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Phosphoinositide-mediated ring anchoring resists perpendicular forces to promote medial cytokinesis.
Snider CE, Willet AH, Chen JS, Arpağ G, Zanic M, Gould KL
(2017) J Cell Biol 216: 3041-3050
MeSH Terms: 1-Phosphatidylinositol 4-Kinase, Cell Cycle Proteins, Cytokinesis, GTP-Binding Proteins, Glycosylphosphatidylinositols, Myosin Type V, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added March 14, 2018
Many eukaryotic cells divide by assembling and constricting an actin- and myosin-based contractile ring (CR) that is physically linked to the plasma membrane (PM). In this study, we report that cells lacking , which encodes a conserved PM scaffold for the phosphatidylinositol-4 kinase Stt4, build CRs that can slide away from the cell middle during anaphase in a myosin V-dependent manner. The Efr3-dependent CR-anchoring mechanism is distinct from previously reported pathways dependent on the Fes/CIP4 homology Bin-Amphiphysin-Rvs167 (F-BAR) protein Cdc15 and paxillin Pxl1. In , the concentrations of several membrane-binding proteins were reduced in the CR and/or on the PM. Our results suggest that proper PM lipid composition is important to stabilize the central position of the CR and resist myosin V-based forces to promote the fidelity of cell division.
© 2017 Snider et al.
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8 MeSH Terms
Nuclear phosphoinositide regulation of chromatin.
Hamann BL, Blind RD
(2018) J Cell Physiol 233: 107-123
MeSH Terms: Animals, Cell Differentiation, Cell Nucleus, Cell Proliferation, Chromatin, Chromatin Assembly and Disassembly, Gene Expression Regulation, Humans, Intracellular Signaling Peptides and Proteins, Phosphatidylinositols, Transcription, Genetic
Show Abstract · Added January 19, 2019
Phospholipid signaling has clear connections to a wide array of cellular processes, particularly in gene expression and in controlling the chromatin biology of cells. However, most of the work elucidating how phospholipid signaling pathways contribute to cellular physiology have studied cytoplasmic membranes, while relatively little attention has been paid to the role of phospholipid signaling in the nucleus. Recent work from several labs has shown that nuclear phospholipid signaling can have important roles that are specific to this cellular compartment. This review focuses on the nuclear phospholipid functions and the activities of phospholipid signaling enzymes that regulate metazoan chromatin and gene expression. In particular, we highlight the roles that nuclear phosphoinositides play in several nuclear-driven physiological processes, such as differentiation, proliferation, and gene expression. Taken together, the recent discovery of several specifically nuclear phospholipid functions could have dramatic impact on our understanding of the fundamental mechanisms that enable tight control of cellular physiology.
© 2017 Wiley Periodicals, Inc.
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MeSH Terms
Phosphoinositide signalling in type 2 diabetes: a β-cell perspective.
Rameh LE, Deeney JT
(2016) Biochem Soc Trans 44: 293-8
MeSH Terms: 1-Phosphatidylinositol 4-Kinase, Animals, Diabetes Mellitus, Type 2, Humans, Insulin, Insulin Secretion, Insulin-Secreting Cells, Phosphatidylinositols, Signal Transduction
Show Abstract · Added November 26, 2018
Type 2 diabetes is a complex disease. It results from a failure of the body to maintain energy homoeostasis. Multicellular organisms have evolved complex strategies to preserve a relatively stable internal nutrient environment, despite fluctuations in external nutrient availability. This complex strategy involves the co-ordinated responses of multiple organs to promote storage or mobilization of energy sources according to the availability of nutrients and cellular bioenergetics needs. The endocrine pancreas plays a central role in these processes by secreting insulin and glucagon. When this co-ordinated effort fails, hyperglycaemia and hyperlipidaemia develops, characterizing a state of metabolic imbalance and ultimately overt diabetes. Although diabetes is most likely a collection of diseases, scientists are starting to identify genetic components and environmental triggers. Genome-wide association studies revealed that by and large, gene variants associated with type 2 diabetes are implicated in pancreatic β-cell function, suggesting that the β-cell may be the weakest link in the chain of events that results in diabetes. Thus, it is critical to understand how environmental cues affect the β-cell. Phosphoinositides are important 'decoders' of environmental cues. As such, these lipids have been implicated in cellular responses to a wide range of growth factors, hormones, stress agents, nutrients and metabolites. Here we will review some of the well-established and potential new roles for phosphoinositides in β-cell function/dysfunction and discuss how our knowledge of phosphoinositide signalling could aid in the identification of potential strategies for treating or preventing type 2 diabetes.
