Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases
| Check out our New Publishers' Select for Free Articles |
BBA - Molecular and Cell Biology of Lipids (v.1791, #9)
Lipid signaling on the mitochondrial surface by Huiyan Huang; Michael A. Frohman ⁎ (pp. 839-844).
Regulated production and elimination of the signaling lipids phosphatidic acid (PA), diacylglycerol (DAG), and phosphatidylinositol 4,5-bisphosphate (PI4,5P2) creates a complex and interconnected signaling network that modulates a wide variety of eukaryotic cell biological events. PA production at the plasma membrane and on trafficking membrane organelles by classical Phospholipase D (PLD) through the hydrolysis of phosphatidylcholine (PC) has been studied widely. In this chapter, we review a newly identified, non-canonical member of the PLD superfamily, MitoPLD, which localizes to the mitochondrial surface and plays a role in mitochondrial fusion via the hydrolysis of cardiolipin (CL) to generate PA. The role of PA in facilitating the mitochondrial fusion event carried out by proteins known as Mitofusins is intriguing in light of the role classic PLD-generated PA plays in facilitating SNARE-mediated fusion of secretory membrane vesicles into the plasma membrane. In addition, however, PA on the mitochondrial surface may also trigger a signaling cascade that elevates DAG, leading to downstream events that affect mitochondrial fission and energy production. PA production on the mitochondrial surface may also stimulate local production of PI4,5P2 to facilitate mitochondrial fission and subcellular trafficking or facilitate Ca2+ influx.
Keywords: Phosphatidic acid; MitoPLD; Mitochondrial fusion; Fission; Insulin signaling; Calcium homeostasis
Phospholipase D in endocytosis and endosomal recycling pathways by Julie G. Donaldson ⁎ (pp. 845-849).
The discovery that Arf GTPases, mediators of membrane traffic, activate phospholipase D (PLD) raised the possibility that Arfs could facilitate membrane traffic by altering membrane lipid composition. PLD hydrolyzes phosphatidylcholine to generate phosphatidic acid (PA), a lipid that favors membranes with negative curvature and thus can facilitate both membrane fission and fusion. This review examines studies that have reported a role for PLD in endocytosis and membrane recycling from endocytic pathways.
Keywords: Arf6; Endocytosis; Recycling; Membrane traffic; Phospholipase D
Phosphatidic acid signaling regulation of Ras superfamily of small guanosine triphosphatases by Yueqiang Zhang; Guangwei Du (pp. 850-855).
Phosphatidic acid (PA) has been increasingly recognized as an important signaling lipid regulating cell growth and proliferation, membrane trafficking, and cytoskeletal reorganization. Recent studies indicate that the signaling PA generated from phospholipase D (PLD) and diacylglycerol kinase (DGK) plays critical roles in regulating the activity of some members of Ras superfamily of small guanosine triphosphatases (GTPases), such as Ras, Rac and Arf. Change of PA levels regulates the activity of small GTPases by modulating membrane localization and activity of small GTPase regulatory proteins, guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). In addition, PA also targets some small GTPases to membranes by direct binding. This review summarizes the roles of PLD and DGK in regulating the activity of several Ras superfamily members and cellular processes they control. Some future directions and the implication of PA regulation of Ras small GTPases in pathology are also discussed.
Keywords: Phospholipid; Phosphatidic acid; Phospholipase D; Diacylglycerol kinase; Ras; Small GTPase
Inter-regulatory dynamics of phospholipase D and the actin cytoskeleton by Simon A. Rudge; Michael J.O. Wakelam ⁎ (pp. 856-861).
Phospholipase D activity has been extensively implicated in the regulation of the actin cytoskeleton. Through this regulation the enzyme controls a number of physiological functions such as cell migration and adhesion and, it also is implicated in the regulation of membrane trafficking. The two phospholipase Ds are closely implicated with the control of the ARF and Rho families of small GTPases. In this article it is proposed that PLD2 plays the role of ‘master regulator’ and in an ill-defined manner regulates Rho function, PLD1 activity is downstream of this activation, however the generated phosphatidic acid controls changes in cytoskeletal organisation through its regulation of phosphatidylinositol-4-phosphate-5-kinase activity.
