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Results: 1 to 10 of 10

Publication Record


Endophilin-A2 functions in membrane scission in clathrin-independent endocytosis.
Renard HF, Simunovic M, Lemière J, Boucrot E, Garcia-Castillo MD, Arumugam S, Chambon V, Lamaze C, Wunder C, Kenworthy AK, Schmidt AA, McMahon HT, Sykes C, Bassereau P, Johannes L
(2015) Nature 517: 493-6
MeSH Terms: Actins, Acyltransferases, Animals, Cell Line, Cell Membrane, Cholera Toxin, Clathrin, Dynamins, Endocytosis, Humans, Rats, Shiga Toxin
Show Abstract · Added January 21, 2015
During endocytosis, energy is invested to narrow the necks of cargo-containing plasma membrane invaginations to radii at which the opposing segments spontaneously coalesce, thereby leading to the detachment by scission of endocytic uptake carriers. In the clathrin pathway, dynamin uses mechanical energy from GTP hydrolysis to this effect, assisted by the BIN/amphiphysin/Rvs (BAR) domain-containing protein endophilin. Clathrin-independent endocytic events are often less reliant on dynamin, and whether in these cases BAR domain proteins such as endophilin contribute to scission has remained unexplored. Here we show, in human and other mammalian cell lines, that endophilin-A2 (endoA2) specifically and functionally associates with very early uptake structures that are induced by the bacterial Shiga and cholera toxins, which are both clathrin-independent endocytic cargoes. In controlled in vitro systems, endoA2 reshapes membranes before scission. Furthermore, we demonstrate that endoA2, dynamin and actin contribute in parallel to the scission of Shiga-toxin-induced tubules. Our results establish a novel function of endoA2 in clathrin-independent endocytosis. They document that distinct scission factors operate in an additive manner, and predict that specificity within a given uptake process arises from defined combinations of universal modules. Our findings highlight a previously unnoticed link between membrane scaffolding by endoA2 and pulling-force-driven dynamic scission.
0 Communities
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12 MeSH Terms
Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by mitochondrion-targeted cytochrome P450 2D6: implications in Parkinson disease.
Bajpai P, Sangar MC, Singh S, Tang W, Bansal S, Chowdhury G, Cheng Q, Fang JK, Martin MV, Guengerich FP, Avadhani NG
(2013) J Biol Chem 288: 4436-51
MeSH Terms: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Adrenergic alpha-Antagonists, Animals, Cell Line, Cytochrome P-450 CYP2D6, Dopamine Agents, Dopaminergic Neurons, Dynamins, Humans, Mice, Mitochondria, Mitochondrial Proteins, Parkinsonian Disorders, Quinidine, Reactive Oxygen Species, Ubiquitin-Protein Ligases
Show Abstract · Added March 26, 2014
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxic side product formed in the chemical synthesis of desmethylprodine opioid analgesic, which induces Parkinson disease. Monoamine oxidase B, present in the mitochondrial outer membrane of glial cells, catalyzes the oxidation of MPTP to the toxic 1-methyl-4-phenylpyridinium ion (MPP(+)), which then targets the dopaminergic neurons causing neuronal death. Here, we demonstrate that mitochondrion-targeted human cytochrome P450 2D6 (CYP2D6), supported by mitochondrial adrenodoxin and adrenodoxin reductase, can efficiently catalyze the metabolism of MPTP to MPP(+), as shown with purified enzymes and also in cells expressing mitochondrial CYP2D6. Neuro-2A cells stably expressing predominantly mitochondrion-targeted CYP2D6 were more sensitive to MPTP-mediated mitochondrial respiratory dysfunction and complex I inhibition than cells expressing predominantly endoplasmic reticulum-targeted CYP2D6. Mitochondrial CYP2D6 expressing Neuro-2A cells produced higher levels of reactive oxygen species and showed abnormal mitochondrial structures. MPTP treatment also induced mitochondrial translocation of an autophagic marker, Parkin, and a mitochondrial fission marker, Drp1, in differentiated neurons expressing mitochondrial CYP2D6. MPTP-mediated toxicity in primary dopaminergic neurons was attenuated by CYP2D6 inhibitor, quinidine, and also partly by monoamine oxidase B inhibitors deprenyl and pargyline. These studies show for the first time that dopaminergic neurons expressing mitochondrial CYP2D6 are fully capable of activating the pro-neurotoxin MPTP and inducing neuronal damage, which is effectively prevented by the CYP2D6 inhibitor quinidine.
