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)

Lacrimal gland protein secretion is primarily under the control of cholinergic muscarinic and alpha 1-adrenergic receptors. Cholinergic agonists are coupled to the activation of phospholipase C (PLC), which leads to the production of two second messenger molecules: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 increases the cytoplasmic concentration of calcium ([Ca2+]i), and DAG activates protein kinase C (PKC), two events that are thought to trigger protein secretion. Lacrimal gland alpha 1-adrenergic receptors are not coupled to the PLC pathway, although their activation leads to a slight increase in [Ca2+]i(3). We have also shown that unlike the cholinergic receptors, alpha 1-adrenergic receptors are not linked to the activation of phospholipase D in lacrimal gland acini. Thus the transduction pathway(s) used by the alpha 1-adrenergic receptors to trigger lacrimal gland protein secretion remains to be identified. PKC was originally described as a Ca2+ and phospholipid-dependent protein kinase activated by DAG produced by the receptor-mediated breakdown of phosphoinositides. Molecular cloning and biochemical techniques have shown that PKC is a family of closely related enzymes consisting of at least eleven different isoforms that has been divided into three categories: (1) conventional PKCs, including PKC alpha, beta I, -beta II and -gamma isoforms have a Ca2+ and DAG-dependent kinase activity; (2) novel PKCs, including PKC epsilon, -delta, -theta, -nu, and -mu isoforms, are Ca(2+)-independent and DAG-stimulated kinases; (3) atypical PKCs, including PKC zeta, and -iota/lambda isoforms, are Ca2+ and DAG-independent kinases. All PKC isoforms, except PKC mu, have a pseudosubstrate sequence in their N-terminal part that is thought to interact with the catalytic domain to keep the enzyme inactive in resting cells. In previous studies, we showed that lacrimal gland acini express three isoforms of PKC: PKC alpha -delta, and -epsilon. In the present study, we report the identification of two other PKC isoforms, namely PKC mu and -iota/lambda. We show that these isoforms are differentially located and that they translocate differentially in response to phorbol esters and cholinergic agonists. We also show that PKC isoforms differentially control lacrimal gland protein secretion and cholinergic-induced Ca2+ elevation. Part of these results has been recently published.
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PMID:Lacrimal gland functions are differentially controlled by protein kinase C isoforms. 959 15

Previous results have shown that the human promyelocytic leukemia HL-60 cell line responds to either proliferating or differentiating stimuli. When these cells are induced to proliferate, protein kinase C (PKC)-beta II migrates toward the nucleus, whereas when they are exposed to differentiating agents, there is a nuclear translocation of the alpha isoform of PKC. As a step toward the elucidation of the early intranuclear events that regulate the proliferation or the differentiation process, we show that in the HL-60 cells, a proliferating stimulus (i.e., insulin-like growth factor-I [IGF-I]) increased nuclear diacylglycerol (DAG) production derived from phosphatidylinositol (4,5) bisphosphate, as indicated by the inhibition exerted by 1-O-octadeyl-2-O-methyl-sn-glycero-3-phosphocholine and U-73122 (1-[6((17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione), which are pharmacological inhibitors of phosphoinositide-specific phospholipase C. In contrast, when HL-60 cells were induced to differentiate along the granulocytic lineage by dimethyl sulfoxide, we observed a rise in the nuclear DAG mass, which was sensitive to either neomycin or propranolol, two compounds with inhibitory effect on phospholipase D (PLD)-mediated DAG generation. In nuclei of dimethyl sulfoxide-treated HL-60 cells, we observed a rise in the amount of a 90-kDa PLD, distinct from PLD1 or PLD2. When a phosphatidylinositol (4,5) bisphosphate-derived DAG pool was generated in the nucleus, a selective translocation of PKC-beta II occurred. On the other hand, nuclear DAG derived through PLD, recruited PKC-alpha to the nucleus. Both of these PKC isoforms were phosphorylated on serine residues. These results provide support for the proposal that in the HL-60 cell nucleus there are two independently regulated sources of DAG, both of which are capable of acting as the driving force that attracts to this organelle distinct, DAG-dependent PKC isozymes. Our results assume a particular significance in light of the proposed use of pharmacological inhibitors of PKC-dependent biochemical pathways for the therapy of cancer disease.
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PMID:Proliferating or differentiating stimuli act on different lipid-dependent signaling pathways in nuclei of human leukemia cells. 1190 74

Listeriolysin O (LLO) and a phosphatidylinositol-specific phospholipase C (PI-PLC) are known virulence factors of Listeria monocytogenes in both tissue cultures and the murine model of infection. LLO is a member of a family of pore-forming cholesterol-dependent cytotoxins and is known to play an essential role in escape from the primary phagocytic vacuole of macrophages. PI-PLC plays an accessory role, in that PI-PLC mutants are partially defective in escape. We have shown that both of these molecules are essential for initiating rapid increases in the calcium level in the J774 murine macrophage cell line (S. J. Wadsworth and H. Goldfine, Infect. Immun. 67:1770-1778, 1999). Here we show that both LLO and PI-PLC are required for translocation of protein kinase C delta (PKC delta) to the periphery of J774 cells and for translocation of PKC beta II to early endosomes beginning within the first minute after addition of bacteria to the culture medium. Treatment with the calcium channel blocker SK&F 96365 inhibited translocation of PKC beta II but not PKC delta. Our findings lead us to propose a host signaling pathway requiring LLO and the formation of diacylglycerol by PI-PLC in which calcium-independent PKC delta is responsible for the initial calcium signal and the subsequent PKC beta II translocation. LLO-dependent translocation of PKC beta I to early endosomes also occurs between 1 and 4 min after infection, but this occurs in the absence of PI-PLC. All of these signals were observed in cells that had not internalized bacteria. Blocking PKC beta translocation with hispidin resulted in more rapid uptake of wild-type bacteria and greatly reduced escape from the primary phagocytic vacuoles of J774 cells.
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PMID:Mobilization of protein kinase C in macrophages induced by Listeria monocytogenes affects its internalization and escape from the phagosome. 1211 79

The primary purpose of this investigation was to determine the relationship between phospholipase C (PLC) and diacylglycerol (DAG) sensitive protein kinase C isoforms in insulin signaling in skeletal muscle. Using an in vitro preparation of rat soleus muscle we found that insulin (0.6 nM) stimulated glucose transport was inhibited approximately 20 and 25% by the PKC inhibitor GF109203X and the phospholipase C inhibitor U73122 respectively (p<0.05). The combined effects of these inhibitors were no greater than the inhibitory effects of either compound alone. Western blot analysis revealed that insulin induced a redistribution of PKC beta II from the cytosol to the membrane that was reversed in the presence of GF109203X (1 microM) and U73122 (20 microM). Similarly, U73122 and GF109203X reversed the insulin induced increase in membrane associated phosphorylated (ser 660) PKC beta II. The novel finding of this investigation is that insulin induces an increase in PKC beta II translocation and phosphorylation through a U73122 sensitive pathway in quantatively the most important insulin responsive tissue, skeletal muscle. Furthermore, these results imply that PKC beta II may be one of the DAG sensitive isoforms involved in glucose transport.
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PMID:Evidence for the involvement of a phospholipase C--protein kinase C signaling pathway in insulin stimulated glucose transport in skeletal muscle. 1272 87

The tryptase locus on mouse chromosome 17A3.3 contains 13 genes that encode enzymatically active serine proteases with different tissue expression profiles and substrate specificities. Mouse mast cell protease (mMCP) 6, mMCP-7, mMCP-11/protease serine member S (Prss) 34, tryptase 6/Prss33, tryptase epsilon/Prss22, implantation serine protease (Isp) 1/Prss28, and Isp-2 are constitutively exocytosed enzymes. We now demonstrate that tryptase 5/Prss32, pancreasin/Prss27, and testis serine protease-1 are inserted into plasma membranes via glycosylphosphatidylinositol (GPI) anchors analogous to Prss21, and that these serine proteases can be released from the cell's surface by a phosphatidylinositol-specific phospholipase C. These data suggest that the C-terminal residues play key roles in determining where tryptases compartmentalize in cells. GPI-anchored proteins are targeted to lipid rafts. Thus, our identification of a number of GPI-anchored tryptases whose genes reside at mouse chromosome 17A3.3 also implicates important biological functions for this new family of serine proteases on the surfaces of cells.
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PMID:Identification of a subgroup of glycosylphosphatidylinositol-anchored tryptases. 1614 3

We have previously elucidated that Epstein-Barr-virus-encoded latent membrane protein 1 (LMP1) can increase the serine phosphorylation level of annexin A2 by activating the protein kinase C (PKC) signaling pathway and that LMP1 induces the nuclear entry of annexin A2 in an energy- and temperature-dependent manner. Here, we further confirm that LMP1 increases the serine phosphorylation level of annexin A2 by activating the phosphoinositide-specific phospholipase C (PI-PLC)-PKC alpha/PKC beta pathway, mainly through the activation of the PKCbeta pathway. Additionally, active recombinant PKC alpha, PKC beta I, and PKC beta II kinases are able to phosphorylate annexin A2 in vitro. Annexin A2 in the nucleus plays an important role in DNA synthesis and cell proliferation. By site-specific substitution of glutamic acid in the place of serine 11 and 25 in the N-terminus, we show that serine 25 phosphorylation of annexin A2 was associated with the nuclear entry of annexin A2, DNA synthesis and cell proliferation, whereas serine 11 has no obvious influence. We demonstrate for the first time that the PI-PLC-PKCalpha/PKCbeta pathway plays an important role in serine phosphorylation and in the nuclear entry of annexin A2 mediated by LMP1. In addition, we show that annexin A2 is the substrate protein of PKC alpha, PKC betaI, and PKC betaII kinases. Serine 25 phosphorylation of annexin A2 is shown to be associated with its nuclear entry, DNA synthesis, and cell proliferation.
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PMID:Epstein-Barr virus latent membrane protein 1 mediates serine 25 phosphorylation and nuclear entry of annexin A2 via PI-PLC-PKCalpha/PKCbeta pathway. 1841 41

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