Keywords: Phospholipase D; Actin; Rho; Phosphatidic acid; Phosphatidylinositol 4,5-bisphosphate; Phosphatidylinositol-4-phosphate-5-kinase
The roles of phospholipase D in EGFR signaling by Chang Sup Lee; Kyung Lock Kim; Jin Hyeok Jang; Yoon Sup Choi; Pann-Ghill Suh; Sung Ho Ryu (pp. 862-868).
Epidermal growth factor receptor (EGFR) is a representative model of receptor tyrosine kinases (RTKs), and offers a means of understanding their common principles and fundamental mechanisms. Furthermore, EGFR plays an essential role in cell proliferation and migration, and the disruption of EGFR signaling has been implicated in the development and growth of cancer. Phospholipase D (PLD) is a key mediator of EGFR function, and can be directly regulated by upstream binding partners in an EGF-dependent manner. PLD regulates downstream molecules by generating phosphatidic acid (PA), but it also dynamically interacts with a variety of intracellular molecules and these interactions spatiotemporally regulate EGFR function and serve as a hub that orchestrates signaling flow. This review summarizes the interrelationship between PLD and its binding molecules in the context of EGFR signaling, and addresses the roles of PLD in the mediation and coordination of this signaling.
Keywords: Phospholipase D (PLD); Epidermal growth factor receptor (EGFR); Interaction; Phox homology (PX) domain; Coordination
Plant PA signaling via diacylglycerol kinase by Steven A. Arisz; Christa Testerink; Teun Munnik (pp. 869-875).
Accumulating evidence suggests that phosphatidic acid (PA) plays a pivotal role in the plant's response to environmental signals. Besides phospholipase D (PLD) activity, PA can also be generated by diacylglycerol kinase (DGK). To establish which metabolic route is activated, a differential32P-radiolabelling protocol can be used. Based on this, and more recently on reverse-genetic approaches, DGK has taken center stage, next to PLD, as a generator of PA in biotic and abiotic stress responses. The DAG substrate is generally thought to be derived from PI-PLC activity. The model plant system Arabidopsis thaliana has 7 DGK isozymes, two of which, AtDGK1 and AtDGK2, resemble mammalian DGKɛ, containing a conserved kinase domain, a transmembrane domain and two C1 domains. The other ones have a much simpler structure, lacking the C1 domains, not matched in animals. Several protein targets have now been discovered that bind PA. Whether the PA molecules engaged in these interactions come from PLD or DGK remains to be elucidated.
Keywords: Phosphatidic acid; Diacylglycerol kinase; Lipid signaling; Plant stress; Phospholipase
Phospholipase D in the Golgi apparatus by Christian Riebeling; Andrew J. Morris; Dennis Shields (pp. 876-880).
Phospholipase D has long been implicated in vesicle formation and vesicular transport through the secretory pathway. The Golgi apparatus has been shown to exhibit a plethora of mechanisms of vesicle formation at different stages to accommodate a wide variety of cargo. Phospholipase D has been found on the Golgi apparatus and is regulated by ADP-ribosylation factors which are themselves regulators of vesicle trafficking. Moreover, the product of phospholipase D activity, phosphatidic acid, as well as its degradation product diacylglycerol, have been implicated in vesicle fission and fusion events. Here we summarize recent advances in the understanding of the role of phospholipase D at the Golgi apparatus.
Keywords: Phospholipase D; Phosphatidic acid; Golgi apparatus; Vesicular trafficking
Biophysics and function of phosphatidic acid: A molecular perspective by Edgar Eduard Kooijman; Koert N.J. Burger (pp. 881-888).
