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Phosphatidylserine translocation at the yeast trans-Golgi network regulates protein sorting into exocytic vesicles.
Hankins HM, Sere YY, Diab NS, Menon AK, Graham TR
(2015) Mol Biol Cell 26: 4674-85
MeSH Terms: Adenosine Triphosphatases, Amino Acid Transport Systems, Basic, Calcium-Transporting ATPases, Cell Membrane, Exocytosis, Membrane Proteins, Mutation, Phosphatidylserines, Protein Transport, Proton-Translocating ATPases, Receptors, Steroid, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Transport Vesicles, trans-Golgi Network
Show Abstract · Added April 6, 2017
Sorting of plasma membrane proteins into exocytic vesicles at the yeast trans-Golgi network (TGN) is believed to be mediated by their coalescence with specific lipids, but how these membrane-remodeling events are regulated is poorly understood. Here we show that the ATP-dependent phospholipid flippase Drs2 is required for efficient segregation of cargo into exocytic vesicles. The plasma membrane proteins Pma1 and Can1 are missorted from the TGN to the vacuole in drs2∆ cells. We also used a combination of flippase mutants that either gain or lose the ability to flip phosphatidylserine (PS) to determine that PS flip by Drs2 is its critical function in this sorting event. The primary role of PS flip at the TGN appears to be to control the oxysterol-binding protein homologue Kes1/Osh4 and regulate ergosterol subcellular distribution. Deletion of KES1 suppresses plasma membrane-missorting defects and the accumulation of intracellular ergosterol in drs2 mutants. We propose that PS flip is part of a homeostatic mechanism that controls sterol loading and lateral segregation of protein and lipid domains at the TGN.
© 2015 Hankins et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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15 MeSH Terms
Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport.
Jin D, Ni TT, Sun J, Wan H, Amack JD, Yu G, Fleming J, Chiang C, Li W, Papierniak A, Cheepala S, Conseil G, Cole SP, Zhou B, Drummond IA, Schuetz JD, Malicki J, Zhong TP
(2014) Nat Cell Biol 16: 841-51
MeSH Terms: Amino Acid Sequence, Animals, Base Sequence, Cilia, Dinoprostone, HEK293 Cells, Humans, Kupffer Cells, Mice, Molecular Sequence Data, Multidrug Resistance-Associated Proteins, Protein Transport, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction, Transport Vesicles, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 19, 2015
Cilia are microtubule-based organelles that mediate signal transduction in a variety of tissues. Despite their importance, the signalling cascades that regulate cilium formation remain incompletely understood. Here we report that prostaglandin signalling affects ciliogenesis by regulating anterograde intraflagellar transport (IFT). Zebrafish leakytail (lkt) mutants show ciliogenesis defects, and the lkt locus encodes an ATP-binding cassette transporter (ABCC4). We show that Lkt/ABCC4 localizes to the cell membrane and exports prostaglandin E2 (PGE2), a function that is abrogated by the Lkt/ABCC4(T804M) mutant. PGE2 synthesis enzyme cyclooxygenase-1 and its receptor, EP4, which localizes to the cilium and activates the cyclic-AMP-mediated signalling cascade, are required for cilium formation and elongation. Importantly, PGE2 signalling increases anterograde but not retrograde velocity of IFT and promotes ciliogenesis in mammalian cells. These findings lead us to propose that Lkt/ABCC4-mediated PGE2 signalling acts through a ciliary G-protein-coupled receptor, EP4, to upregulate cAMP synthesis and increase anterograde IFT, thereby promoting ciliogenesis.
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17 MeSH Terms
Bves and NDRG4 regulate directional epicardial cell migration through autocrine extracellular matrix deposition.