0 Communities
1 Members
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16 MeSH Terms
Drosophila rolling blackout displays lipase domain-dependent and -independent endocytic functions downstream of dynamin.
Vijayakrishnan N, Phillips SE, Broadie K
(2010) Traffic 11: 1567-78
MeSH Terms: Animals, Carboxylic Ester Hydrolases, Catalytic Domain, Drosophila Proteins, Drosophila melanogaster, Dynamins, Endocytosis, Female, Genes, Lethal, Lipase, Male, Protein Structure, Tertiary, Synapses
Show Abstract · Added March 29, 2017
Drosophila temperature-sensitive rolling blackout (rbo(ts) ) mutants display a total block of endocytosis in non-neuronal cells and a weaker, partial defect at neuronal synapses. RBO is an integral plasma membrane protein and is predicted to be a serine esterase. To determine if lipase activity is required for RBO function, we mutated the catalytic serine 358 to alanine in the G-X-S-X-G active site, and assayed genomic rescue of rbo mutant non-neuronal and neuronal phenotypes. The rbo(S358A) mutant is unable to rescue rbo null 100% embryonic lethality, indicating that the lipase domain is critical for RBO essential function. Likewise, the rbo(S358A) mutant cannot provide any rescue of endocytic blockade in rbo(ts) Garland cells, showing that the lipase domain is indispensable for non-neuronal endocytosis. In contrast, rbo(ts) conditional paralysis, synaptic transmission block and synapse endocytic defects are all fully rescued by the rbo(S358A) mutant, showing that the RBO lipase domain is dispensable in neuronal contexts. We identified a synthetic lethal interaction between rbo(ts) and the well-characterized dynamin GTPase conditional shibire (shi(ts1)) mutant. In both non-neuronal cells and neuronal synapses, shi(ts1); rbo(ts) phenocopies shi(ts1) endocytic defects, indicating that dynamin and RBO act in the same pathway, with dynamin functioning upstream of RBO. We conclude that RBO possesses both lipase domain-dependent and scaffolding functions with differential requirements in non-neuronal versus neuronal endocytosis mechanisms downstream of dynamin GTPase activity.
© 2010 John Wiley & Sons A/S.
0 Communities
1 Members
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13 MeSH Terms
Internalization and intracellular trafficking of a PTD-conjugated anti-fibrotic peptide, AZX100, in human dermal keloid fibroblasts.
Flynn CR, Cheung-Flynn J, Smoke CC, Lowry D, Roberson R, Sheller MR, Brophy CM
(2010) J Pharm Sci 99: 3100-21
MeSH Terms: Actins, Amino Acid Sequence, Caveolae, Dermis, Dynamins, Fibroblasts, Heat-Shock Proteins, Small, Humans, Molecular Sequence Data, Peptides, Phosphoproteins, Protein Transport, Up-Regulation, rab GTP-Binding Proteins
Show Abstract · Added December 10, 2013
A challenge in advanced drug delivery is selectively traversing the plasma membrane, a barrier that prohibits the intracellular delivery of most peptide and nucleic acid-based therapeutics. A variety of short amino acid sequences termed protein transduction domains (PTDs) first identified in viral proteins have been utilized for over 20 years to deliver proteins nondestructively into cells, however, the mechanisms by which this occurs are varied and cell-specific. Here we describe the results of live cell imaging experiments with AZX100, a cell-permeable anti-fibrotic peptide bearing an "enhanced" PTD (PTD4). We monitored fluorescently labeled AZX100 upon cell surface binding and subsequent intracellular trafficking in the presence of cellular process inhibitors and various well-defined fluorescently labeled cargos. We conclude that AZX100 enters cells via caveolae rapidly, in a manner that is independent of glycoconjugates, actin/microtubule polymerization, dynamins, multiple GTPases, and clathrin, but is associated with lipid rafts as revealed by methyl-beta-cylodextrin. AZX100 treatment increases the expression of phospho-caveolin (Y14), a critical effector of focal adhesion dynamics, suggesting a mechanistic link between caveolin-1 phosphorylation and actin cytoskeleton dynamics. Our results reveal novel and interesting properties of PTD4 and offer new insight into the cellular mechanisms facilitating an advanced drug delivery tool.