Phosphatidic acid is the simplest (diacyl)glycerophospholipid present in cells and is now a well established second messenger with direct biological functions. It is specifically recognized by diverse proteins and plays an important role in cellular signaling and membrane dynamics in all eukaryotes. An important determinant of the biological functions of phosphatidic acid is its anionic headgroup. In this review we will focus on the peculiar ionization properties of phosphatidic acid and their crucial role in lipid–protein interactions. We will take a molecular approach focusing entirely on the physical chemistry of the lipid and develop a model explaining the ionization properties of phosphatidic acid, termed the electrostatic-hydrogen bond switch model. Diverse examples from recent literature in support of this model will be presented and the broader implications of our findings will be discussed.
Keywords: Electrostatic-hydrogen bond switch; Lipid–protein interaction; Model membrane; MAS NMR; Phosphomonoester; Anionic lipid; Hydrogen bond
Emerging findings from studies of phospholipase D in model organisms (and a short update on phosphatidic acid effectors) by Padinjat Raghu; Maria Manifava; John Coadwell; Nicholas T. Ktistakis ⁎ (pp. 889-897).
Phospholipase D (PLD) catalyses the hydrolysis of phosphatidylcholine to generate phosphatidic acid and choline. Historically, much PLD work has been conducted in mammalian settings although genes encoding enzymes of this family have been identified in all eukaryotic organisms. Recently, important insights on PLD function are emerging from work in yeast, but much less is known about PLD in other organisms. In this review we will summarize what is known about phospholipase D in several model organisms, including C. elegans, D. discoideum, D. rerio and D. melanogaster. In the cases where knockouts are available ( C. elegans, Dictyostelium and Drosophila) the PLD gene(s) appear not to be essential for viability, but several studies are beginning to identify pathways where this activity has a role. Given that the proteins in model organisms are very similar to their mammalian counterparts, we expect that future studies in model organisms will complement and extend ongoing work in mammalian settings. At the end of this review we will also provide a short update on phosphatidic acid targets, a topic last reviewed in 2006.
Keywords: Phospholipase D; Phosphatidic acid; Lipid signalling; Model organisms
Phospholipase D signalling and its involvement in neurite outgrowth by Yasunori Kanaho ⁎; Yuji Funakoshi; Hiroshi Hasegawa (pp. 898-904).
Since the original discovery and structural elucidation of the mammalian phospholipase D (PLD), its potential to play a role in the lipid signalling pathway has attracted considerable interest. Now, it is generally accepted that different PLD isozymes are likely to serve diverse functions in membrane trafficking, endocytosis, exocytosis, cell growth, differentiation and actin cytoskeletal organization. In addition, PLDs are known to play a key role in neurite outgrowth, especially axon outgrowth, in neuronal cells.
Keywords: Neurite outgrowth; MAP kinase; Phospholipase D; Phosphatidic acid
Phosphatidic acid regulation of phosphatidylinositol 4-phosphate 5-kinases by Shamshad Cockcroft ⁎ (pp. 905-912).
Phosphatidic acid (PA) production by receptor-stimulated phospholipase D is believed to play an important role in the regulation of cell function. The second messenger function of PA remains to be elucidated. PA can bind and affect the activities of different enzymes and here we summarise the current status of activation of Type I phosphatidylinositol 4-phosphate 5-kinase by PA. Type 1 phosphatidylinositol 4-phosphate 5-kinase is also regulated by ARF proteins as is phospholipase D and we discuss the contributions of ARF and PA towards phosphatidylinositol(4,5)bisphosphate synthesis at the plasma membrane.
Keywords: Abbreviations; PLD; phospholipase D; ARF; ADP ribosylation factor; PIP5K or PIP 5-kinase; Phosphatidylinositol 4-phosphate 5-kinase; PIP4K; phosphatidylinositol 5-phosphate 4-kinase; PI; phosphatidylinositol; PC; phosphatidylcholine; PI(4,5)P; 2; phosphatidylinositol(4,5)bisphosphate; PS; phosphatidylserine; PE; phosphatidylethanolamine; TG; triacylglycerol; PAP-1; phosphatidate phosphohydrolase; DAG; diacylglycerol; PKC; Protein kinase CPIP 5-kinase; Phosphatidylinositol(4,5)bisphosphate; ARF; Phosphatidic acid
Modulation of phospholipase D activity in vitro by Johanna Mansfeld; Renate Ulbrich-Hofmann ⁎ (pp. 913-926).