© 2016 Authors; published by Portland Press Limited.
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9 MeSH Terms
Analysis of the Phosphoinositide Composition of Subcellular Membrane Fractions.
Sarkes DA, Rameh LE
(2016) Methods Mol Biol 1376: 213-27
MeSH Terms: Cell Fractionation, Cell Membrane, Chromatography, High Pressure Liquid, Phosphatidylinositols, Staining and Labeling, Subcellular Fractions, Tritium
Show Abstract · Added November 26, 2018
Phosphoinositides play critical roles in the transduction of extracellular signals through the plasma membrane and also in endomembrane events important for vesicle trafficking and organelle function (Di Paolo and De Camilli, Nature 443(7112):651-657, 2006). The response triggered by these lipids is heavily dependent on the microenvironment in which they are found. HPLC analysis of labeled phosphoinositides allows quantification of the levels of each phosphoinositide species relative to their precursor, phosphatidylinositol. When combined with subcellular fractionation techniques, this strategy allows measurement of the relative phosphoinositide composition of each membrane fraction or organelle and determination of the microenvironment in which each species is enriched. Here, we describe the steps to separate and quantify total or localized phosphoinositides from cultured cells.
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Structure of Liver Receptor Homolog-1 (NR5A2) with PIP3 hormone bound in the ligand binding pocket.
Sablin EP, Blind RD, Uthayaruban R, Chiu HJ, Deacon AM, Das D, Ingraham HA, Fletterick RJ
(2015) J Struct Biol 192: 342-348
MeSH Terms: Binding Sites, Crystallography, X-Ray, DAX-1 Orphan Nuclear Receptor, Humans, Models, Molecular, Phosphatidylinositols, Protein Binding, Protein Structure, Tertiary, Receptors, Cytoplasmic and Nuclear, Steroidogenic Factor 1
Show Abstract · Added January 19, 2019
The nuclear receptor LRH-1 (Liver Receptor Homolog-1, NR5A2) is a transcription factor that regulates gene expression programs critical for many aspects of metabolism and reproduction. Although LRH-1 is able to bind phospholipids, it is still considered an orphan nuclear receptor (NR) with an unknown regulatory hormone. Our prior cellular and structural studies demonstrated that the signaling phosphatidylinositols PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3) bind and regulate SF-1 (Steroidogenic Factor-1, NR5A1), a close homolog of LRH-1. Here, we describe the crystal structure of human LRH-1 ligand binding domain (LBD) bound by PIP3 - the first phospholipid with a head group endogenous to mammals. We show that the phospholipid hormone binds LRH-1 with high affinity, stabilizing the receptor LBD. While the hydrophobic PIP3 tails (C16/C16) are buried inside the LRH-1 ligand binding pocket, the negatively charged PIP3 head group is presented on the receptor surface, similar to the phosphatidylinositol binding mode observed in the PIP3-SF-1 structure. Thus, data presented in this work reinforce our earlier findings demonstrating that signaling phosphatidylinositols regulate the NR5A receptors LRH-1 and SF-1.
Published by Elsevier Inc.
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MeSH Terms
Non-small cell lung cancer is characterized by dramatic changes in phospholipid profiles.
Marien E, Meister M, Muley T, Fieuws S, Bordel S, Derua R, Spraggins J, Van de Plas R, Dehairs J, Wouters J, Bagadi M, Dienemann H, Thomas M, Schnabel PA, Caprioli RM, Waelkens E, Swinnen JV
(2015) Int J Cancer 137: 1539-48
MeSH Terms: Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Phosphatidylinositols, Phospholipids, Spectrometry, Mass, Electrospray Ionization, Sphingomyelins, Tandem Mass Spectrometry
Show Abstract · Added October 15, 2015
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death globally. To develop better diagnostics and more effective treatments, research in the past decades has focused on identification of molecular changes in the genome, transcriptome, proteome, and more recently also the metabolome. Phospholipids, which nevertheless play a central role in cell functioning, remain poorly explored. Here, using a mass spectrometry (MS)-based phospholipidomics approach, we profiled 179 phospholipid species in malignant and matched non-malignant lung tissue of 162 NSCLC patients (73 in a discovery cohort and 89 in a validation cohort). We identified 91 phospholipid species that were differentially expressed in cancer versus non-malignant tissues. Most prominent changes included a decrease in sphingomyelins (SMs) and an increase in specific phosphatidylinositols (PIs). Also a decrease in multiple phosphatidylserines (PSs) was observed, along with an increase in several phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, particularly those with 40 or 42 carbon atoms in both fatty acyl chains together. 2D-imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. We identified lipid markers that can discriminate tumor versus normal tissue and different NSCLC subtypes with an AUC (area under the ROC curve) of 0.999 and 0.885, respectively. In conclusion, using both shotgun and 2D-imaging lipidomics analysis, we uncovered a hitherto unrecognized alteration in phospholipid profiles in NSCLC. These changes may have important biological implications and may have significant potential for biomarker development.
