosphatidylinositol was purified as the 14C-labeled amidinated lipid. Glycosyl phosphatidylinositol molecules from fetal and adult cells were sensitive to hydrolysis by a phosphatidylinositol-specific phospholipase C from B. cereus. The product of this hydrolysis inhibits the activity of a cAMP-dependent protein kinase, whereas this effect was abolished by nitrous acid deamination. In isolated hepatocytes from adult animals, an inverse correlation between extracellular insulin and the number of insulin receptors and the cellular content of glycosyl phosphatidylinositol was observed. However, in fetal hepatocytes insulin failed to reduce the glycosyl-phosphatidylinositol content when labeled either with [1-14C]isethionyl acetimidate or [3H]glucosamine, whereas insulin-like growth factor I produced a significant hydrolysis of glycosyl phosphatidylinositol. Fetal and adult hepatocytes were incubated with insulin or inositol phosphoglycan after which glycogen phosphorylase activities were determined. Inositol phosphoglycan mimicked the action of insulin on both forms of the enzyme from adult hepatocytes, whereas in fetal cells insulin did not change, and purified inositol phosphoglycan reduced the activities of glycogen phosphorylase. These findings suggest a dissociation between insulin receptor occupancy and the expected hormonal effects in fetal hepatocytes. This could be related to alterations at a postreceptor level.
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PMID:Insulin does not induce the hydrolysis of a glycosyl phosphatidylinositol in rat fetal hepatocytes. 834 37

The molecular events that lead from the interaction of insulin with its receptor to the activation of protein serine/threonine kinases are still unknown. In this study, we have examined the role of GTP-binding proteins in this signaling pathway using differentiated 3T3-L1 adipocytes permeabilized with alpha-toxin from Staphylococcus aureus. Addition of GTP gamma S (guanosine 5'-O-(3-thiotriphosphate)) or insulin to such permeabilized cells markedly increases protein kinase activities in cell lysates using the microtubule-associated protein-2 kinase substrate peptide KRELVE-PLTPSGEAPNQALLR, which contains the threonine 669 phosphorylation site on the epidermal growth factor receptor. Similar stimulations of protein kinase activity by these agents are observed using the peptide KRRRLASLAA, which is selectively phosphorylated by ribosomal protein S6 kinases. The effects of insulin and GTP gamma S are not additive. Importantly, the GTP-binding protein antagonist GDP beta S (guanosine 5'-O-(2-thiodiphosphate)) inhibits the activation of the protein kinase activities by insulin in permeabilized 3T3-L1 adipocytes. These data are consistent with the hypothesis that activation of Ras or other GTP-binding proteins is a key element of the signaling mechanism whereby insulin receptor tyrosine kinase activates the microtubule-associated protein-2 kinase cascade.
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PMID:Activation of protein kinases by insulin and non-hydrolyzable GTP analogs in permeabilized 3T3-L1 adipocytes. 838 15


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