Most phospholipases D (PLDs) occurring in microorganisms, plants and animals belong to a superfamily which is characterized by several conserved regions of amino acid sequence including the two HKD motifs necessary for catalytic activity. Most eukaryotic PLDs possess additional regulatory structures such as the Phox and Pleckstrin homology domains in mammalian PLDs and the C2 domain in most plant PLDs. Owing to recombinant expression techniques, an increasing number of PLDs from different organisms has been obtained in purified form, allowing the investigation of specific and unspecific interactions of the enzymes with regulatory components in vitro. The present paper gives an overview on different factors which can modulate PLD activity and compares their influence on the enzymes from different sources. While no biological regulator can be recognized for extracellular bacterial PLDs, the most prominent specific activator of eukaryotic PLDs is phosphatidylinositol-4,5-bisphosphate (PIP2). In a sophisticated interplay PIP2 seems to cooperate with several regulatory proteins in mammalian PLDs, whereas in plant PLDs it mainly acts in concert with Ca2+ ions. Moreover, curvature, charges and heterogeneities of membrane surfaces are assessed as unspecific modulators. A possible physiological role of the transphosphatidylation reaction catalyzed by PLDs in competition with phospholipid hydrolysis is discussed.
Keywords: Phospholipase D; Modulation of activity; Calcium; Regulator; Phosphatidic acid; Phosphatidylinositide
Phospholipase D- and phosphatidic acid-mediated signaling in plants by Maoyin Li; Yueyun Hong; Xuemin Wang ⁎ (pp. 927-935).
The phospholipase D (PLD) family in higher plants is composed of multiple members, and each of the Arabidopsis PLDs characterized displays distinguishable properties in activity regulation and/or lipid preferences. The molecular and biochemical heterogeneities of the plant PLDs play important roles in the timing, location, and amount of phosphatidic acid (PA) produced. PLD-catalyzed production of PA has been shown to play important roles in plant growth, development, and response to various stresses, including drought, salinity, freezing, and nutrient deficiency. PLD and PA affect cellular processes through different modes of action, including direct target protein binding and biophysical effects on cell membranes. Improved knowledge on the mechanism by which specific PLDs and PA mediate given plant responses will facilitate the understanding of the molecular processes that connect the stimulus perception on membranes to intracellular actions and physiological responses.
Keywords: Abbreviations; ABA; abscisic acid; C2; Ca; 2+; -dependent phospholipid-binding; C2-PLD; PLD containing the C2 domain; G protein; heterotrimeric GTP-binding protein; GPA1; Arabidopsis; G protein α subunit 1 gene; JA; jasmonic acid; AS; anti-sense suppression; KO; knockout; MAPK; mitogen-activated protein kinase; NADPH; nicotinamide adenine dinucleotide phosphate hydrogen oxidase; PA; phosphatidic acid; PI(4,5)P; 2; phosphatidylinositol 4,5-bisphosphate; PI(4)P; phosphatidylinositol 4 phosphate; PH; pleckstrin homology; PLC; phospholipase C; PLD; phospholipase D; PP2C; protein phosphatase 2C; PX; phox homology; PX/PH-PLDs; PLD containing PX and PH domains; ROS; reactive oxygen speciesPhosphatidic acid; Phospholipase D; Lipid signaling; Abscisic acid; N signaling; Hyperosmotic stress; Arabidopsis; drought; G proteins; Protein kinase; Protein phosphatase
Phospholipase D in calcium-regulated exocytosis: Lessons from chromaffin cells by Marie-France Bader; Nicolas Vitale ⁎ (pp. 936-941).