Benesh EC, Miller PM, Pfaltzgraff ER, Grega-Larson NE, Hager HA, Sung BH, Qu X, Baldwin HS, Weaver AM, Bader DM
(2013) Mol Biol Cell 24: 3496-510
MeSH Terms: Animals, Autocrine Communication, COS Cells, Cell Adhesion Molecules, Cell Membrane, Cell Movement, Cercopithecus aethiops, Embryo, Mammalian, Endosomes, Extracellular Matrix, Fibronectins, Gene Expression Regulation, Developmental, Mice, Mice, Inbred C57BL, Muscle Proteins, Nerve Tissue Proteins, Pericardium, Primary Cell Culture, Signal Transduction, Transport Vesicles
Show Abstract · Added March 7, 2014
Directional cell movement is universally required for tissue morphogenesis. Although it is known that cell/matrix interactions are essential for directional movement in heart development, the mechanisms governing these interactions require elucidation. Here we demonstrate that a novel protein/protein interaction between blood vessel epicardial substance (Bves) and N-myc downstream regulated gene 4 (NDRG4) is critical for regulation of epicardial cell directional movement, as disruption of this interaction randomizes migratory patterns. Our studies show that Bves/NDRG4 interaction is required for trafficking of internalized fibronectin through the "autocrine extracellular matrix (ECM) deposition" fibronectin recycling pathway. Of importance, we demonstrate that Bves/NDRG4-mediated fibronectin recycling is indeed essential for epicardial cell directional movement, thus linking these two cell processes. Finally, total internal reflectance fluorescence microscopy shows that Bves/NDRG4 interaction is required for fusion of recycling endosomes with the basal cell surface, providing a molecular mechanism of motility substrate delivery that regulates cell directional movement. This is the first evidence of a molecular function for Bves and NDRG4 proteins within broader subcellular trafficking paradigms. These data identify novel regulators of a critical vesicle-docking step required for autocrine ECM deposition and explain how Bves facilitates cell-microenvironment interactions in the regulation of epicardial cell-directed movement.
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20 MeSH Terms
Phosphatidylserine flipping enhances membrane curvature and negative charge required for vesicular transport.
Xu P, Baldridge RD, Chi RJ, Burd CG, Graham TR
(2013) J Cell Biol 202: 875-86
MeSH Terms: ATP-Binding Cassette Transporters, Adenosine Triphosphatases, Amino Acid Motifs, Amino Acid Sequence, Blotting, Western, Calcium-Transporting ATPases, Cell Membrane, DNA-Binding Proteins, Endosomes, GTPase-Activating Proteins, Immunoprecipitation, Membrane Lipids, Models, Molecular, Molecular Sequence Data, Phosphatidylserines, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Transport Vesicles, trans-Golgi Network
Show Abstract · Added May 29, 2014
Vesicle-mediated protein transport between organelles of the secretory and endocytic pathways is strongly influenced by the composition and organization of membrane lipids. In budding yeast, protein transport between the trans-Golgi network (TGN) and early endosome (EE) requires Drs2, a phospholipid translocase in the type IV P-type ATPase family. However, downstream effectors of Drs2 and specific phospholipid substrate requirements for protein transport in this pathway are unknown. Here, we show that the Arf GTPase-activating protein (ArfGAP) Gcs1 is a Drs2 effector that requires a variant of the ArfGAP lipid packing sensor (+ALPS) motif for localization to TGN/EE membranes. Drs2 increases membrane curvature and anionic phospholipid composition of the cytosolic leaflet, both of which are sensed by the +ALPS motif. Using mutant forms of Drs2 and the related protein Dnf1, which alter their ability to recognize phosphatidylserine, we show that translocation of this substrate to the cytosolic leaflet is essential for +ALPS binding and vesicular transport between the EE and the TGN.
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20 MeSH Terms
Phospholipid flippases: building asymmetric membranes and transport vesicles.