(c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association
0 Communities
2 Members
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14 MeSH Terms
A differential role for endocytosis in receptor-mediated activation of Nox1.
Miller FJ, Chu X, Stanic B, Tian X, Sharma RV, Davisson RL, Lamb FS
(2010) Antioxid Redox Signal 12: 583-93
MeSH Terms: Activating Transcription Factor 1, Animals, Cells, Cultured, Cytoplasmic Vesicles, Dynamins, Endocytosis, Endosomes, Enzyme Activation, Humans, Isoenzymes, Membrane Microdomains, Mice, Mice, Inbred C57BL, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, NADPH Oxidases, Oxidation-Reduction, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Reactive Oxygen Species, Signal Transduction, Thrombin, Tumor Necrosis Factor-alpha
Show Abstract · Added February 22, 2016
Internalization of activated receptors to a compartment enriched with NAPDH oxidase and associated signaling molecules is expected to facilitate regulation of redox-mediated signal transduction. The aim of this study was to test the hypothesis that endocytosis is necessary for generation of reactive oxygen species (ROS) by Nox1 and for redox-dependent signaling in smooth muscle cells (SMCs). Within minutes of treatment with tumor necrosis factor (TNF)-alpha or thrombin, SMCs increased cellular levels of ROS that was inhibited by shRNA to Nox1. Treatment of SMC with TNF-alpha induced a dynamin-dependent endosomal generation of ROS, whereas thrombin-mediated ROS production did not occur within endosomes and was not prevented by dominant-negative dynamin (dn-dynamin), but instead required transactivation of the epidermal growth factor receptor (EGFR). Activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-activating transcription factor-1 (ATF-1) pathway by TNF-alpha and thrombin were both Nox1- and dynamin-dependent. In conclusion, we show that formation of specific ligand-receptor complexes results in spatially distinct mechanisms of Nox1 activation and generation of ROS. These findings provide novel insights into the role of compartmentalization for integrating redox-dependent cell signaling.
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1 Members
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23 MeSH Terms
Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models.
Brooks C, Wei Q, Cho SG, Dong Z
(2009) J Clin Invest 119: 1275-85
MeSH Terms: Adenosine Triphosphate, Animals, Apoptosis, Caspase Inhibitors, Cell Line, Cells, Cultured, Cisplatin, Cytochromes c, Dynamins, Enzyme Inhibitors, GTP Phosphohydrolases, Imaging, Three-Dimensional, Kidney Tubular Necrosis, Acute, Kidney Tubules, Proximal, Male, Mice, Mice, Inbred C57BL, Microtubule-Associated Proteins, Mitochondria, Proto-Oncogene Proteins c-bcl-2, RNA, Small Interfering, Rats, Reperfusion Injury, Sodium Azide
Show Abstract · Added September 12, 2016
The mechanism of mitochondrial damage, a key contributor to renal tubular cell death during acute kidney injury, remains largely unknown. Here, we have demonstrated a striking morphological change of mitochondria in experimental models of renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. This change contributed to mitochondrial outer membrane permeabilization, release of apoptogenic factors, and consequent apoptosis. Following either ATP depletion or cisplatin treatment of rat renal tubular cells, mitochondrial fragmentation was observed prior to cytochrome c release and apoptosis. This mitochondrial fragmentation was inhibited by Bcl2 but not by caspase inhibitors. Dynamin-related protein 1 (Drp1), a critical mitochondrial fission protein, translocated to mitochondria early during tubular cell injury, and both siRNA knockdown of Drp1 and expression of a dominant-negative Drp1 attenuated mitochondrial fragmentation, cytochrome c release, caspase activation, and apoptosis. Further in vivo analysis revealed that mitochondrial fragmentation also occurred in proximal tubular cells in mice during renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. Notably, both tubular cell apoptosis and acute kidney injury were attenuated by mdivi-1, a newly identified pharmacological inhibitor of Drp1. This study demonstrates a rapid regulation of mitochondrial dynamics during acute kidney injury and identifies mitochondrial fragmentation as what we believe to be a novel mechanism contributing to mitochondrial damage and apoptosis in vivo in mouse models of disease.