Membrane fusion remains one of the less well-understood processes in cell biology. A variety of mechanisms have been proposed to explain how the generation of fusogenic lipids at sites of exocytosis facilitates secretion in mammalian cells. Over the last decade, chromaffin cells have served as an important cellular model to demonstrate a key role for phospholipase D1 (PLD1) generated phosphatidic acid in regulated exocytosis. The current model proposes that phosphatidic acid plays a biophysical role, generating a negative curvature and thus promoting fusion of secretory vesicles with the plasma membrane. Moreover, multiple signaling pathways converging on PLD1 regulation have been unraveled in chromaffin cells, suggesting a complex level of regulation dependant on the physiological context.
Keywords: Chromaffin cell; Exocytosis; Membrane fusion; Phosphatidic acid; Phospholipase D
Diacylglycerol kinases as sources of phosphatidic acid by Jinjin Cai; Hanan Abramovici; Stephen H. Gee; Matthew K. Topham ⁎ (pp. 942-948).
There are ten mammalian diacylglycerol kinases (DGKs) whose primary role is to terminate diacylglycerol (DAG) signaling. However, it is becoming increasingly apparent that DGKs also influence signaling events through their product, phosphatidic acid (PA). They do so in some cases by associating with proteins and then modifying their activity by generating PA. In other cases, DGKs broadly regulate signaling events by virtue of their ability to provide PA for the synthesis of phosphatidylinositols (PtdIns).
Keywords: Abbreviations; DGKs; diacylglycerol kinases; DAG; diacylglycerol; PA; phosphatidic acid; PtdIns; phosphatidylinositols; PtdIns(4,5)P; 2; phosphatidylinositol-4,5-bisphosphate; PLC; phospholipase C; PKC; protein kinase C; RasGRPs; Ras guanyl nucleotide-releasing proteins; MuLK; multisubstrate lipid kinase; PH; pleckstrin homology; SAM; sterile alpha motif; RA; Ras association domain; 7TMR; seven-transmembrane receptor; M1R; M1 muscarinic receptor; RhoGDI; Rho guanine dissociation inhibitor; PAK1; p21-activated kinase 1; mTOR; mammalian target of rapamycin; PLD; phospholipase D; p70S6K; p70 S6 kinase; TLR; Toll-like receptor; LPP; lipid phosphate phosphohydrolase; PAP; PA phosphatase; PtdIns4P; phosphatidylinositol-4-phosphate; PI5K; PtdIns4P 5-kinaseDiacylglycerol kinase; Diacylglycerol; Phosphatidic acid; Phosphatidylinositol; Lipid signaling
Phosphatidic acid signaling to mTOR: Signals for the survival of human cancer cells by David A. Foster ⁎ (pp. 949-955).
During the past decade elevated phospholipase D (PLD) activity has been reported in virtually all cancers where it has been examined. PLD catalyzes the hydrolysis of phosphatidylcholine to generate the lipid second messenger phosphatidic acid (PA). While many targets of PA signaling have been identified, the most critical target of PA in cancer cells is likely to be mTOR — the mammalian target of rapamycin. mTOR has been widely implicated in signals that suppress apoptotic programs in cancer cells — frequently referred to as survival signals. mTOR exists as two multi-component complexes known as mTORC1 and mTORC2. Recent data has revealed that PA is required for the stability of both mTORC1 and mTORC2 complexes — and therefore also required for the kinase activity of both mTORC1 and mTORC2. PA interacts with mTOR in a manner that is competitive with rapamycin, and as a consequence, elevated PLD activity confers rapamycin resistance — a point that has been largely overlooked in clinical trials involving rapamycin-based strategies. The earliest genetic changes occurring in an emerging tumor are generally ones that suppress default apoptotic programs that likely represent the first line of defense of cancer. Targeting survival signals in human cancers represents a rational anti-cancer therapeutic strategy. Therefore, understanding the signals that regulate PA levels and how PA impacts upon mTOR could be important for developing strategies to de-repress the survival signals that suppress apoptosis. This review summarizes the role of PA in regulating the mTOR-mediated signals that promote cancer cell survival.
