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1
Min, Sang H., and Charles S. Abrams. "Regulation of platelet plug formation by phosphoinositide metabolism." Blood 122, no. 8 (August 22, 2013): 1358–65. http://dx.doi.org/10.1182/blood-2013-05-427716.
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Abstract Phosphatidylinositol and its phosphorylated derivatives, phosphoinositides, are minor constituents of phospholipids at the cellular membrane level. Nevertheless, phosphatidylinositol and phosphoinositides represent essential components of intracellular signaling that regulate diverse cellular processes, including platelet plug formation. Accumulating evidence indicates that the metabolism of phosphoinositides is temporally and spatially modulated by the opposing effects of specific phosphoinositide-metabolizing enzymes, including lipid kinases, lipid phosphatases, and phospholipases. Each of these enzymes generates a selective phosphoinositide or second messenger within precise cellular compartments. Intriguingly, phosphoinositide-metabolizing enzymes exist in different isoforms, which all produce the same phosphoinositide products. Recent studies using isoform-specific mouse models and chemical inhibitors have elucidated that the different isoforms of phosphoinositide-metabolizing enzymes have nonredundant functions and provide an additional layer of complexity to the temporo-spatial organization of intracellular signaling events. In this review, we will discuss recent advances in our understanding of phosphoinositide organization during platelet activation.
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Balla, Tamas, Zsofia Szentpetery, and Yeun Ju Kim. "Phosphoinositide Signaling: New Tools and Insights." Physiology 24, no. 4 (August 2009): 231–44. http://dx.doi.org/10.1152/physiol.00014.2009.
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Phosphoinositides constitute only a small fraction of cellular phospholipids, yet their importance in the regulation of cellular functions can hardly be overstated. The rapid metabolic response of phosphoinositides after stimulation of certain cell surface receptors was the first indication that these lipids could serve as regulatory molecules. These early observations opened research areas that ultimately clarified the plasma membrane role of phosphoinositides in Ca2+ signaling. However, research of the last 10 years has revealed a much broader range of processes dependent on phosphoinositides. These lipids control organelle biology by regulating vesicular trafficking, and they modulate lipid distribution and metabolism more generally via their close relationship with lipid transfer proteins. Phosphoinositides also regulate ion channels, pumps, and transporters as well as both endocytic and exocytic processes. The significance of phosphoinositides found within the nucleus is still poorly understood, and a whole new research concerns the highly phosphorylated inositols that also appear to control multiple nuclear processes. The expansion of research and interest in phosphoinositides naturally created a demand for new approaches to determine where, within the cell, these lipids exert their effects. Imaging of phosphoinositide dynamics within live cells has become a standard cell biological method. These new tools not only helped us localize phosphoinositides within the cell but also taught us how tightly phosphoinositide control can be linked with distinct effector protein complexes. The recent progress allows us to understand the underlying causes of certain human diseases and design new strategies for therapeutic interventions.
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Finkelstein, Stella, Sidney M. Gospe, Kai Schuhmann, Andrej Shevchenko, Vadim Y. Arshavsky, and Ekaterina S. Lobanova. "Phosphoinositide Profile of the Mouse Retina." Cells 9, no. 6 (June 7, 2020): 1417. http://dx.doi.org/10.3390/cells9061417.
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Phosphoinositides are known to play multiple roles in eukaryotic cells. Although dysregulation of phosphoinositide metabolism in the retina has been reported to cause visual dysfunction in animal models and human patients, our understanding of the phosphoinositide composition of the retina is limited. Here, we report a characterization of the phosphoinositide profile of the mouse retina and an analysis of the subcellular localization of major phosphorylated phosphoinositide forms in light-sensitive photoreceptor neurons. Using chromatography of deacylated phosphatidylinositol headgroups, we established PI(4,5)P2 and PI(4)P as two major phosphorylated phosphoinositides in the retina. Using high-resolution mass spectrometry, we revealed 18:0/20:4 and 16:0/20:4 as major fatty-acyl chains of retinal phosphoinositides. Finally, analysis of fluorescent phosphoinositide sensors in rod photoreceptors demonstrated distinct subcellular distribution patterns of major phosphoinositides. The PI(4,5)P2 reporter was enriched in the inner segments and synapses, but was barely detected in the light-sensitive outer segments. The PI(4)P reporter was mostly found in the outer and inner segments and the areas around nuclei, but to a lesser degree in the synaptic region. These findings provide support for future mechanistic studies defining the biological significance of major mono- (PI(4)P) and bisphosphate (PI(4,5)P2) phosphatidylinositols in photoreceptor biology and retinal health.
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Zhainazarov, Asylbek B., Richard Doolin, John-David Herlihy, and Barry W. Ache. "Odor-Stimulated Phosphatidylinositol 3-Kinase in Lobster Olfactory Receptor Cells." Journal of Neurophysiology 85, no. 6 (June 1, 2001): 2537–44. http://dx.doi.org/10.1152/jn.2001.85.6.2537.
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Two antagonists of phosphoinositide 3-OH kinases (PI3Ks), LY294002 and Wortmannin, reduced the magnitude of the receptor potential in lobster olfactory receptor neurons (ORNs) recorded by patch clamping the cells in vivo. An antibody directed against the c-terminus of human PI3K-P110β detected a molecule of predicted size in the outer dendrites of the ORNs. Two 3-phosphoinositides, PI(3,4)P2 (1–4 μM) and PI(3,4,5)P3 (1–4 μM) applied to the cytoplasmic side of inside-out patches taken from cultured lobster ORNs, reversibly activated a Na+-gated channel previously implicated in the transduction cascade in these cells. 3-Phosphoinositides were the most effective phosphoinositide (1 μM) in enhancing the open probability of the channel. Collectively, these results implicate 3-phosphoinositides in lobster olfactory transduction and raise the need to consider the 3-phosphoinositide pathway in olfactory transduction.
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Picas, Laura, Frederique Gaits-Iacovoni, and Bruno Goud. "The emerging role of phosphoinositide clustering in intracellular trafficking and signal transduction." F1000Research 5 (March 31, 2016): 422. http://dx.doi.org/10.12688/f1000research.7537.1.
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Phosphoinositides are master regulators of multiple cellular processes: from vesicular trafficking to signaling, cytoskeleton dynamics, and cell growth. They are synthesized by the spatiotemporal regulated activity of phosphoinositide-metabolizing enzymes. The recent observation that some protein modules are able to cluster phosphoinositides suggests that alternative or complementary mechanisms might operate to stabilize the different phosphoinositide pools within cellular compartments. Herein, we discuss the different known and potential molecular players that are prone to engage phosphoinositide clustering and elaborate on how such a mechanism might take part in the regulation of intracellular trafficking and signal transduction.
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Gandhi, C. R., K. Stephenson, and M. S. Olson. "A comparative study of endothelin- and platelet-activating-factor-mediated signal transduction and prostaglandin synthesis in rat Kupffer cells." Biochemical Journal 281, no. 2 (January 15, 1992): 485–92. http://dx.doi.org/10.1042/bj2810485.
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Endothelin-3 (ET-3) stimulated phosphoinositide metabolism and synthesis of prostaglandins in cultured rat Kupffer cells. ET-3-induced hydrolysis of phosphoinositides was characterized by the production of various inositol phosphates and of glycerophosphoinositol. The mechanism of ET-3-stimulated metabolism of phosphoinositides and synthesis of prostaglandins appeared to be distinct from the effect of platelet-activating factor (PAF) on these processes described previously [Gandhi, Hanahan & Olson (1990) J. Biol. Chem. 265, 18234-18241]. On a molar basis ET-3 was significantly more potent than PAF in stimulating phosphoinositide metabolism, e.g. ET-3-induced hydrolysis of phosphoinositides occurred at 1 pM, whereas PAF was ineffective at concentrations less than 1 nM. Upon challenging Kupffer cells with both ET-3 and PAF, an additive stimulation of phosphoinositide metabolism was observed, suggesting that the actions of these factors may be exerted on separate phosphoinositide pools. Treatment of Kupffer cells with pertussis toxin resulted in an inhibition of ET-3-induced phospholipase C activation; in contrast, cholera toxin treatment caused potentiation of ET-3-stimulated phospholipase C activity. Both toxins, however, inhibited PAF-stimulated phospholipase C activity. The present results suggest that the stimulatory effects of ET-3 and PAF on the phosphodiesteric metabolism of phosphoinositides in Kupffer cells require different guanine-nucleotide-binding proteins. Furthermore, the effects of bacterial toxins on ET-3- and PAF-induced phosphoinositide metabolism were not mediated by cyclic AMP. ET-3-induced metabolism of phosphoinositides was inhibited completely in Kupffer cells pretreated with ET-3, suggesting homologous ligand-induced desensitization of the ET-3 receptors. In contrast, similar experiments using PAF showed only a partial desensitization of subsequent PAF-induced phosphoinositide metabolism. In contrast to the increased production of prostaglandins E2 and D2 observed upon stimulation of Kupffer cells with PAF, ET-3 stimulated the biosynthesis of prostaglandin E2 only. Consistent with their additive effects on phosphoinositide metabolism, PAF and ET-3 exhibited an additive stimulation of the synthesis of prostaglandin E2.