Sebastian TT, Baldridge RD, Xu P, Graham TR
(2012) Biochim Biophys Acta 1821: 1068-77
MeSH Terms: Animals, Cell Membrane, Endosomes, Gene Expression, Golgi Apparatus, Humans, Phospholipid Transfer Proteins, Phospholipids, Phylogeny, Plants, Protein Isoforms, Protein Transport, Saccharomyces cerevisiae, Transport Vesicles
Show Abstract · Added January 20, 2015
Phospholipid flippases in the type IV P-type ATPase family (P4-ATPases) are essential components of the Golgi, plasma membrane and endosomal system that play critical roles in membrane biogenesis. These pumps flip phospholipid across the bilayer to create an asymmetric membrane structure with substrate phospholipids, such as phosphatidylserine and phosphatidylethanolamine, enriched within the cytosolic leaflet. The P4-ATPases also help form transport vesicles that bud from Golgi and endosomal membranes, thereby impacting the sorting and localization of many different proteins in the secretory and endocytic pathways. At the organismal level, P4-ATPase deficiencies are linked to liver disease, obesity, diabetes, hearing loss, neurological deficits, immune deficiency and reduced fertility. Here, we review the biochemical, cellular and physiological functions of P4-ATPases, with an emphasis on their roles in vesicle-mediated protein transport. This article is part of a Special Issue entitled Lipids and Vesicular Transport.
Copyright © 2011 Elsevier B.V. All rights reserved.
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14 MeSH Terms
A nonaggregating surfactant protein C mutant is misdirected to early endosomes and disrupts phospholipid recycling.
Beers MF, Hawkins A, Maguire JA, Kotorashvili A, Zhao M, Newitt JL, Ding W, Russo S, Guttentag S, Gonzales L, Mulugeta S
(2011) Traffic 12: 1196-210
MeSH Terms: Adult, Cell Membrane, Cells, Cultured, Child, Endocytosis, Endoplasmic Reticulum, Endosomes, Humans, Lung Diseases, Interstitial, Lysosomes, Mutation, Phospholipids, Protein Isoforms, Protein Precursors, Protein Transport, Pulmonary Surfactant-Associated Protein C, Recombinant Fusion Proteins, Transferrin, Transport Vesicles
Show Abstract · Added January 20, 2015
Interstitial lung disease in both children and adults has been linked to mutations in the lung-specific surfactant protein C (SFTPC) gene. Among these, the missense mutation [isoleucine to threonine at codon 73 = human surfactant protein C (hSP-C(I73T) )] accounts for ∼30% of all described SFTPC mutations. We reported previously that unlike the BRICHOS misfolding SFTPC mutants, expression of hSP-C(I73T) induces lung remodeling and alveolar lipoproteinosis without a substantial Endoplasmic Reticulum (ER) stress response or ER-mediated intrinsic apoptosis. We show here that, in contrast to its wild-type counterpart that is directly routed to lysosomal-like organelles for processing, SP-C(I73T) is misdirected to the plasma membrane and subsequently internalized to the endocytic pathway via early endosomes, leading to the accumulation of abnormally processed proSP-C isoforms. Functionally, cells expressing hSP-C(I73T) demonstrated both impaired uptake and degradation of surfactant phospholipid, thus providing a molecular mechanism for the observed lipid accumulation in patients expressing hSP-C(I73T) through the disruption of normal phospholipid recycling. Our data provide evidence for a novel cellular mechanism for conformational protein-associated diseases and suggest a paradigm for mistargeted proteins involved in the disruption of the endosomal/lysosomal sorting machinery.
© 2011 John Wiley & Sons A/S.
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19 MeSH Terms
Rab GTPase-Myo5B complexes control membrane recycling and epithelial polarization.
Roland JT, Bryant DM, Datta A, Itzen A, Mostov KE, Goldenring JR
(2011) Proc Natl Acad Sci U S A 108: 2789-94
MeSH Terms: Animals, Cell Line, Cell Polarity, DNA Primers, Dogs, Epithelial Cells, Fluorescence Resonance Energy Transfer, Humans, Immunohistochemistry, Membranes, Mice, Multiprotein Complexes, Mutagenesis, Myosin Heavy Chains, Myosin Type V, Protein Transport, RNA Interference, Transferrin, Transport Vesicles, Two-Hybrid System Techniques, rab GTP-Binding Proteins
Show Abstract · Added October 7, 2013
The Rab GTPases are the largest family of proteins regulating membrane traffic. Rab proteins form a nidus for the assembly of multiprotein complexes on distinct vesicle membranes to regulate particular membrane trafficking pathways. Recent investigations have demonstrated that Myosin Vb (Myo5B) is an effector for Rab8a, Rab10, and Rab11a, all of which are implicated in regulating different pathways for recycling of proteins to the plasma membrane. It remains unclear how specific interactions of Myo5B with individual Rab proteins can lead to specificity in the regulation of alternate trafficking pathways. We examined the relative contributions of Rab/Myo5B interactions with specific pathways using Myo5B mutants lacking binding to either Rab11a or Rab8a. Myo5B Q1300L and Y1307C mutations abolished Rab8a association, whereas Myo5B Y1714E and Q1748R mutations uncoupled association with Rab11a. Expression of Myo5B tails containing these mutants demonstrated that Rab11a, but not Rab8a, was required for recycling of transferrin in nonpolarized cells. In contrast, in polarized epithelial cyst cultures, Myo5B was required for apical membrane trafficking and de novo lumen formation, dependent on association with both Rab8a and Rab11a. These data demonstrate that different combinations of Rab GTPase association with Myo5B control distinct membrane trafficking pathways.
1 Communities
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21 MeSH Terms
Coordination of Golgi functions by phosphatidylinositol 4-kinases.
Graham TR, Burd CG
(2011) Trends Cell Biol 21: 113-21
MeSH Terms: 1-Phosphatidylinositol 4-Kinase, Animals, Golgi Apparatus, Humans, Intracellular Membranes, Lipid Metabolism, Transport Vesicles, Yeasts
Show Abstract · Added April 6, 2017
Phosphatidylinositol 4-kinases (PI4Ks) regulate vesicle-mediated export from the Golgi apparatus via phosphatidylinositol 4-phosphate (PtdIns4P) binding effector proteins that control vesicle budding reactions and regulate membrane dynamics. Evidence has emerged from the characterization of Golgi PI4K effectors that vesicle budding and lipid dynamics are tightly coupled via a regulatory network that ensures that the appropriate membrane composition is established before a transport vesicle buds from the Golgi. An important hub of this network is protein kinase D, which regulates the activity of PI4K and several PtdIns4P effectors that control sphingolipid and sterol content of Golgi membranes. Other newly identified PtdIns4P effectors include Vps74/GOLPH3, a phospholipid flippase called Drs2 and Sec2, a Rab guanine nucleotide exchange factor (GEF). These effectors orchestrate membrane transformation events facilitating vesicle formation and targeting. In this review, we discuss how PtdIns4P signaling is integrated with membrane biosynthetic and vesicle budding machineries to potentially coordinate these crucial functions of the Golgi apparatus.
Copyright © 2010 Elsevier Ltd. All rights reserved.
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8 MeSH Terms
Alterations in the proteome of the NHERF1 knockout mouse jejunal brush border membrane vesicles.
Donowitz M, Singh S, Singh P, Salahuddin FF, Chen Y, Chakraborty M, Murtazina R, Gucek M, Cole RN, Zachos NC, Kovbasnjuk O, Broere N, Smalley-Freed WG, Reynolds AB, Hubbard AL, Seidler U, Weinman E, de Jonge HR, Hogema BM, Li X
(2010) Physiol Genomics 42A: 200-10
MeSH Terms: Animals, Cadherins, Chromatography, Ion Exchange, Female, Immunoblotting, Immunohistochemistry, Jejunum, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Microvilli, Phosphoproteins, Proteome, Proteomics, Sodium-Hydrogen Exchangers, Tandem Mass Spectrometry, Transport Vesicles, beta Catenin
Show Abstract · Added March 5, 2014
Na/H exchanger regulatory factor 1 (NHERF1) is a scaffold protein made up of two PDZ domains and an ERM binding domain. It is in the brush border of multiple epithelial cells where it modulates 1) Na absorption by regulating NHE3 complexes and cytoskeletal association, 2) Cl secretion through trafficking of CFTR, and 3) Na-coupled phosphate absorption through membrane retention of NaPi2a. To further understand the role of NHERF1 in regulation of small intestinal Na absorptive cell function, with emphasis on apical membrane transport regulation, quantitative proteomic analysis was performed on brush border membrane vesicles (BBMV) prepared from wild-type (WT) and homozygous NHERF1 knockout mouse jejunal villus Na absorptive cells. Jejunal architecture appeared normal in NHERF1 null; however, there was increased proliferative activity, as indicated by increased crypt BrdU staining. LC-MS/MS analysis using iTRAQ to compare WT and NHERF1 null BBMV identified 463 proteins present in both WT and NHERF1 null BBMV of simultaneously prepared and studied samples. Seventeen proteins had an altered amount of expression between WT and NHERF1 null in two or more separate preparations, and 149 total proteins were altered in at least one BBMV preparation. The classes of the majority of proteins altered included transport proteins, signaling and trafficking proteins, and proteins involved in proliferation and cell division. Affected proteins also included tight junction and adherens junction proteins, cytoskeletal proteins, as well as metabolic and BB digestive enzymes. Changes in abundance of several proteins were confirmed by immunoblotting [increased CEACAM1, decreased ezrin (p-ezrin), NHERF3, PLCβ3, E-cadherin, p120, β-catenin]. The changes in the jejunal BBMV proteome of NHERF1 null mice are consistent with a more complex role of NHERF1 than just forming signaling complexes and anchoring proteins to the apical membrane and include at least alterations in proteins involved in transport, signaling, and proliferation.
1 Communities
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20 MeSH Terms
Ahi1, whose human ortholog is mutated in Joubert syndrome, is required for Rab8a localization, ciliogenesis and vesicle trafficking.
Hsiao YC, Tong ZJ, Westfall JE, Ault JG, Page-McCaw PS, Ferland RJ
(2009) Hum Mol Genet 18: 3926-41
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Cell Line, Cells, Cultured, Cilia, Female, Fibroblasts, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Nervous System Diseases, Protein Binding, Protein Transport, Proto-Oncogene Proteins, Transport Vesicles, rab GTP-Binding Proteins
Show Abstract · Added January 7, 2014
The primary non-motile cilium, a membrane-ensheathed, microtubule-bundled organelle, extends from virtually all cells and is important for development. Normal functioning of the cilium requires proper axoneme assembly, membrane biogenesis and ciliary protein localization, in tight coordination with the intraflagellar transport system and vesicular trafficking. Disruptions at any level can induce severe alterations in cell function, giving rise to a myriad of human genetic diseases known as ciliopathies. Here we show that the Abelson helper integration site 1 (Ahi1) gene, whose human ortholog is mutated in Joubert syndrome, regulates cilium formation via its interaction with Rab8a, a small GTPase critical for polarized membrane trafficking. We find that the Ahi1 protein localizes to a single centriole, the mother centriole, which becomes the basal body of the primary cilium. In order to determine whether Ahi1 functions in ciliogenesis, loss of function analysis of Ahi1 was performed in cell culture models of ciliogenesis. Knockdown of Ahi1 expression by shRNAi in cells or targeted deletion of Ahi1 (Ahi1 knockout mouse) leads to impairments in ciliogenesis. In Ahi1-knockdown cells, Rab8a is destabilized and does not properly localize to the basal body. Since Rab8a is implicated in vesicular trafficking, we next examined this process in Ahi1-knockdown cells. Defects in the trafficking of endocytic vesicles from the plasma membrane to the Golgi and back to the plasma membrane were observed in Ahi1-knockdown cells. Overall, our data indicate that the distribution and functioning of Rab8a is regulated by Ahi1, not only affecting cilium formation, but also vesicle transport.
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19 MeSH Terms