© 2015 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.
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8 MeSH Terms
The signaling phospholipid PIP3 creates a new interaction surface on the nuclear receptor SF-1.
Blind RD, Sablin EP, Kuchenbecker KM, Chiu HJ, Deacon AM, Das D, Fletterick RJ, Ingraham HA
(2014) Proc Natl Acad Sci U S A 111: 15054-9
MeSH Terms: Amino Acids, Animals, Biological Transport, Cell Nucleus, Chromatography, Computer Simulation, Crystallography, X-Ray, Electrons, Humans, Ligands, Lipids, Mice, Models, Molecular, Molecular Conformation, Mutation, Mutation, Missense, Peptides, Phosphatidylinositols, Signal Transduction, Solvents, Steroidogenic Factor 1, Surface Plasmon Resonance, Surface Properties, Temperature, Water
Show Abstract · Added August 18, 2015
The signaling phosphatidylinositol lipids PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3) bind nuclear receptor 5A family (NR5As), but their regulatory mechanisms remain unknown. Here, the crystal structures of human NR5A1 (steroidogenic factor-1, SF-1) ligand binding domain (LBD) bound to PIP2 and PIP3 show the lipid hydrophobic tails sequestered in the hormone pocket, as predicted. However, unlike classic nuclear receptor hormones, the phosphoinositide head groups are fully solvent-exposed and complete the LBD fold by organizing the receptor architecture at the hormone pocket entrance. The highest affinity phosphoinositide ligand PIP3 stabilizes the coactivator binding groove and increases coactivator peptide recruitment. This receptor-ligand topology defines a previously unidentified regulatory protein-lipid surface on SF-1 with the phosphoinositide head group at its nexus and poised to interact with other proteins. This surface on SF-1 coincides with the predicted binding site of the corepressor DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region on chromosome X), and importantly harbors missense mutations associated with human endocrine disorders. Our data provide the structural basis for this poorly understood cluster of human SF-1 mutations and demonstrates how signaling phosphoinositides function as regulatory ligands for NR5As.
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25 MeSH Terms
An efficient, nonlinear stability analysis for detecting pattern formation in reaction diffusion systems.
Holmes WR
(2014) Bull Math Biol 76: 157-83
MeSH Terms: Chemotaxis, Computer Simulation, Diffusion, GTP Phosphohydrolases, Kinetics, Linear Models, Mathematical Concepts, Models, Biological, Nonlinear Dynamics, Pattern Recognition, Automated, Phosphatidylinositols, Systems Biology
Show Abstract · Added February 26, 2016
Reaction diffusion systems are often used to study pattern formation in biological systems. However, most methods for understanding their behavior are challenging and can rarely be applied to complex systems common in biological applications. I present a relatively simple and efficient, nonlinear stability technique that greatly aids such analysis when rates of diffusion are substantially different. This technique reduces a system of reaction diffusion equations to a system of ordinary differential equations tracking the evolution of a large amplitude, spatially localized perturbation of a homogeneous steady state. Stability properties of this system, determined using standard bifurcation techniques and software, describe both linear and nonlinear patterning regimes of the reaction diffusion system. I describe the class of systems this method can be applied to and demonstrate its application. Analysis of Schnakenberg and substrate inhibition models is performed to demonstrate the methods capabilities in simplified settings and show that even these simple models have nonlinear patterning regimes not previously detected. The real power of this technique, however, is its simplicity and applicability to larger complex systems where other nonlinear methods become intractable. This is demonstrated through analysis of a chemotaxis regulatory network comprised of interacting proteins and phospholipids. In each case, predictions of this method are verified against results of numerical simulation, linear stability, asymptotic, and/or full PDE bifurcation analyses.
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12 MeSH Terms
SDF-1 fused to a fractalkine stalk and a GPI anchor enables functional neovascularization.
Stachel G, Trenkwalder T, Götz F, El Aouni C, Muenchmeier N, Pfosser A, Nussbaum C, Sperandio M, Hatzopoulos AK, Hinkel R, Nelson PJ, Kupatt C
(2013) Stem Cells 31: 1795-805
MeSH Terms: Animals, Cell Adhesion, Chemokine CX3CL1, Chemokine CXCL12, Endocytosis, Glycosylphosphatidylinositols, Human Umbilical Vein Endothelial Cells, Humans, Mice, Neovascularization, Physiologic, Rabbits, Receptors, CXCR4, Recombinant Fusion Proteins, Stem Cells
Show Abstract · Added May 27, 2014
The facilitated recruitment of vascular progenitor cells (VPCs) to ischemic areas might be a therapeutic target for neovascularization and repair. However, efficient and directed attraction of VPCs remains a major challenge in clinical application. To enhance VPC homing, we developed a fusion protein (S1FG), based on the biology of stroma-derived factor-1/CXCL12 and the mucin backbone taken from fractalkine/CXCL12. A GPI-anchor was included to link the fusion-protein to the cell surface. HUVECs transfected with S1FG were capable of increasing firm adhesion of CXCR4+-mononuclear cells (THP-1) under shear stress conditions in vitro. In an in vivo rabbit model of chronic hind limb ischemia, local S1FG application enhanced the recruitment of adoptively transferred embryonic EPCs (eEPCs) to the ischemic muscles 2.5-fold. S1FG combined with eEPC(low) (2 × 10(6)) yielded similar capillary growth as eEPC(high) (5 × 10(6)) alone. Compared to controls, collateral formation was increased in the S1FG eEPC(low) group, but not the eEPC(high) group without S1FG, whereas perfusion was found enhanced in both groups. In addition, S1FG also increased collateral formation and flow when combined with AMD3100 treatment, to increase circulating levels of endogenous VPC. These data demonstrate that the fusion protein S1FG is capable of enhancing the recruitment of exogenously applied or endogenously mobilized progenitor cells to sites of injury. Recombinant versions of S1FG applied via catheters in combination with progenitor cell mobilization may be useful in the treatment of chronic ischemic syndromes requiring improved perfusion.
© AlphaMed Press.
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14 MeSH Terms
Modulation of turkey myogenic satellite cell differentiation through the shedding of glypican-1.
Velleman SG, Song Y, Shin J, McFarland DC
(2013) Comp Biochem Physiol A Mol Integr Physiol 164: 36-43
MeSH Terms: Animals, Blotting, Western, Cell Differentiation, Cell Membrane, Cells, Cultured, Cloning, Molecular, Culture Media, Fibroblast Growth Factor 2, Genetic Vectors, Glycosaminoglycans, Glycosylation, Glycosylphosphatidylinositols, Glypicans, Green Fluorescent Proteins, Immunohistochemistry, Male, Muscle Development, Muscle Fibers, Skeletal, MyoD Protein, Myogenin, Protein Structure, Tertiary, RNA, Small Interfering, Satellite Cells, Skeletal Muscle, Solubility, Transcription, Genetic, Transfection, Turkeys
Show Abstract · Added March 3, 2014
Glypican-1 is a cell membrane heparan sulfate proteoglycan. It is composed of a core protein with covalently attached glycosaminoglycan, and N-linked glycosylated (N-glycosylated) chains, and is attached to the cell membrane by a glycosylphosphatidylinositol (GPI) linkage. Glypican-1 plays a key role in the growth and development of muscle by regulating fibroblast growth factor 2 (FGF2). The GPI anchor of glypican-1 can be cleaved, resulting in glypican-1 being secreted or shed into the extracellular matrix environment. The objective of the current study was to investigate the role of glypican-1 shedding and the glycosaminoglycan and N-glycosylated chains in regulating the differentiation of turkey myogenic satellite cells. A glypican-1 construct without the GPI anchor was cloned into the mammalian expression vector pCMS-EGFP, and glypican-1 without the GPI anchor and glycosaminoglycan and N-glycosylated chains were also cloned. These constructs were co-transfected into turkey myogenic satellite cells with a small interference RNA targeting the GPI anchor of endogenous glypican-1. The soluble glypican-1 mutants were not detected in the satellite cells but in the cell medium, suggesting the secretion of the soluble glypican-1 mutants. Soluble glypican-1 increased satellite cell differentiation and enhanced myotube formation in the presence of exogenous FGF2. The increase in differentiation was supported by the elevated expression of myogenin. In conclusion, the shedding of glypican-1 from the satellite cell surface acts as a positive regulator of satellite cell differentiation and sequesters FGF2, permitting further differentiation.
Copyright © 2012 Elsevier Inc. All rights reserved.
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27 MeSH Terms