Keywords: Phospholipase D; Phosphatidic acid; mTOR; Rapamycin; Survival signal; Cancer
Phosphatidate degradation: Phosphatidate phosphatases (lipins) and lipid phosphate phosphatases by David N. Brindley ⁎; Carlos Pilquil; Meltem Sariahmetoglu; Karen Reue (pp. 956-961).
Three lipid phosphate phosphatases (LPPs) regulate cell signaling by modifying the concentrations of a variety of lipid phosphates versus their dephosphorylated products. In particular, the LPPs are normally considered to regulate signaling by the phospholipase D (PLD) pathway by converting phosphatidate (PA) to diacylglycerol (DAG). LPP activities do modulate the accumulations of PA and DAG following PLD activation, but this could also involve an effect upstream of PLD activation. The active sites of the LPPs are on the exterior surface of plasma membranes, or on the luminal surface of internal membranes. Consequently, the actions of the LPPs in metabolizing PA formed by PLD1 or PLD2 should depend on the access of this substrate to the active site of the LPPs. Alternatively, PA generated on the cytosolic surface of membranes should be readily accessible to the family of specific phosphatidate phosphatases, namely the lipins. Presently, there is only indirect evidence for the lipins participating in cell signaling following PLD activation. So far, we know relatively little about how individual LPPs and specific phosphatidate phosphatases (lipins) modulate cell signaling through controlling the turnover of bioactive lipids that are formed after PLD activation.
Keywords: Abbreviations; DAG; diacylglycerol; LPA; lysophosphatidate; LPP; lipid phosphate phosphatase; LPR/PRGs; lipid phosphatase-related proteins or plasticity-related genes; MAG; monoacylglycerol; PAP; phosphatidate phosphatase; PC; phosphatidylcholine; PE; phosphatidylethanolamine; S1P; sphingosine 1-phosphate; TAG; triacylglycerolDiacylglycerol; Lysophosphatidate; Phosphatidate; Phospholipase D; Triacylglycerol synthesis
Phospholipase D mechanism using Streptomyces PLD by Yoshiko Uesugi; Tadashi Hatanaka ⁎ (pp. 962-969).
Phospholipase D (PLD) plays various roles in important biological processes and physiological functions, including cell signaling. Streptomyces PLDs show significant sequence similarity and belong to the PLD superfamily containing two catalytic HKD motifs. These PLDs have conserved catalytic regions and are among the smallest PLD enzymes. Therefore, Streptomyces PLDs are thought to be suitable models for studying the reaction mechanism among PLDs from other sources. Furthermore, Streptomyces PLDs present advantages related to their broad substrate specificity and ease of enzyme preparation. Moreover, the tertiary structure of PLD has been elucidated only for PLD from Streptomyces sp. PMF. This article presents a review of recently reported studies of the mechanism of the catalytic reaction, substrate recognition, substrate specificity and stability of Streptomyces PLD using various protein engineering methods and surface plasmon resonance analysis.
Keywords: Streptomyces; Phospholipase D
Phospholipase D function in Saccharomyces cerevisiae by Rima Mendonsa; JoAnne Engebrecht ⁎ (pp. 970-974).
Phosphatidylinositol 4,5-bisphosphate-regulated phosphatidylcholine-specific phospholipase D is conserved from yeast to man. The essential role of this enzyme in yeast is to mediate the fusion of Golgi and endosome-derived vesicles to generate the prospore membrane during the developmental program of sporulation, through the production of the fusogenic lipid phosphatidic acid. In addition to recruiting proteins required for fusion, phosphatidic acid is believed to lower the energy barrier to stimulate membrane curvature. During mitotic growth, phospholipase D activity is dispensable unless the major phosphatidylinositol/phosphatidylcholine transfer protein is absent; it also appears to play a nonessential role in the mating signal transduction pathway. The regulation of phospholipase D activity during both sporulation and mitotic growth is still not fully understood and awaits further characterization.
Keywords: Membrane trafficking; Phosphatidic acid; Phosphatidylinositol 4,5-bisphosphate; Phospholipase D; Prospore membrane formation; SNARE; Sporulation