7
Conduit, Sarah E., and Bart Vanhaesebroeck. "Phosphoinositide lipids in primary cilia biology." Biochemical Journal 477, no. 18 (September 24, 2020): 3541–65. http://dx.doi.org/10.1042/bcj20200277.
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Primary cilia are solitary signalling organelles projecting from the surface of most cell types. Although the ciliary membrane is continuous with the plasma membrane it exhibits a unique phospholipid composition, a feature essential for normal cilia formation and function. Recent studies have illustrated that distinct phosphoinositide lipid species localise to specific cilia subdomains, and have begun to build a ‘phosphoinositide map’ of the cilium. The abundance and localisation of phosphoinositides are tightly regulated by the opposing actions of lipid kinases and lipid phosphatases that have also been recently discovered at cilia. The critical role of phosphoinositides in cilia biology is highlighted by the devastating consequences of genetic defects in cilia-associated phosphoinositide regulatory enzymes leading to ciliopathy phenotypes in humans and experimental mouse and zebrafish models. Here we provide a general introduction to primary cilia and the roles phosphoinositides play in cilia biology. In addition to increasing our understanding of fundamental cilia biology, this rapidly expanding field may inform novel approaches to treat ciliopathy syndromes caused by deregulated phosphoinositide metabolism.
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Ebner, Michael, Philipp Alexander Koch, and Volker Haucke. "Phosphoinositides in the control of lysosome function and homeostasis." Biochemical Society Transactions 47, no. 4 (August 5, 2019): 1173–85. http://dx.doi.org/10.1042/bst20190158.
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Abstract Lysosomes are the main degradative compartments of mammalian cells and serve as platforms for cellular nutrient signaling and sterol transport. The diverse functions of lysosomes and their adaptation to extracellular and intracellular cues are tightly linked to the spatiotemporally controlled synthesis, turnover and interconversion of lysosomal phosphoinositides, minor phospholipids that define membrane identity and couple membrane dynamics to cell signaling. How precisely lysosomal phosphoinositides act and which effector proteins within the lysosome membrane or at the lysosomal surface recognize them is only now beginning to emerge. Importantly, mutations in phosphoinositide metabolizing enzyme cause lysosomal dysfunction and are associated with numerous diseases ranging from neurodegeneration to cancer. Here, we discuss the phosphoinositides and phosphoinositide metabolizing enzymes implicated in lysosome function and homeostasis and outline perspectives for future research.
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Le Ma, Lewis C. Cantley, Paul A. Janmey, and Marc W. Kirschner. "Corequirement of Specific Phosphoinositides and Small GTP-binding Protein Cdc42 in Inducing Actin Assembly in Xenopus Egg Extracts." Journal of Cell Biology 140, no. 5 (March 9, 1998): 1125–36. http://dx.doi.org/10.1083/jcb.140.5.1125.
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Both phosphoinositides and small GTP-binding proteins of the Rho family have been postulated to regulate actin assembly in cells. We have reconstituted actin assembly in response to these signals in Xenopus extracts and examined the relationship of these pathways. We have found that GTPγS stimulates actin assembly in the presence of endogenous membrane vesicles in low speed extracts. These membrane vesicles are required, but can be replaced by lipid vesicles prepared from purified phospholipids containing phosphoinositides. Vesicles containing phosphatidylinositol (4,5) bisphosphate or phosphatidylinositol (3,4,5) trisphosphate can induce actin assembly even in the absence of GTPγS. RhoGDI, a guanine-nucleotide dissociation inhibitor for the Rho family, inhibits phosphoinositide-induced actin assembly, suggesting the involvement of the Rho family small G proteins. Using various dominant mutants of these G proteins, we demonstrate the requirement of Cdc42 for phosphoinositide-induced actin assembly. Our results suggest that phosphoinositides may act to facilitate GTP exchange on Cdc42, as well as to anchor Cdc42 and actin nucleation activities. Hence, both phosphoinositides and Cdc42 are required to induce actin assembly in this cell-free system.
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Coronas, Sophie, Damien Ramel, Caroline Pendaries, Frédérique Gaits-Iacovoni, Hélène Tronchère, and Bernard Payrastre. "PtdIns5P: a little phosphoinositide with big functions?" Biochemical Society Symposia 74 (January 12, 2007): 117–28. http://dx.doi.org/10.1042/bss2007c11.
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Phosphoinositides are minor constituents of cell membranes playing a critical role in the regulation of many cellular functions. Recent discoveries indicate that mutations in several phosphoinositide kinases and phosphatases generate imbalances in the levels of phosphoinositides, thereby leading to the development of human diseases. Although the roles of phosphoinositide 3-kinase products and PtdIns(4,5)P2 were largely studied these last years, the potential role of phosphatidylinositol monophosphates as direct signalling molecules is just emerging. PtdIns5P, the least characterized phosphoinositide, appears to be a new player in cell regulation. This review will summarize the current knowledge on the mechanisms of synthesis and degradation of PtdIns5P as well as its potential roles.
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Choudhury, Rawshan R., Noora Hyvola, and Martin Lowe. "Phosphoinositides and membrane traffic at the trans-Golgi network." Biochemical Society Symposia 72 (January 1, 2005): 31–38. http://dx.doi.org/10.1042/bss0720031.
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Cargo proteins moving along the secretory pathway are sorted at the TGN (trans-Golgi network) into distinct carriers for delivery to the plasma membrane or endosomes. Recent studies in yeast and mammals have shown that formation of these carriers is regulated by PtdIns(4)P. This phosphoinositide is abundant at the TGN and acts to recruit components required for carrier formation to the membrane. Other phosphoinositides are also present on the TGN, but the extent to which they regulate trafficking is less clear. Further characterization of phosphoinositide kinases and phosphatases together with identification of new TGN-associated phosphoinositide-binding proteins will reveal the extent to which different phosphoinositides regulate TGN trafficking, and help define the molecular mechanisms involved.
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Wojcikiewicz, R. J., and S. R. Nahorski. "Modulation of signalling initiated by phosphoinositidase-C-linked receptors." Journal of Experimental Biology 184, no. 1 (November 1, 1993): 145–59. http://dx.doi.org/10.1242/jeb.184.1.145.
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An extensive group of cell surface receptors are coupled to phosphoinositidase C and thus to the production of the intracellular second messengers inositol 1,4,5-trisphosphate and 1,2-diacylglycerol. While the mechanisms and consequences of phosphoinositidase C activation have been the target of intensive study for over a decade, information is scarce regarding the regulatory processes that modulate this system during receptor stimulation. This situation, however, is now beginning to change. Recent data indicate (a) that Ca2+, mobilized concurrently with activation of phosphoinositidase-C-linked receptors, is a feedback activator and amplifier of phosphoinositide hydrolysis, (b) that rapid desensitization, possibly associated with receptor phosphorylation, regulates phosphoinositidase-C-linked receptors, (c) that receptor internalization can mediate desensitization at later times and (d) that signalling can be regulated at additional sites downstream of phosphoinositidase C. These diverse regulatory events provide the means by which the breakdown of phosphoinositides and cellular responsiveness to their products are controlled during cell stimulation.
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Walpole, Glenn F. W., and Sergio Grinstein. "Endocytosis and the internalization of pathogenic organisms: focus on phosphoinositides." F1000Research 9 (May 15, 2020): 368. http://dx.doi.org/10.12688/f1000research.22393.1.
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Despite their comparatively low abundance in biological membranes, phosphoinositides are key to the regulation of a diverse array of signaling pathways and direct membrane traffic. The role of phosphoinositides in the initiation and progression of endocytic pathways has been studied in considerable depth. Recent advances have revealed that distinct phosphoinositide species feature prominently in clathrin-dependent and -independent endocytosis as well as in phagocytosis and macropinocytosis. Moreover, a variety of intracellular and cell-associated pathogens have developed strategies to commandeer host cell phosphoinositide metabolism to gain entry and/or metabolic advantage, thereby promoting their survival and proliferation. Here, we briefly survey the current knowledge on the involvement of phosphoinositides in endocytosis, phagocytosis, and macropinocytosis and highlight several examples of molecular mimicry employed by pathogens to either “hitch a ride” on endocytic pathways endogenous to the host or create an entry path of their own.
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Roth, Michael G. "Phosphoinositides in Constitutive Membrane Traffic." Physiological Reviews 84, no. 3 (July 2004): 699–730. http://dx.doi.org/10.1152/physrev.00033.2003.
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Proteins that make, consume, and bind to phosphoinositides are important for constitutive membrane traffic. Different phosphoinositides are concentrated in different parts of the central vacuolar pathway, with phosphatidylinositol 4-phosphate predominate on Golgi, phosphatidylinositol 4,5-bisphosphate predominate at the plasma membrane, phosphatidylinositol 3-phosphate the major phosphoinositide on early endosomes, and phosphatidylinositol 3,5-bisphosphate found on late endocytic organelles. This spatial segregation may be the mechanism by which the direction of membrane traffic is controlled. Phosphoinositides increase the affinity of membranes for peripheral membrane proteins that function for sorting protein cargo or for the docking and fusion of transport vesicles. This implies that constitutive membrane traffic may be regulated by the mechanisms that control the activity of the enzymes that produce and consume phosphoinositides. Although the lipid kinases and phosphatases that function in constitutive membrane traffic are beginning to be identified, their regulation is poorly understood.
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Qiu, Shirley, and Marceline Côté. "From hitchhiker to hijacker: pathogen exploitation of endosomal phosphoinositides." Biochemistry and Cell Biology 97, no. 1 (February 2019): 1–9. http://dx.doi.org/10.1139/bcb-2017-0317.
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Signalling through phosphoinositide lipids is essential for regulating many cellular processes, including endosomal trafficking. A number of intracellular pathogens have found ways to subvert host trafficking pathways via exploitation of endosomal phosphoinositides. This review will discuss how pathogens such as bacteria, viruses, and eukaryotic parasites depend on endosomal phosphoinositides for infection as well as the mechanisms through which some are able to actively manipulate these signalling lipids to facilitate invasion, survival, replication, and immune evasion.
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Fan, Zheng, and Jonathan C. Makielski. "Phosphoinositides Decrease Atp Sensitivity of the Cardiac Atp-Sensitive K+ Channel." Journal of General Physiology 114, no. 2 (August 1, 1999): 251–70. http://dx.doi.org/10.1085/jgp.114.2.251.
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Anionic phospholipids modulate the activity of inwardly rectifying potassium channels (Fan, Z., and J.C. Makielski. 1997. J. Biol. Chem. 272:5388–5395). The effect of phosphoinositides on adenosine triphosphate (ATP) inhibition of ATP-sensitive potassium channel (KATP) currents was investigated using the inside-out patch clamp technique in cardiac myocytes and in COS-1 cells in which the cardiac isoform of the sulfonylurea receptor, SUR2, was coexpressed with the inwardly rectifying channel Kir6.2. Phosphoinositides (1 mg/ml) increased the open probability of KATP in low [ATP] (1 μM) within 30 s. Phosphoinositides desensitized ATP inhibition with a longer onset period (>3 min), activating channels inhibited by ATP (1 mM). Phosphoinositides treatment for 10 min shifted the half-inhibitory [ATP] (Ki) from 35 μM to 16 mM. At the single-channel level, increased [ATP] caused a shorter mean open time and a longer mean closed time. Phosphoinositides prolonged the mean open time, shortened the mean closed time, and weakened the [ATP] dependence of these parameters resulting in a higher open probability at any given [ATP]. The apparent rate constants for ATP binding were estimated to be 0.8 and 0.02 mM−1 ms−1 before and after 5-min treatment with phosphoinositides, which corresponds to a Ki of 35 μM and 5.8 mM, respectively. Phosphoinositides failed to desensitize adenosine inhibition of KATP. In the presence of SUR2, phosphoinositides attenuated MgATP antagonism of ATP inhibition. Kir6.2ΔC35, a truncated Kir6.2 that functions without SUR2, also exhibited phosphoinositide desensitization of ATP inhibition. These data suggest that (a) phosphoinositides strongly compete with ATP at a binding site residing on Kir6.2; (b) electrostatic interaction is a characteristic property of this competition; and (c) in conjunction with SUR2, phosphoinositides render additional, complex effects on ATP inhibition. We propose a model of the ATP binding site involving positively charged residues on the COOH-terminus of Kir6.2, with which phosphoinositides interact to desensitize ATP inhibition.
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Dove, S. K., C. W. Lloyd, and B. K. Drøbak. "Identification of a phosphatidylinositol 3-hydroxy kinase in plant cells: association with the cytoskeleton." Biochemical Journal 303, no. 2 (October 15, 1994): 347–50. http://dx.doi.org/10.1042/bj3030347.
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Radiolabelling experiments have revealed that plant cells contain the two 3-phosphorylated phosphoinositides: PtdIns3P and PtdIns(3,4)P2 [Brearley and Hanke (1992) Biochem. J. 283, 255-260]. However, nothing is known about the enzymes involved in the metabolism of these plant 3-phosphorylated phosphoinositides. In this study we demonstrate the presence of a PtdIns 3-hydroxy kinase(s) in plant cells. This activity was enriched in the cytoskeletal fraction whereas only low levels of phosphoinositide 3-hydroxy kinase could be detected in plasma membranes and microsomal preparations. This cytoskeletal phosphoinositide 3-hydroxy kinase was found to be wortmannin insensitive and thus resembles PtdIns-specific 3-hydroxy kinases of which vps34p is one example.
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Dale, GL. "Quantitation of adenosine-5'-triphosphate used for phosphoinositide metabolism in human erythrocytes." Blood 66, no. 5 (November 1, 1985): 1133–37. http://dx.doi.org/10.1182/blood.v66.5.1133.1133.
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Abstract The human erythrocyte actively phosphorylates and dephosphorylates phosphatidylinositol present in the membrane in an apparent “futile cycle.” Recent reports have proposed that this phosphorylation/dephosphorylation cycle is a significant consumer of adenosine-5′-triphosphate (ATP) in the erythrocyte. This study details two independent techniques for quantitating the ATP consumed by this phosphoinositide futile cycle. With the first technique a quasi-steady- state labeling of erythrocyte ATP with 32P-phosphate was obtained, and the rate of synthesis of 32P-phosphoinositides was then monitored. The second technique used a novel labeling strategy that allowed only ATP to be labeled with 32P; the transfer of 32P from ATP to phosphoinositides was then an independent measure of the ATP consumed for phosphoinositide synthesis. These two techniques documented that 0.5% to 1.0% of net ATP produced by the erythrocyte is used for phosphoinositide synthesis.
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Dale, GL. "Quantitation of adenosine-5'-triphosphate used for phosphoinositide metabolism in human erythrocytes." Blood 66, no. 5 (November 1, 1985): 1133–37. http://dx.doi.org/10.1182/blood.v66.5.1133.bloodjournal6651133.
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The human erythrocyte actively phosphorylates and dephosphorylates phosphatidylinositol present in the membrane in an apparent “futile cycle.” Recent reports have proposed that this phosphorylation/dephosphorylation cycle is a significant consumer of adenosine-5′-triphosphate (ATP) in the erythrocyte. This study details two independent techniques for quantitating the ATP consumed by this phosphoinositide futile cycle. With the first technique a quasi-steady- state labeling of erythrocyte ATP with 32P-phosphate was obtained, and the rate of synthesis of 32P-phosphoinositides was then monitored. The second technique used a novel labeling strategy that allowed only ATP to be labeled with 32P; the transfer of 32P from ATP to phosphoinositides was then an independent measure of the ATP consumed for phosphoinositide synthesis. These two techniques documented that 0.5% to 1.0% of net ATP produced by the erythrocyte is used for phosphoinositide synthesis.
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Lemmon, M. A., and K. M. Ferguson. "Molecular determinants in pleckstrin homology domains that allow specific recognition of phosphoinositides." Biochemical Society Transactions 29, no. 4 (August 1, 2001): 377–84. http://dx.doi.org/10.1042/bst0290377.
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More than 250 pleckstrin homology (PH) domains have been identified in the human proteome. All PH domains studied to date appear to bind phosphoinositides, most binding only weakly and non-specifically. Members of a small subclass of PH domains show both high affinity and specificity for particular phosphoinositides, and recent structural studies have provided detailed views of these specific interactions. We discuss the architecture of the specific phosphoinositide-binding sites of PH domains, and how selectivity can be modulated by sequence changes.
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Poccia, Dominic, and Banafshé Larijani. "Phosphatidylinositol metabolism and membrane fusion." Biochemical Journal 418, no. 2 (February 11, 2009): 233–46. http://dx.doi.org/10.1042/bj20082105.
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Membrane fusion underlies many cellular events, including secretion, exocytosis, endocytosis, organelle reconstitution, transport from endoplasmic reticulum to Golgi and nuclear envelope formation. A large number of investigations into membrane fusion indicate various roles for individual members of the phosphoinositide class of membrane lipids. We first review the phosphoinositides as membrane recognition sites and their regulatory functions in membrane fusion. We then consider how modulation of phosphoinositides and their products may affect the structure and dynamics of natural membranes facilitating fusion. These diverse roles underscore the importance of these phospholipids in the fusion of biological membranes.
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Lemmon, M. A. "Pleckstrin homology domains: not just for phosphoinositides." Biochemical Society Transactions 32, no. 5 (October 26, 2004): 707–11. http://dx.doi.org/10.1042/bst0320707.
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PH domains (pleckstrin homology domains) are the 11th most common domain in the human genome and are best known for their ability to target cellular membranes by binding specifically to phosphoinositides. Recent studies in yeast have shown that, in fact, this is a property of only a small fraction of the known PH domains. Most PH domains are not capable of independent membrane targeting, and those capable of doing so (approx. 33%) appear, most often, to require both phosphoinositide and non-phosphoinositide determinants for their subcellular localization. Several recent studies have suggested that small GTPases such as ARF family proteins play a role in defining PH domain localization. Some others have described a signalling role for PH domains in regulating small GTPases, although phosphoinositides may also play a role. These findings herald a change in our perspective of PH domain function, which will be significantly more diverse than previously supposed.
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Lemmon, Mark A. "Pleckstrin homology (PH) domains and phosphoinositides." Biochemical Society Symposia 74 (January 12, 2007): 81–93. http://dx.doi.org/10.1042/bss2007c08.
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PH (pleckstrin homology) domains represent the 11th most common domain in the human proteome. They are best known for their ability to bind phosphoinositides with high affinity and specificity, although it is now clear that less than 10% of all PH domains share this property. Cases in which PH domains bind specific phosphoinositides with high affinity are restricted to those phosphoinositides that have a pair of adjacent phosphates in their inositol headgroup. Those that do not [PtdIns3P, PtdIns5P and PtdIns(3,5)P2] are instead recognized by distinct classes of domains including FYVE domains, PX (phox homology) domains, PHD (plant homeodomain) fingers and the recently identified PROPPINs (b-propellers that bind polyphosphoinositides). Of the 90% of PH domains that do not bind strongly and specifically to phosphoinositides, few are well understood. One group of PH domains appears to bind both phosphoinositides (with little specificity) and Arf (ADP-ribosylation factor) family small G-proteins, and are targeted to the Golgi apparatus where both phosphoinositides and the relevant Arfs are both present. Here, the PH domains may function as coincidence detectors. A central challenge in understanding the majority of PH domains is to establish whether the very low affinity phosphoinositide binding reported in many cases has any functional relevance. For PH domains from dynamin and from Dbl family proteins, this weak binding does appear to be functionally important, although its precise mechanistic role is unclear. In many other cases, it is quite likely that alternative binding partners are more relevant, and that the observed PH domain homology represents conservation of structural fold rather than function.
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PEYROLLIER, Karine, Eric HAJDUCH, Alexander GRAY, Gary J. LITHERLAND, Alan R. PRESCOTT, Nick R. LESLIE, and Harinder S. HUNDAL. "A role for the actin cytoskeleton in the hormonal and growth-factor-mediated activation of protein kinase B." Biochemical Journal 352, no. 3 (December 8, 2000): 617–22. http://dx.doi.org/10.1042/bj3520617.
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We show here that cytochalasin D-induced depolymerization of actin filaments markedly reduces the stimulus-dependent activation of protein kinase B (PKB) in four different cell types (HEK-293 cells, L6 myotubes, 3T3-L1 adipocytes and U87MG cells). HEK-293 cells expressing the pleckstrin homology (PH) domains of PKB and general receptor for phosphoinositides-1 (GRP1) fused to green fluorescent protein (GFP) were used to monitor production of 3-phosphoinositides in the plasma membrane. Disassembly of the actin cytoskeleton significantly reduced the insulin-mediated translocation of both PKB-PHŐGFP and GRP1-PHŐGFP to the plasma membrane, consistent with diminished synthesis of 3-phosphoinositides. Actin depolymerization did not affect the hormonal activation of phosphoinositide 3-kinase (PI 3-kinase), and since cytochalasin D treatment also led to reduced platelet-derived growth factor (PDGF)-induced phosphorylation of PKB in U87MG cells, a PTEN (phosphatase and tensin homologue deleted on chromosome 10) null cell line, lipid phosphatase activity was unlikely to account for any reduction in cellular 3-phosphoinositides. Withdrawal of cytochalasin D from the extracellular medium induced actin filament repolymerization, and reinstated both the recruitment of PHŐGFP fusion proteins to the plasma membrane and PKB activation in response to insulin and PDGF. Our findings indicate that an intact actin network is a crucial requirement for PI 3-kinase-mediated production of 3-phosphoinositides and, therefore, for the activation of PKB.
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Divecha, Nullin. "Phosphoinositides in the nucleus and myogenic differentiation: how a nuclear turtle with a PHD builds muscle." Biochemical Society Transactions 44, no. 1 (February 9, 2016): 299–306. http://dx.doi.org/10.1042/bst20150238.
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Phosphoinositides are a family of phospholipid messenger molecules that control various aspects of cell biology in part by interacting with and regulating downstream protein partners. Importantly, phosphoinositides are present in the nucleus. They form part of the nuclear envelope and are present within the nucleus in nuclear speckles, intra nuclear chromatin domains, the nuclear matrix and in chromatin. What their exact role is within these compartments is not completely clear, but the identification of nuclear specific proteins that contain phosphoinositide interaction domains suggest that they are important regulators of DNA topology, chromatin conformation and RNA maturation and export. The plant homeo domain (PHD) finger is a phosphoinositide binding motif that is largely present in nuclear proteins that regulate chromatin conformation. In the present study I outline how changes in the levels of the nuclear phosphoinositide PtdIns5P impact on muscle cell differentiation through the PHD finger of TAF3 (TAF, TATA box binding protein (TBP)-associated factor), which is a core component of a number of different basal transcription complexes.
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Badheka, Doreen, Istvan Borbiro, and Tibor Rohacs. "Transient receptor potential melastatin 3 is a phosphoinositide-dependent ion channel." Journal of General Physiology 146, no. 1 (June 29, 2015): 65–77. http://dx.doi.org/10.1085/jgp.201411336.
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Phosphoinositides are emerging as general regulators of the functionally diverse transient receptor potential (TRP) ion channel family. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) has been reported to positively regulate many TRP channels, but in several cases phosphoinositide regulation is controversial. TRP melastatin 3 (TRPM3) is a heat-activated ion channel that is also stimulated by chemical agonists, such as pregnenolone sulfate. Here, we used a wide array of approaches to determine the effects of phosphoinositides on TRPM3. We found that channel activity in excised inside-out patches decreased over time (rundown), an attribute of PI(4,5)P2-dependent ion channels. Channel activity could be restored by application of either synthetic dioctanoyl (diC8) or natural arachidonyl stearyl (AASt) PI(4,5)P2. The PI(4,5)P2 precursor phosphatidylinositol 4-phosphate (PI(4)P) was less effective at restoring channel activity. TRPM3 currents were also restored by MgATP, an effect which was inhibited by two different phosphatidylinositol 4-kinase inhibitors, or by pretreatment with a phosphatidylinositol-specific phospholipase C (PI-PLC) enzyme, indicating that MgATP acted by generating phosphoinositides. In intact cells, reduction of PI(4,5)P2 levels by chemically inducible phosphoinositide phosphatases or a voltage-sensitive 5′-phosphatase inhibited channel activity. Activation of PLC via muscarinic receptors also inhibited TRPM3 channel activity. Overall, our data indicate that TRPM3 is a phosphoinositide-dependent ion channel and that decreasing PI(4,5)P2 abundance limits its activity. As all other members of the TRPM family have also been shown to require PI(4,5)P2 for activity, our data establish PI(4,5)P2 as a general positive cofactor of this ion channel subfamily.
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Currinn, Heather, and Thomas Wassmer. "The amyloid precursor protein (APP) binds the PIKfyve complex and modulates its function." Biochemical Society Transactions 44, no. 1 (February 9, 2016): 185–90. http://dx.doi.org/10.1042/bst20150179.
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Phosphoinositides are important components of eukaryotic membranes that are required for multiple forms of membrane dynamics. Phosphoinositides are involved in defining membrane identity, mediate cell signalling and control membrane trafficking events. Due to their pivotal role in membrane dynamics, phosphoinositide de-regulation contributes to various human diseases. In this review, we will focus on the newly emerging regulation of the PIKfyve complex, a phosphoinositide kinase that converts the endosomal phosphatidylinositol-3-phosphate [PI(3)P] to phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2)], a low abundance phosphoinositide of outstanding importance for neuronal integrity and function. Loss of PIKfyve function is well known to result in neurodegeneration in both mouse models and human patients. Our recent work has surprisingly identified the amyloid precursor protein (APP), the central molecule in Alzheimer's disease aetiology, as a novel interaction partner of a subunit of the PIKfyve complex, Vac14. Furthermore, it has been shown that APP modulates PIKfyve function and PI(3,5)P2 dynamics, suggesting that the APP gene family functions as regulator of PI(3,5)P2 metabolism. The recent advances discussed in this review suggest a novel, unexpected, β-amyloid-independent mechanism for neurodegeneration in Alzheimer's disease.
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Janardan, Vishnu, Sanjeev Sharma, Urbashi Basu, and Padinjat Raghu. "A Genetic Screen in Drosophila To Identify Novel Regulation of Cell Growth by Phosphoinositide Signaling." G3: Genes|Genomes|Genetics 10, no. 1 (November 8, 2019): 57–67. http://dx.doi.org/10.1534/g3.119.400851.