0 Communities
1 Members
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24 MeSH Terms
S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA2.
Ghavami S, Kerkhoff C, Chazin WJ, Kadkhoda K, Xiao W, Zuse A, Hashemi M, Eshraghi M, Schulze-Osthoff K, Klonisch T, Los M
(2008) Biochim Biophys Acta 1783: 297-311
MeSH Terms: Animals, Apoptosis Regulatory Proteins, Calgranulin A, Calgranulin B, Cell Death, Cell Line, Tumor, Down-Regulation, Dynamins, Fas-Associated Death Domain Protein, High-Temperature Requirement A Serine Peptidase 2, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mitochondria, Mitochondrial Proteins, Protein Binding, Protein Processing, Post-Translational, Receptor for Advanced Glycation End Products, Receptors, Immunologic, Serine Endopeptidases, Signal Transduction, X-Linked Inhibitor of Apoptosis Protein, bcl-X Protein
Show Abstract · Added May 19, 2014
A complex of two S100 EF-hand calcium-binding proteins S100A8/A9 induces apoptosis in various cells, especially tumor cells. Using several cell lines, we have shown that S100A8/A9-induced cell death is not mediated by the receptor for advanced glycation endproducts (RAGE), a receptor previously demonstrated to engage S100 proteins. Investigation of cell lines either deficient in, or over-expressing components of the death signaling machinery provided insight into the S100A8/A9-mediated cell death pathway. Treatment of cells with S100A8/A9 caused a rapid decrease in the mitochondrial membrane potential (DeltaPsi(m)) and activated Bak, but did not cause release of apoptosis-inducing factor (AIF), endonuclease G (Endo G) or cytochrome c. However, both Smac/DIABLO and Omi/HtrA2 were selectively released into the cytoplasm concomitantly with a decrease in Drp1 expression, which inhibits mitochondrial fission machinery. S100A8/A9 treatment also resulted in decreased expression of the anti-apoptotic proteins Bcl2 and Bcl-X(L), whereas expression of the pro-apoptotic proteins Bax, Bad and BNIP3 was not altered. Over-expression of Bcl2 partially reversed the cytotoxicity of S100A8/A9. Together, these data indicate that S100A8/A9-induced cell death involves Bak, selective release of Smac/DIABLO and Omi/HtrA2 from mitochondria, and modulation of the balance between pro- and anti-apoptotic proteins.
0 Communities
1 Members
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23 MeSH Terms
Reverse endocytosis of transmembrane ephrin-B ligands via a clathrin-mediated pathway.
Parker M, Roberts R, Enriquez M, Zhao X, Takahashi T, Pat Cerretti D, Daniel T, Chen J
(2004) Biochem Biophys Res Commun 323: 17-23
MeSH Terms: Animals, Biotinylation, Blotting, Western, CHO Cells, Cell Membrane, Cell Separation, Cells, Cultured, Clathrin, Cricetinae, DNA, Complementary, Dynamins, Endocytosis, Ephrin-B1, Flow Cytometry, Genes, Dominant, Genetic Vectors, Humans, Ligands, Microscopy, Confocal, Microscopy, Electron, Mutation, Potassium, Receptors, Eph Family, Signal Transduction, Time Factors, Transfection, Umbilical Veins
Show Abstract · Added August 27, 2013
Eph/ephrin receptors and ligands mediate cell-cell interaction through reciprocal signaling upon juxtacrine contact, and play a critical role in embryonic patterning, neuronal targeting, and vascular assembly. To study transmembrane ephrin-B ligand trafficking, we determined the cellular localization of ephrin-B1-GFP upon engagement by EphB1. Under normal culture conditions ephrin-B1-GFP is localized to the plasma membrane, mostly at the lateral cell borders. Addition of soluble EphB1-Fc receptor induces ephrin-B1-GFP clustering on the cell surface and subsequent internalization, as judged by biochemical studies, electron microscopy, and co-localization with endosomal markers. A dominant-negative mutant of dynamin or potassium depletion blocks ephrin-B1 endocytosis. These results suggest that ephrin-B1 internalization is an active receptor-mediated process that utilizes the clathrin-mediated endocytic pathway.
Copyright 2004 Elsevier Inc.
1 Communities
2 Members
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27 MeSH Terms
PI 3-kinase regulation of dopamine uptake.
Carvelli L, Morón JA, Kahlig KM, Ferrer JV, Sen N, Lechleiter JD, Leeb-Lundberg LM, Merrill G, Lafer EM, Ballou LM, Shippenberg TS, Javitch JA, Lin RZ, Galli A
(2002) J Neurochem 81: 859-69
MeSH Terms: Amphetamine, Animals, Biological Transport, Cell Line, Cell Membrane, Chromones, Corpus Striatum, Cytosol, Dopamine, Dopamine Plasma Membrane Transport Proteins, Dose-Response Relationship, Drug, Dynamin I, Dynamins, Enzyme Inhibitors, GTP Phosphohydrolases, Genes, Dominant, Humans, Insulin, Kidney, Male, Membrane Glycoproteins, Membrane Transport Proteins, Morpholines, Nerve Tissue Proteins, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Protein Transport, Rats, Recombinant Fusion Proteins, Synaptosomes, Transfection
Show Abstract · Added February 19, 2015
The magnitude and duration of dopamine (DA) signaling is defined by the amount of vesicular release, DA receptor sensitivity, and the efficiency of DA clearance, which is largely determined by the DA transporter (DAT). DAT uptake capacity is determined by the number of functional transporters on the cell surface as well as by their turnover rate. Here we show that inhibition of phosphatidylinositol (PI) 3-kinase with LY294002 induces internalization of the human DAT (hDAT), thereby reducing transport capacity. Acute treatment with LY294002 reduced the maximal rate of [(3) H]DA uptake in rat striatal synaptosomes and in human embryonic kidney (HEK) 293 cells stably expressing the hDAT (hDAT cells). In addition, LY294002 caused a significant redistribution of the hDAT from the plasma membrane to the cytosol. Conversely, insulin, which activates PI 3-kinase, increased [(3)H]DA uptake and blocked the amphetamine-induced hDAT intracellular accumulation, as did transient expression of constitutively active PI 3-kinase. The LY294002-induced reduction in [(3)H]DA uptake and hDAT cell surface expression was inhibited by expression of a dominant negative mutant of dynamin I, indicating that dynamin-dependent trafficking can modulate transport capacity. These data implicate DAT trafficking in the hormonal regulation of dopaminergic signaling, and suggest that a state of chronic hypoinsulinemia, such as in diabetes, may alter synaptic DA signaling by reducing the available cell surface DATs.
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31 MeSH Terms
Role of clathrin-mediated endocytosis in CXCR2 sequestration, resensitization, and signal transduction.
Yang W, Wang D, