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PubMed2006

Identification of mitogen-activated protein kinase docking sites in enzymes that metabolize phosphatidylinositols and inositol phosphates.

BACKGROUND: Reversible interactions between the components of cellular signaling pathways allow for the formation and dissociation of multimolecular complexes with spatial and temporal resolution and, thus, are an important means of integrating multiple signals into a coordinated cellular response. Several mechanisms that underlie these interactions have been identified, including the recognition of specific docking sites, termed a D-domain and FXFP motif, on proteins that bind mitogen-activated protein kinases (MAPKs). We recently found that phosphatidylinositol-specific phospholipase C-gamma1 (PLC-gamma1) directly binds to extracellular signal-regulated kinase 2 (ERK2), a MAPK, via a D-domain-dependent mechanism. In addition, we identified D-domain sequences in several other PLC isozymes. In the present studies we sought to determine whether MAPK docking sequences could be recognized in other enzymes that metabolize phosphatidylinositols (PIs), as well as in enzymes that metabolize inositol phosphates (IPs). RESULTS: We found that several, but not all, of these enzymes contain identifiable D-domain sequences. Further, we found a high degree of conservation of these sequences and their location in human and mouse proteins; notable exceptions were PI 3-kinase C2-gamma, PI 4-kinase type IIbeta, and inositol polyphosphate 1-phosphatase. CONCLUSION: The results indicate that there may be extensive crosstalk between MAPK signaling and signaling pathways that are regulated by cellular levels of PIs or IPs.

Journal Article↗
PubMed1997

Anti-HLA antibody ligation to HLA class I molecules expressed by endothelial cells stimulates tyrosine phosphorylation, inositol phosphate generation, and proliferation.

The major threat to long-term survival of solid organ allografts is chronic rejection. Progressive narrowing and ultimate luminal occlusion of the arteries and arterioles of the transplanted organ are the hallmarks of the disease. The mechanism of chronic rejection is poorly understood, but it is suspected that the associated vascular changes are a result of anti-HLA antibody-mediated injury to the endothelium. We have postulated that anti-HLA antibodies initiate chronic rejection by binding to class I molecules on the endothelium and transducing signals that result in endothelial cell activation and proliferation. Our data demonstrate that anti-HLA class I antibodies transduce signals in endothelial cells stimulating increased tyrosine phosphorylation of intracellular proteins. Antibody binding to class I antigens also leads to the generation of inositol phosphate and endothelial cell proliferation. These results indicate that anti-HLA antibodies can deliver functionally important signals to endothelial cells, a finding that may be fundamental to an understanding of the mechanisms of chronic rejection.

Antibodies, Monoclonal↗
PubMed1998

The glycosyl-inositol-phosphate and dimyristoylglycerol moieties of the glycosylphosphatidylinositol anchor of the trypanosome variant-specific surface glycoprotein are distinct macrophage-activating factors.

The TNF-alpha-inducing capacity of different trypanosome components was analyzed in vitro, using as indicator cells a macrophage cell line (2C11/12) or peritoneal exudate cells from LPS-resistant C3H/HeJ mice and LPS-sensitive C3H/HeN mice. The variant-specific surface glycoprotein (VSG) was identified as the major TNF-alpha-inducing component present in trypanosome-soluble extracts. Both soluble (sVSG) and membrane-bound VSG (mfVSG) were shown to manifest similar TNF-alpha-inducing capacities, indicating that the dimyristoylglycerol (DMG) compound of the mfVSG anchor was not required for TNF-alpha triggering. Detailed analysis indicated that the glycosyl-inositol-phosphate (GIP) moiety was responsible for the TNF-alpha-inducing activity of VSG and that the presence of the GIP-associated galactose side chain was essential for optimal TNF-alpha production. Furthermore, the results showed that the responsiveness of macrophages toward the TNF-alpha-inducing activity of VSG was strictly dependent on the activation state of the macrophages, since resident macrophages required IFN-gamma preactivation to become responsive. Comparative analysis of the ability of both forms of VSG to activate macrophages revealed that mfVSG but not sVSG stimulates macrophages toward IL-1alpha secretion and acquisition of LPS responsiveness. The priming activity of mfVSG toward LPS responsiveness was also demonstrated in vivo and may be relevant during trypanosome infections, since Trypanosoma brucei-infected mice became gradually LPS-hypersensitive during the course of infection. Collectively, the VSG of trypanosomes encompasses two distinct macrophage-activating components: while the GIP moiety of sVSG mediates TNF-alpha induction, the DMG compound of the mfVSG anchor contributes to IL-1 alpha induction and LPS sensitization.

Animals↗
PubMed1993

A Gq-type G protein couples muscarinic receptors to inositol phosphate and calcium signaling in exocrine cells from the avian salt gland.

Muscarinic acetylcholine receptor (mAChR) activation in isolated cells from the nasal salt gland of the domestic duck (Anas platyrhynchos) results in a rapid increase in the rate of phosphatidylinositol hydrolysis and pronounced intracellular calcium signals. Both responses can be elicited by treating these cells with fluoroaluminate (AlF4-) indicating the involvement of a heterotrimeric G protein in the transmembrane signaling process. To characterize this G protein, electrophoretically separated membrane proteins were blotted onto nitrocellulose filters and probed with peptide-antibodies raised against portions of different alpha-subunits of mammalian G proteins. We could demonstrate the presence of at least four different G proteins in salt gland cell membranes. Two of these proteins (40 and 41 kD) were ADP-ribosylated by pertussis toxin and were recognized by an antiserum against a common sequence in all G protein alpha-subunits. One protein (46 kD) was a cholera toxin-substrate and was recognized by a Gs-specific antiserum; the other (42 kD) was recognized by Gq-specific antisera and was resistant to ADP-ribosylation. Since the initial inositol phosphate production upon receptor activation with carbachol and the resulting calcium signals were not affected by pertussis toxin-pretreatment of salt gland cells, we conclude that muscarinic receptors are coupled to phospholipase C by a Gq-type G protein.

Animals↗
PubMed2000

Human urotensin II mediates vasoconstriction via an increase in inositol phosphates.

The cyclic peptide urotensin II has recently been cloned from human and reported to potently constrict primate blood vessels. To elucidate the cellular signalling mechanisms of this peptide, we investigated a possible relationship of vasomotor effects of human urotensin II and phosphoinositide turnover in isolated rabbit thoracic aorta. Human urotensin II produced a slowly developing increase in isometric contractile force (pEC(50)=9.0) that was endothelium-independent. The contractile effect of urotensin II was significantly inhibited by the phospholipase C inhibitor, 2-nitro-4-carboxyphenyl-N,N,-diphenylcarbamate (NCDC), but not by the cyclooxygenase inhibitor, indomethacin. In slices of rabbit thoracic aorta, human urotensin II increased phosphoinositide hydrolysis, and this effect was also inhibited by NCDC. The potency of urotensin II (pEC(50)=8.6) was similar to that found in the contractile studies. Thus, vasoconstrictor effects of human urotensin II appear to be mediated by a phospholipase C-dependent increase in inositol phosphates, suggesting that the peptide acts via a G(q) protein-coupled receptor.

Animals↗
PubMed1989

Photolabile precursors of inositol phosphates. Preparation and properties of 1-(2-nitrophenyl)ethyl esters of myo-inositol 1,4,5-trisphosphate.

1-(2-Nitrophenyl)ethyl esters of D-myo-inositol 1,4,5-trisphosphate (InsP3) have been synthesized and shown to have suitable properties for use as photolabile precursors of InsP3. Synthesis was accomplished by treatment of InsP3 with 1-(2-nitrophenyl)diazoethane in a CHCl3/water mixture. This resulted in esterification of each of the three phosphate residues in InsP3, the 1-phosphate being more reactive than the 4- or 5-phosphate. Singly esterified P-1, P-4, and P-5 esters, termed P-1, P-4, and P-5 caged InsP3, were isolated from the reaction mixture by anion-exchange HPLC and characterized by 500-MHz 1H NMR spectroscopy. Each of these caged InsP3 esters exists as a pair of diastereoisomers and was identified by examining the effects of pH and nitrophenyl ring current shielding on the chemical shifts of nonexchangeable inositol protons. 1H NMR spectra of InsP3 were analyzed for comparison. On photolysis the compounds released InsP3 with rate constants of 175 (P-1), 225 (P-4), and 280 s-1 (P-5) as determined by monitoring the aci-nitro decay reaction at pH 7.1, 0.2 M ionic strength, 21 degrees C. Quantum yields determined by steady-state near-UV photolysis were 0.65 +/- 0.08 for each compound. P-4 and P-5 caged InsP3 were the most promising biologically inactive InsP3 precursors since at concentrations up to 50 microM they did not release Ca2+ from smooth muscle sarcoplasmic reticulum (SR) and were not metabolized by vascular smooth muscle InsP3 5-phosphatase or bovine brain InsP3 3-kinase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Light-induced changes in the content of inositol phosphates in squid (Loligo pealei) retina.

Illumination induced an increase in inositol polyphosphates, inositol 1,4-bisphosphate and inositol 1,4,5-trisphosphate, in the photoreceptors of the squid, Loligo pealei. There was a concomitant decrease in phosphatidylinositol 4,5-bisphosphate, but no light-induced change in any other phosphoinositide. None of these stimulus-induced changes were altered by treatment in vivo with pertussis toxin, which ADP-ribosylated a Mr-39000-peptide. These findings support the hypothesis that inositol 1,4,5-trisphosphate participates as either a messenger or a modulator in transduction in invertebrate photoreceptors.

Animals↗
PubMed2006

Phosphoinositides, inositol phosphates, and phospholipase C in embryonic stem cells.

The stimulation of inositol phospholipid metabolism via phospholipase C (PLC) is an important signal transduction pathway in a wide variety of cell types. Activation of the pathway is associated with many aspects of cellular activity, including cell growth and differentiation. Activation of hormone-sensitive PLC results in the rapid breakdown of polyphosphoinositides to generate two second messengers: inositol trisphosphate and diacylglycerol. The water-soluble inositol trisphosphate is involved in the release of intracellular calcium from internal stores, whereas the lipophilic diacylglycerol is involved in protein kinase C activation. Inositol supplementation is essential for the in vitro growth of rabbit blastocysts, and studies have shown that the components of the signaling system are present in mouse and cattle embryos and in mouse embryonic stem (ES) cells. In ES cells, the signaling system appears to be constitutively active and essential for normal ES cell proliferation. Here, we describe in detail the materials required and some of techniques involved in studying the phosphoinositide signaling system in mouse ES cells. Furthermore, we describe methods of analyzing the effects of modulating the PtdIns signaling system on ES cell proliferation and the induction of apoptosis.

Animals↗
PubMed1994

Effects of lithium chloride on rabbit blastocyst expansion, and accumulation of phosphoinositides and inositol phosphates.

The effects of lithium, an inhibitor of the recycling of inositol in the phosphatidylinositol cycle, on rabbit blastocyst growth and metabolism of phosphoinositides were investigated. Day 2 rabbit morulae were first cultured for 2 days in basic culture medium and then transferred to medium containing myo-[2-3H]inositol for culture for a further 3 days. At the end of culture, the resulting blastocysts were incubated with LiCl (0, 1, 5, 10, 20 mmol l-1) for 1 h. The blastocysts were then lysed and both the aqueous and lipid portions were analysed for incorporated radioactivity. Thin layer chromatographic separation of the lipid portion indicated that lithium had no significant effect on formation of radiolabelled phosphoinositides. However, high performance anion exchange chromatography indicated that lithium significantly stimulated accumulation of radiolabelled inositol monophosphate and inositol 1,4,5-trisphosphate. This result indicates that the phosphatidylinositol cycle is turning over in rabbit blastocysts. Continuous culture of rabbit embryos for 5 days in media containing LiCl (5, 10, 15 and 20 mmol l-1) significantly decreased blastocyst growth as measured by blastocyst expansion and incorporation of [3H]thymidine. However, supplementing the medium with excess inositol (up to 9375 mumol l-1), in an attempt to increase the intracellular uptake of inositol and thus compensate for the inhibitory effect of lithium on inositol recycling, did not reverse the inhibitory effect of lithium on blastocyst growth.

Animals↗
PubMed1984

Actions of inositol phosphates on Ca2+ pools in guinea-pig hepatocytes.

In permeabilized hepatocytes, inositol 1,4,5-trisphosphate, inositol 2,4,5-trisphosphate and inositol 4,5-bisphosphate induced rapid release of Ca2+ from an ATP-dependent, non-mitochondrial vesicular pool, probably endoplasmic reticulum. The order of potency was inositol 1,4,5-trisphosphate greater than inositol 2,4,5-trisphosphate greater than inositol 4,5-bisphosphate. The Ca2+-releasing action of inositol 1,4,5-trisphosphate is not inhibited by high [Ca2+], nor is it dependent on [ATP] in the range of 50 microM-1.5 mM. These results suggest a role for inositol 1,4,5-trisphosphate as a second messenger in hormone-induced Ca2+ mobilisation, and that a specific receptor is involved in the Ca2+-release mechanism.

Adenosine Triphosphate↗
PubMed1987

Modes of inhibitory action of protein kinase C in the chemotactic peptide-induced formation of inositol phosphates in differentiated human leukemic (HL-60) cells.

Using the [3H]inositol-labeled plasma membranes isolated from the differentiated human leukemic (HL-60) cells, the mode of inhibitory action of the Ca2+/phospholipid-dependent enzyme protein kinase C in the chemotactic peptide, fMet-Leu-Phe (fMLP)-induced, phospholipase C-mediated hydrolysis of phosphoinositides was investigated. In this cell-free membrane system, fMLP in the presence of GTP plus Ca2+, GTP in the presence of Ca2+, or Ca2+ alone could induce the formation of inositol bis- and trisphosphate (IP2 and IP3, respectively). When the intact cells were pre-treated with 12-O-tetradecanoylphorbol-13-acetate, the fMLP- and GTP-induced formation of IP2 and IP3 was markedly reduced but the Ca2+-induced reactions were not reduced in the isolated membranes. This result suggests that protein kinase C impairs the coupling of the GTP-binding protein to the phospholipase C. In another experiment, preincubation of the isolated membranes with pure rat brain protein kinase C inhibited the fMLP-induced formation of IP2, but did not inhibit the GTP- or Ca2+-induced reaction. Under the same conditions, protein kinase C did not inhibit the fMLP-, GTP-, or Ca2+-induced formation of IP3. This result suggests that protein kinase C impairs additionally the coupling of the fMLP receptor to the GTP-binding protein leading to the formation of IP2. The reason for the failure of protein kinase C to inhibit the fMLP-induced formation of IP3 in the cell-free membrane system is unknown, but several possible mechanisms are discussed.

2,3-Diphosphoglycerate↗
PubMed1993

Locus of action of Ni2+ on histamine-induced inositol phosphate formation in brain slices and in HeLa cells.

Histamine-induced [3H]inositol monophosphate ([3H]IP1) accumulation in slices of rat cerebral cortex and guinea-pig cerebral cortex and cerebellum was inhibited in a concentration-dependent manner by Ni2+ ions. The effect of Ni2+ on the concentration-response curve for histamine in rat cerebral cortex was consistent with non-competitive inhibition. In membranes from guinea-pig cerebral cortex inhibition by Ni2+ of the binding of [3H]mepyramine had the characteristics expected for an allosteric inhibitor at the histamine H1 receptor. Ni2+ had no effect on carbachol-induced [3H]IP1 formation in HeLa cells, but displaced the concentration-response curve for histamine to the right. The evidence suggests that Ni2+ can act at two sites to block histamine-induced [3H]IP1 accumulation in brain slices; at the level of the H1 receptor and on a probable Ca2+ entry component. In HeLa cells only the direct H1 receptor action is evident.

Animals↗
PubMed1996

New compatible solutes related to Di-myo-inositol-phosphate in members of the order Thermotogales.

The accumulation of intracellular organic solutes was examined in six species of the order Thermotogales by nuclear magnetic resonance spectroscopy. The newly discovered compounds di-2-O-beta-mannosyl-di-myo-inositol-1,1'(3,3')-phosphate and di-myo-inositol-1,3'-phosphate were identified in Thermotoga maritima and Thermotoga neapolitana. In the latter species, at the optimum temperature and salinity the organic solute pool was composed of di-myo-inositol-1,1'(3,3')-phosphate, beta-glutamate, and alpha-glutamate in addition to di-myo-inositol-1,3'-phosphate and di-2-O-beta-mannosyl-di-myo-inositol-1,1'(3,3')-phosphate. The concentrations of the last two solutes increased dramatically at supraoptimal growth temperatures, whereas beta-glutamate increased mainly in response to a salinity stress. Nevertheless, di-myo-inositol-1,1'(3,3')-phosphate was the major compatible solute at salinities above the optimum for growth. The amino acids alpha-glutamate and proline were identified under optimum growth conditions in Thermosipho africanus, and beta-mannosylglycerate, trehalose, and glycine betaine were detected in Petrotoga miotherma. Organic solutes were not detected, under optimum growth conditions, in Thermotoga thermarum and Fervidobacterium islandicum, which have a low salt requirement or none.

Gram-Negative Anaerobic Bacteria↗