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Phosphoinositides are lipid signaling molecules that regulate several conserved sub-cellular processes in eukaryotes, including cell growth. Phosphoinositides are generated by the enzymatic activity of highly specific lipid kinases and phosphatases. For example, the lipid PIP3, the Class I PI3 kinase that generates it and the phosphatase PTEN that metabolizes it are all established regulators of growth control in metazoans. To identify additional functions for phosphoinositides in growth control, we performed a genetic screen to identify proteins which when depleted result in altered tissue growth. By using RNA-interference mediated depletion coupled with mosaic analysis in developing eyes, we identified and classified additional candidates in the developing Drosophila melanogaster eye that regulate growth either cell autonomously or via cell-cell interactions. We report three genes: Pi3K68D, Vps34 and fwd that are important for growth regulation and suggest that these are likely to act via cell-cell interactions in the developing eye. Our findings define new avenues for the understanding of growth regulation in metazoan tissue development by phosphoinositide metabolizing proteins.
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Zhao, Liang, Lurong Lian, Aae Suzuki, and Charles S. Abrams. "Class I Phosphatidylinositol Transfer Proteins (PITPs) Promote Platelet Activation by Functioning As Essential Cofactors for Phospholipid Kinases and Hydrolases." Blood 120, no. 21 (November 16, 2012): 91. http://dx.doi.org/10.1182/blood.v120.21.91.91.
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Abstract Abstract 91 In contrast to the more abundant phospholipids within the platelet membrane bilayer, phosphatidylinositol (PI) can be phosphorylated by PI kinases to generate seven distinct phosphoinositides that function as signaling molecules in series of cellular events including platelet activation. The synthesis of individual phosphoinositides in different cellular compartments is tightly regulated both in time and in space, and the relative amount of various phosphoinositides change within a few seconds after agonist stimulation of platelets. Thus, demonstrating how the synthesis of specific phosphoinositides is regulated in platelet activation would be critical to understanding their role in platelet biology. Class I PhosphatidylInositol Transfer Proteins (PITPs) are a small family of proteins that bind and transfer PI monomers from one cellular compartment to another in vitro. Studies in yeast cells suggested that PITP proteins are essential for the biosynthesis of phosphoinositides. Mammalian cells class I PITP has two members, PITPα and PITPβ. These two isoforms are 77% identical in primary sequence and are 94% homologous. It is notable that PITPα is approximately 7-fold more abundant than PITPβ in murine platelets. To characterize the role of each PITP isoform in platelet activation, we generated mice containing conditional null mutations within the gene of each isoform specifically in their megakaryocytes, and consequently to knock out these proteins in their platelets. Mice lacking individual platelet PITP isoforms have approximately 25% lower platelet counts than their littermate controls. Mice lacking both PITP isoforms have platelet counts that are 45% lower than wild type littermates, but otherwise have normal blood counts and appear phenotypically normal. Although the loss of either PITP isoform caused only mild ex vivo platelet function defects, loss of both isoforms led to significant impairment of cell spreading, aggregation, and secretion. To distinguish the role of both PITP isoforms in platelet phosphoinositide production, we 32P-labeled platelets ex vivo, and then analyzed by thin layer chromatography the concentration of individual phosphoinositides. Despite the fact that PITPα is far more abundant than PITPβ, we found that the loss of either isoform impaired the synthesis of PI(4)P and PI(4,5)P2 by 40–50% in either resting or thrombin stimulated platelets. To determine whether PITPs mediate their effect on phosphoinositide synthesis via PI transfer activity, we analyzed in vitro phospholipid kinase activity in lysates of knockout platelets using either PI or PI(4)P as the exogenous substrate. We reasoned that providing abundant quantities of exogenous substrate should eliminate the need for any transfer activity, and any effect of PITP on phosphoinositide synthesis in this circumstance would instead be due to an effect of PITPs on phospholipid kinase activity. We observed that the loss of either PITPα or PITPβ resulted in decreased synthesis of PIP and PI(4,5)P2 in vitro. Interestingly, even though PITPβ is far less abundant than PITPα, PITPβ is required for the majority (approximately 70%) of thrombin induced PI(4,5)P2 synthesis in vitro. In contrast, PITPα is required for 60% of thrombin induced PI(4)P synthesis. As expected, we could reverse the phosphoinositide synthesis defect by adding back recombinant PITPα to the PITPα-null platelet lysates or by adding back recombinant PITPβ to the PITPβ-null platelet lysates. Finally, we analyzed whether the loss of either PITP isoform affected the ability of the production of the second messenger IP3 (a product of PLC-mediated hydrolysis of PI(4,5)P2). We observed that the PITPα-null mutation caused an 80% decrease of thrombin-induced IP3 formation, and the PITPβ-null mutation caused a 56% loss in IP3 production. Together, the data demonstrate that although both PITPα and PITPβ are required for phosphoinositides synthesis and IP3 formation, they appear to have non-redundant functions. PITPα plays a larger role in maintaining PI(4)P levels and PLC signaling, and PITPβ contributes more to PI(4,5)P2 synthesis. Both isoforms cooperate together to promote platelet activation. Most importantly, our work demonstrates that despite their name, PhosphatidylInositol Transfer Proteins (PITPs) do more than just transfer phospholipids. They also possess critical cofactor activity for the synthesis of phosphoinositides. Disclosures: No relevant conflicts of interest to declare.
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Castano, Enrique, Sukriye Yildirim, Veronika Fáberová, Alžběta Krausová, Lívia Uličná, Darina Paprčková, Martin Sztacho, and Pavel Hozák. "Nuclear Phosphoinositides—Versatile Regulators of Genome Functions." Cells 8, no. 7 (June 28, 2019): 649. http://dx.doi.org/10.3390/cells8070649.
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The many functions of phosphoinositides in cytosolic signaling were extensively studied; however, their activities in the cell nucleus are much less clear. In this review, we summarize data about their nuclear localization and metabolism, and review the available literature on their involvements in chromatin remodeling, gene transcription, and RNA processing. We discuss the molecular mechanisms via which nuclear phosphoinositides, in particular phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2), modulate nuclear processes. We focus on PI(4,5)P2’s role in the modulation of RNA polymerase I activity, and functions of the nuclear lipid islets—recently described nucleoplasmic PI(4,5)P2-rich compartment involved in RNA polymerase II transcription. In conclusion, the high impact of the phosphoinositide–protein complexes on nuclear organization and genome functions is only now emerging and deserves further thorough studies.
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Gerasimova, М. М., and Т. V. Menshikova. "Role of phosphoinositide metabolism in multiple sclerosis pathogenesis." Neurology Bulletin XXX, no. 3-4 (September 27, 2021): 27–29. http://dx.doi.org/10.17816/nb81033.
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Phosphoinositides in lymphocytes and machrophages in 20 patients with multiple sclerosis have been studied with the help of highly effective liquid and thin-layer chromatography. In all patients phosphoinositide metabolism inpairment was revealed, which can be caused both by impairment of phosphoinositide response of immunocompetent cells, and by connecting myelin with consequent demyelinization. The revealed fact may serve one of criteria of demyelinizathion process activity, and also evidences the certain role of the revealed impairment in multiple sclerosis pathogenesis.
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Waugh, M. G., S. Minogue, J. S. Anderson, M. dos Santos, and J. J. Hsuan. "Signalling and non-caveolar rafts." Biochemical Society Transactions 29, no. 4 (August 1, 2001): 509–12. http://dx.doi.org/10.1042/bst0290509.
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Rafts are small membrane domains containing discrete subsets of lipids and proteins. Although microscopic raft structures termed ‘caveolae’ were described nearly 50 years ago, the importance of rafts, particularly signalling within rafts, is only beginning to be understood. Our studies focus on receptor-dependent phosphoinositide signalling. Using their characteristic buoyancy in density gradients, we and others found that the epidermal growth factor (EGF) receptor, phosphatidyl-inositol 4-kinase and phosphoinositides are localized within a caveolin-rich fraction of A431 carcinoma cells. We subsequently found that membrane fragments containing the EGF receptor and most cellular phosphoinositides can be separated from caveolae. Consequently, components of EGF-dependent phosphoinositide signalling localize to one or more novel types of raft, the composition of which we are currently determining. A key component is the type II phosphatidylinositol 4-kinase, which, for many years, has proven difficult to purify and clone. We describe our recent purification from rafts and cloning of this elusive enzyme, and discuss how the structure sheds light on the rafting of this enzyme.
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LEMMON, Mark A., and Kathryn M. FERGUSON. "Signal-dependent membrane targeting by pleckstrin homology (PH) domains." Biochemical Journal 350, no. 1 (August 9, 2000): 1–18. http://dx.doi.org/10.1042/bj3500001.
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Pleckstrin homology (PH) domains are small protein modules of around 120 amino acids found in many proteins involved in cell signalling, cytoskeletal rearrangement and other processes. Although several different protein ligands have been proposed for PH domains, their only clearly demonstrated physiological function to date is to bind membrane phosphoinositides. The PH domain from phospholipase C-δ1 binds specifically to PtdIns(4,5)P2 and its headgroup, and has become a valuable tool for studying cellular PtdIns(4,5)P2 functions. More recent developments have demonstrated that a subset of PH domains recognizes the products of agonist-stimulated phosphoinositide 3-kinases. Fusion of these PH domains to green fluorescent protein has allowed dramatic demonstrations of their independent ability to drive signal-dependent recruitment of their host proteins to the plasma membrane. We discuss the structural basis for this 3-phosphoinoistide recognition and the role that it plays in cellular signalling. PH domains that bind specifically to phosphoinositides comprise only a minority (perhaps 15%) of those known, raising questions as to the physiological role of the remaining 85% of PH domains. Most (if not all) PH domains bind weakly and non-specifically to phosphoinositides. Studies of dynamin-1 have indicated that oligomerization of its PH domain may be important in driving membrane association. We discuss the possibility that membrane targeting by PH domains with low affinity for phosphoinositides could be driven by alteration of their oligomeric state and thus the avidity of their membrane binding.
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Zhao, Liang, Lurong Liang, Aae Suzuki, Sang Min, and Charles S. Abrams. "Class I Phosphatidylinositol Transfer Proteins (PITPs) Promote PIP2 Synthesis and IP3 Production in Mouse Platelets." Blood 118, no. 21 (November 18, 2011): 363. http://dx.doi.org/10.1182/blood.v118.21.363.363.
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Abstract Abstract 363 Phosphoinositides are the phosphorylated forms of phosphatidylinositol. Although they constitute only 1% of platelet membrane phospholipids, phosphoinositides are important contributors to platelet signaling. As an example the phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2 or PIP2) has been shown to regulate integrin activation, actin assembly, and secretion in platelets. PtdIns(4,5)P2 contributes to these events by directly binding to signaling proteins, and also by serving as a substrate for PLC and PI3K to generate the second messengers Inositol(3,4,5)P3 (Ins(3,4,5)P3) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3). The phosphoinositide concentration in different cellular compartments is tightly regulated both in time and space, and their relative amounts of various phosphoinositides change within seconds of agonist stimulation. Given their importance in platelet biology, we sought to better understand the mechanism of phosphoinositide synthesis and function. Class I PhosphatidylInositol Transfer Proteins (PITPs) are a small family of proteins that bind to and transfer phosphoinositide monomers from one cellular compartment to another in an energy independent manner. Although there are no studies on the function of PITPs in hematopoietic cells, the proteins are essential in yeast cells for the biosynthesis and metabolism of phosphoinositides. This suggests that PITPs may also be essential for phosphoinositide metabolism in platelets. There are two dominant Class I PITP family members, PITPα and PITPβ in murine platelets. We introduced conditional loss-of-function mutations into the murine PITPα and PITPβ genes These mice were crossed with transgenic mice expressing Cre recombinase under the control of the platelet specific promoter PF4, thereby generating mice lacking individual PITP isoforms only in platelets and megakaryocytes. Mice lacking either platelet PITP isoform have approximately one-third lower platelet counts than littermate controls, but otherwise have normal blood counts and appear phenotypically normal. We have also generated a few viable double knockout (PITPαfl/fl PITPβfl/fl PF4Cre+) mice and found that these mice produce some platelets even in the absence of both PITP isoforms. Next, we analyzed the concentration of individual phosphoinositides in platelets of the knockout mice by thin layer chromatography. Although loss of either PITP isoform did not affect PtdIns(4)P synthesis in resting or thrombin stimulated platelets, PtdIns(4,5)P2 synthesis was significantly inhibited in platelets lacking either PITPα (∼40% of normal) or PITPβ (∼50% of normal). This suggests that both PITPα and PITPβ are required for normal PtdIns(4,5)P2 synthesis in platelets. To test whether PITP isoforms are critical for second messenger formation, we analyzed the formation of Ins(3,4,5)P3 in response to thrombin stimulation. We found that the PITPα-null mutation causes an almost absence of Ins(3,4,5)P3 formation. The PITPβ-null mutation also caused a profound defect in Ins(3,4,5)P3 formation, albeit less than that seen following PITPα deletion. Nonetheless, both PITPα and PITPβ knockout platelets were able to increase their intracellular calcium concentration following thrombin stimulation to approximately 50% of normal. These data imply that a significant portion of the calcium response in platelets results from the influx of extracellular calcium and not by the Ins(3,4,5)P3–dependent release of calcium from intracellular stores. Further, platelets lacking either PITP isoform exhibited only a moderate (∼50%) defect in Akt phosphorylation – a PtdIns(3,4,5)P3 synthesis-dependent event. Although both Ins(3,4,5)P3 and PtdIns(3,4,5)P3 are derived from PtdIns(4,5)P2, it is remarkable that PITP enzymes are more critical for Ins(3,4,5)P3-synthesis than for PtdIns(3,4,5)P3-synthesis (as suggested by Akt phosphorylation). Finally, we performed pilot experiments of the ex vivo function of platelets lacking both PITP isoforms and found that double knockout platelets had a profound loss of agonist-induced platelet aggregation. Together, our data suggest that PITPα and PITPβ are both critical for the synthesis of essential platelet phosphoinositides and second messengers. Thus, these enzymes may represent novel therapeutic targets for the prevention and treatment of arterial occlusion. Disclosures: No relevant conflicts of interest to declare.
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Kanaho, Y., and T. Suzuki. "Phosphoinositide Kinases as Enzymes that Produce Versatile Signaling Lipids, Phosphoinositides." Journal of Biochemistry 131, no. 4 (April 1, 2002): 503–9. http://dx.doi.org/10.1093/oxfordjournals.jbchem.a003127.
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Hope, H. R., and L. J. Pike. "Phosphoinositides and phosphoinositide-utilizing enzymes in detergent-insoluble lipid domains." Molecular Biology of the Cell 7, no. 6 (June 1996): 843–51. http://dx.doi.org/10.1091/mbc.7.6.843.
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Recent evidence has implicated caveolae/DIGs in various aspects of signal transduction, a process in which polyphosphoinositides play a central role. We therefore undertook a study to determine the distribution of phosphoinositides and the enzymes that utilize them in these detergent-insoluble domains. We report here that the polyphosphoinositide phosphatase, but not several other phosphoinositide-utilizing enzymes, is highly enriched in a low density, Triton-insoluble membrane fraction that contains caveolin. This fraction is also enriched in polyphosphoinositides, containing approximately one-fifth of the total cellular phosphatidylinositol (4,5)P2. Treatment of cells with the tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), did not alter the distribution of polyphosphoinositides or the polyphosphoinositide phosphatase. However, PMA treatment did lead to a decrease in the mitogen-activated protein kinase and actin present in these domains. PMA also induced the recruitment of protein kinase C alpha to the caveolae/DIGs fraction. These findings suggest that polyphosphoinositides, the polyphosphoinositide phosphatase and protein kinase C play an important role in the structure or function of detergent-insoluble membrane domains.
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Beziau, Anne, Denys Brand, and Eric Piver. "The Role of Phosphatidylinositol Phosphate Kinases during Viral Infection." Viruses 12, no. 10 (October 3, 2020): 1124. http://dx.doi.org/10.3390/v12101124.
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Phosphoinositides account for only a small proportion of cellular phospholipids, but have long been known to play an important role in diverse cellular processes, such as cell signaling, the establishment of organelle identity, and the regulation of cytoskeleton and membrane dynamics. As expected, given their pleiotropic regulatory functions, they have key functions in viral replication. The spatial restriction and steady-state levels of each phosphoinositide depend primarily on the concerted action of specific phosphoinositide kinases and phosphatases. This review focuses on a number of remarkable examples of viral strategies involving phosphoinositide kinases to ensure effective viral replication.
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Schmid, A. C., and R. Woscholski. "Phosphatases as small-molecule targets: inhibiting the endogenous inhibitors of kinases." Biochemical Society Transactions 32, no. 2 (April 1, 2004): 348–49. http://dx.doi.org/10.1042/bst0320348.
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Inositols and their phosphorylated derivatives, phosphoinositides, play an important role in diverse cellular functions. They have been recognized as second messengers and are accurately controlled by phosphatases and kinases, such as phosphoinositide 3-kinase and the phosphatidylinositol 3-phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10). Specific inhibitors targeting phosphoinositide 3-kinase and protein phosphatases have been described and characterized, but no small-molecule tools for phosphoinositide phosphatases are currently available. The present mini-review gives an overview of representative phosphatase inhibitors and summarizes the work that has been done recently on molecules that inhibit PTEN.
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Viaud, Julien, and Bernard Payrastre. "Les phosphoinositides." médecine/sciences 31, no. 11 (November 2015): 996–1005. http://dx.doi.org/10.1051/medsci/20153111014.
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Pathmasiri, Koralege C., Melissa R. Pergande, Fernando Tobias, Rima Rebiai, Avia Rosenhouse-Dantsker, Ernesto R. Bongarzone, and Stephanie M. Cologna. "Mass spectrometry imaging and LC/MS reveal decreased cerebellar phosphoinositides in Niemann-Pick type C1-null mice." Journal of Lipid Research 61, no. 7 (May 5, 2020): 1004–13. http://dx.doi.org/10.1194/jlr.ra119000606.
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Niemann-Pick disease type C1 (NPC1) is a lipid storage disorder in which cholesterol and glycosphingolipids accumulate in late endosomal/lysosomal compartments because of mutations in the NPC1 gene. A hallmark of NPC1 is progressive neurodegeneration of the cerebellum as well as visceral organ damage; however, the mechanisms driving this disease pathology are not fully understood. Phosphoinositides are phospholipids that play distinct roles in signal transduction and vesicle trafficking. Here, we utilized a consensus spectra analysis of MS imaging data sets and orthogonal LC/MS analyses to evaluate the spatial distribution of phosphoinositides and quantify them in cerebellar tissue from Npc1-null mice. Our results suggest significant depletion of multiple phosphoinositide species, including PI, PIP, and PIP2, in the cerebellum of the Npc1-null mice in both whole-tissue lysates and myelin-enriched fractions. Additionally, we observed altered levels of the regulatory enzyme phosphatidylinositol 4-kinase type 2α in Npc1-null mice. In contrast, the levels of related kinases, phosphatases, and transfer proteins were unaltered in the Npc1-null mouse model, as observed by Western blot analysis. Our discovery of phosphoinositide lipid biomarkers for NPC1 opens new perspectives on the pathophysiology underlying this fatal neurodegenerative disease.
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Wensel, Theodore G. "Phosphoinositides in Retinal Function and Disease." Cells 9, no. 4 (April 2, 2020): 866. http://dx.doi.org/10.3390/cells9040866.
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Phosphatidylinositol and its phosphorylated derivatives, the phosphoinositides, play many important roles in all eukaryotic cells. These include modulation of physical properties of membranes, activation or inhibition of membrane-associated proteins, recruitment of peripheral membrane proteins that act as effectors, and control of membrane trafficking. They also serve as precursors for important second messengers, inositol (1,4,5) trisphosphate and diacylglycerol. Animal models and human diseases involving defects in phosphoinositide regulatory pathways have revealed their importance for function in the mammalian retina and retinal pigmented epithelium. New technologies for localizing, measuring and genetically manipulating them are revealing new information about their importance for the function and health of the vertebrate retina.
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Balla, Andras, Yeun Ju Kim, Peter Varnai, Zsofia Szentpetery, Zachary Knight, Kevan M. Shokat, and Tamas Balla. "Maintenance of Hormone-sensitive Phosphoinositide Pools in the Plasma Membrane Requires Phosphatidylinositol 4-Kinase IIIα." Molecular Biology of the Cell 19, no. 2 (February 2008): 711–21. http://dx.doi.org/10.1091/mbc.e07-07-0713.
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Type III phosphatidylinositol (PtdIns) 4-kinases (PI4Ks) have been previously shown to support plasma membrane phosphoinositide synthesis during phospholipase C activation and Ca2+ signaling. Here, we use biochemical and imaging tools to monitor phosphoinositide changes in the plasma membrane in combination with pharmacological and genetic approaches to determine which of the type III PI4Ks (α or β) is responsible for supplying phosphoinositides during agonist-induced Ca2+ signaling. Using inhibitors that discriminate between the α- and β-isoforms of type III PI4Ks, PI4KIIIα was found indispensable for the production of phosphatidylinositol 4-phosphate (PtdIns4P), phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], and Ca2+ signaling in angiotensin II (AngII)-stimulated cells. Down-regulation of either the type II or type III PI4K enzymes by small interfering RNA (siRNA) had small but significant effects on basal PtdIns4P and PtdIns(4,5)P2 levels in 32P-labeled cells, but only PI4KIIIα down-regulation caused a slight impairment of PtdIns4P and PtdIns(4,5)P2 resynthesis in AngII-stimulated cells. None of the PI4K siRNA treatments had a measurable effect on AngII-induced Ca2+ signaling. These results indicate that a small fraction of the cellular PI4K activity is sufficient to maintain plasma membrane phosphoinositide pools, and they demonstrate the value of the pharmacological approach in revealing the pivotal role of PI4KIIIα enzyme in maintaining plasma membrane phosphoinositides.
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WHITEFORD, Craig C., Christie BEST, Andrius KAZLAUSKAS, and Emin T. ULUG. "D-3 phosphoinositide metabolism in cells treated with platelet-derived growth factor." Biochemical Journal 319, no. 3 (November 1, 1996): 851–60. http://dx.doi.org/10.1042/bj3190851.
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Despite extensive analysis of phosphoinositide 3-hydroxykinases (PI 3-kinases) at the molecular level, comparatively little is known about the mechanisms by which products of these enzymes exert their expected second-messenger functions. This study examines the metabolism of D-3 phosphoinositides in mouse Ph-N2 fibroblasts lacking the platelet-derived growth factor (PDGF) α-receptor. Treatment of these cultures with BB PDGF, but not AA PDGF, resulted in transient activation of PI 3-kinase activity measured in vitro. Treatment of myo-[3H]inositol-labelled Ph-N2 cells with BB PDGF resulted in the rapid induction of PtdIns(3,4)P2 and PtdIns(3,4,5)P3 and, to a smaller extent, PtdIns3P. The appearance of PtdIns(3,4,5)P3 preceded that of PtdIns(3,4)P2 and PtdIns3P after the addition of PDGF, suggesting that PtdIns(4,5)P2 is the preferred substrate of the agonist-stimulated PI 3-kinase in intact cells. Treatment of both resting and PDGF-stimulated cells with the fungal metabolite wortmannin resulted in pronounced, selective effects on the levels of all D-3 phosphoinositides. Kinetic studies with this PI 3-kinase inhibitor revealed the presence of at least two independent routes for the biosynthesis of D-3 phosphoinositides in PDGF-treated cells.
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Zeng, Wei-Zhong, Horng-Huei Liou, U. Murali Krishna, J. R. Falck, and Chou-Long Huang. "Structural determinants and specificities for ROMK1-phosphoinositide interaction." American Journal of Physiology-Renal Physiology 282, no. 5 (May 1, 2002): F826—F834. http://dx.doi.org/10.1152/ajprenal.00300.2001.
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We have recently reported that direct interaction between phosphatidylinositol bisphosphate (PIP2) and the COOH-terminal cytoplasmic domain of ROMK1 is important for opening of the channel. We identified arginine-188 of ROMK1 as a critical residue for this interaction. Here, we further report that substitution of a neutral amino acid for lysine-181, arginine-217, or lysine-218 decreases single-channel open probability for the full-conductance state and increases the frequency of opening at a subconductance state. Compared with wild-type ROMK1 channels, these substitution mutants also display an increased sensitivity to the block by anti-PIP2 antibodies and to inhibition by intracellular protons. These results indicate that, like arginine-188, lysine-181, arginine-217, and lysine-218 are also involved in interactions with PIP2 and are critical for ROMK1 to open at full conductance. Using synthetic phosphoinositides containing phosphates at different positions in the head group, we also examined the specificities of phosphoinositides in the regulation of ROMK1 channels. We found that phosphoinositides containing phosphate at both positions 4 and 5 of the inositol head group have the highest efficacy in activating ROMK1 channels. These results suggest that phosphatidylinositol 4,5-bisphosphate is likely the important phosphoinositide in the regulation of ROMK1 channels in a physiological membrane milieu.
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Walsh, Ciara M., Michael Chvanov, Lee P. Haynes, Ole H. Petersen, Alexei V. Tepikin, and Robert D. Burgoyne. "Role of phosphoinositides in STIM1 dynamics and store-operated calcium entry." Biochemical Journal 425, no. 1 (December 14, 2009): 159–68. http://dx.doi.org/10.1042/bj20090884.
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Ca2+ entry through store-operated Ca2+ channels involves the interaction at ER–PM (endoplasmic reticulum–plasma membrane) junctions of STIM (stromal interaction molecule) and Orai. STIM proteins are sensors of the luminal ER Ca2+ concentration and, following depletion of ER Ca2+, they oligomerize and translocate to ER–PM junctions where they form STIM puncta. Direct binding to Orai proteins activates their Ca2+ channel function. It has been suggested that an additional interaction of the C-terminal polybasic domain of STIM1 with PM phosphoinositides could contribute to STIM1 puncta formation prior to binding to Orai. In the present study, we investigated the role of phosphoinositides in the formation of STIM1 puncta and SOCE (store-operated Ca2+ entry) in response to store depletion. Treatment of HeLa cells with inhibitors of PI3K (phosphatidylinositol 3-kinase) and PI4K (phosphatidylinositol 4-kinase) (wortmannin and LY294002) partially inhibited formation of STIM1 puncta. Additional rapid depletion of PtdIns(4,5)P2 resulted in more substantial inhibition of the translocation of STIM1–EYFP (enhanced yellow fluorescent protein) into puncta. The inhibition was extensive at a concentration of LY294002 (50 μM) that should primarily inhibit PI3K, consistent with a major role for PtdIns(4,5)P2 and PtdIns(3,4,5)P3 in puncta formation. Depletion of phosphoinositides also inhibited SOCE based on measurement of the rise in intracellular Ca2+ concentration after store depletion. Overexpression of Orai1 resulted in a recovery of translocation of STMI1 into puncta following phosphoinositide depletion and, under these conditions, SOCE was increased to above control levels. These observations support the idea that phosphoinositides are not essential but contribute to STIM1 accumulation at ER–PM junctions with a second translocation mechanism involving direct STIM1–Orai interactions.
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Pan, Weijun, Van N. Pham, Amber N. Stratman, Daniel Castranova, Makoto Kamei, Kameha R. Kidd, Brigid D. Lo, et al. "CDP-diacylglycerol synthetase-controlled phosphoinositide availability limits VEGFA signaling and vascular morphogenesis." Blood 120, no. 2 (July 12, 2012): 489–98. http://dx.doi.org/10.1182/blood-2012-02-408328.
Full textAbstract:
Abstract Understanding the mechanisms that regulate angiogenesis and translating these into effective therapies are of enormous scientific and clinical interests. In this report, we demonstrate the central role of CDP-diacylglycerol synthetase (CDS) in the regulation of VEGFA signaling and angiogenesis. CDS activity maintains phosphoinositide 4,5 bisphosphate (PIP2) availability through resynthesis of phosphoinositides, whereas VEGFA, mainly through phospholipase Cγ1, consumes PIP2 for signal transduction. Loss of CDS2, 1 of 2 vertebrate CDS enzymes, results in vascular-specific defects in zebrafish in vivo and failure of VEGFA-induced angiogenesis in endothelial cells in vitro. Absence of CDS2 also results in reduced arterial differentiation and reduced angiogenic signaling. CDS2 deficit-caused phenotypes can be successfully rescued by artificial elevation of PIP2 levels, and excess PIP2 or increased CDS2 activity can promote excess angiogenesis. These results suggest that availability of CDS-controlled resynthesis of phosphoinositides is essential for angiogenesis.
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Jung, Seung-Ryoung, Yifei Jiang, Jong Bae Seo, Daniel T. Chiu, Bertil Hille, and Duk-Su Koh. "β-arrestin–dependent PI(4,5)P2synthesis boosts GPCR endocytosis." Proceedings of the National Academy of Sciences 118, no. 17 (April 20, 2021): e2011023118. http://dx.doi.org/10.1073/pnas.2011023118.
Full textAbstract:
β-arrestins regulate many cellular functions including intracellular signaling and desensitization of G protein–coupled receptors (GPCRs). Previous studies show that β-arrestin signaling and receptor endocytosis are modulated by the plasma membrane phosphoinositide lipid phosphatidylinositol-(4, 5)-bisphosphate (PI(4,5)P2). We found that β-arrestin also helped promote synthesis of PI(4,5)P2and up-regulated GPCR endocytosis. We studied these questions with the Gq-coupled protease-activated receptor 2 (PAR2), which activates phospholipase C, desensitizes quickly, and undergoes extensive endocytosis. Phosphoinositides were monitored and controlled in live cells using lipid-specific fluorescent probes and genetic tools. Applying PAR2 agonist initiated depletion of PI(4,5)P2, which then recovered during rapid receptor desensitization, giving way to endocytosis. This endocytosis could be reduced by various manipulations that depleted phosphoinositides again right after phosphoinositide recovery: PI(4)P, a precusor of PI(4,5)P2,could be depleted at either the Golgi or the plasma membrane (PM) using a recruitable lipid 4-phosphatase enzyme and PI(4,5)P2could be depleted at the PM using a recruitable 5-phosphatase. Endocytosis required the phosphoinositides. Knock-down of β-arrestin revealed that endogenous β-arrestin normally doubles the rate of PIP5-kinase (PIP5K) after PAR2 desensitization, boosting PI(4,5)P2-dependent formation of clathrin-coated pits (CCPs) at the PM. Desensitized PAR2 receptors were swiftly immobilized when they encountered CCPs, showing a dwell time of ∼90 s, 100 times longer than for unactivated receptors. PAR2/β-arrestin complexes eventually accumulated around the edges or across the surface of CCPs promoting transient binding of PIP5K-Iγ. Taken together, β-arrestins can coordinate potentiation of PIP5K activity at CCPs to induce local PI(4,5)P2generation that promotes recruitment of PI(4,5)P2-dependent endocytic machinery.
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Racagni, G., M. G. de Lema, G. Hernández, and E. E. Machado-Domenech. "Fetal bovine serum induces changes in fatty acid composition ofTrypanosoma cruziphosphoinositides." Canadian Journal of Microbiology 41, no. 10 (October 1, 1995): 951–54. http://dx.doi.org/10.1139/m95-132.
Full textAbstract:
Fetal bovine serum (FBS) is a necessary constituent of the culture media employed to foster the growth of Trypanosoma cruzi epimastigote forms. In different laboratories, the serum is used at final concentrations of 5 or 10%. We have normally supplemented the complex medium with 10% FBS. Under this condition we have described the fatty acid composition of the total lipids and of the phosphoinositide fractions. Additionally, we have reported the increase of polyphosphoinositides and phosphatidic acid after cholinergic stimulation. Since further attempts to reproduce these results with 5% FBS in the culture medium were not successful, the effect of the FBS concentration on the fatty acid composition of phospholipids from the T. cruzi epimastigote forms was thoroughly examined. This work showed that when the FBS concentration supplementing the culture medium was reduced from 10 to 5%, the fatty acid composition of the phosphoinositides was altered while the other major phospholipids were not significantly affected. The most relevant result was the decrease in the content of linoleic acid (18:2) and the increase of palmitoleic acid (16:1) in phosphatidylinositol 4,5-bisphosphate. Phosphatidylinositol (PI) and phosphatidylinositol phosphate also exhibited similar changes in the same fatty acids. The C2fatty acid composition of the phosphoinositides, under the same conditions, is also reported here for the first time.Key words: Trypanosoma cruzi, fatty acids, phosphoinositides, fetal bovine serum, phospholipids.
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Stallings, Jonathan D., Edward G. Tall, Srinivas Pentyala, and Mario J. Rebecchi. "Nuclear Translocation of Phospholipase C-δ1 Is Linked to the Cell Cycle and Nuclear Phosphatidylinositol 4,5-Bisphosphate." Journal of Biological Chemistry 280, no. 23 (April 4, 2005): 22060–69. http://dx.doi.org/10.1074/jbc.m413813200.
Full textAbstract:
Nuclear phosphoinositides, especially phosphatidylinositol 4,5-bisphosphate, fluctuate throughout the cell cycle and are linked to proliferation and differentiation. Here we report that phospholipase C-δ1 accumulates in the nucleus at the G1/S boundary and in G0 phases of the cell cycle. Furthermore, as wild-type protein accumulated in the nucleus, nuclear phosphatidylinositol 4,5-bisphosphate levels were elevated 3–5-fold, whereas total levels were decreased compared with asynchronous cultures. To test whether phosphatidylinositol 4,5-bisphosphate binding is important during this process, we introduced a R40D point mutation within the pleckstrin homology domain of phospholipase C-δ1, which disables high affinity phosphatidylinositol 4,5-bisphosphate binding, and found that nuclear translocation was significantly reduced at G1/S and in G0. These results demonstrate a cell cycle-dependent compartmentalization of phospholipase C-δ1 and support the idea that relative levels of phosphoinositides modulate the portioning of phosphoinositide-binding proteins between the nucleus and other compartments.
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Backer, Jonathan M. "New methods for capturing the mystery lipid, PtdIns5P." Biochemical Journal 428, no. 3 (May 27, 2010): e1-e2. http://dx.doi.org/10.1042/bj20100688.
Full textAbstract:
The enormous versatility of phosphatidylinositol as a mediator of intracellular signalling is due to its variable phosphorylation on every combination of the 3′, 4′ and 5′ positions, as well as an even more complex range of phosphorylated products when inositol phosphate is released by phospholipase C activity. The phosphoinositides are produced by distinct enzymes in distinct intracellular membranes, and recruit and regulate downstream signalling proteins containing binding domains [PH (pleckstrin homology), PX (Phox homology), FYVE etc.] that are relatively specific for these lipids. Specific recruitment of downstream proteins presumably involves a coincidence detection mechanism, in which a combination of lipid–protein and protein–protein interactions define specificity. Of the seven intrucellular phosphoinositide, quantification of PtdIns5P levels in intact cells has remained difficult. In this issue of the Biochemical Journal, Sarkes and Rameh describe a novel HPLC-based approach which makes possible an analysis of the subcellular distribution of PtdIns5P and other phosphoinositides.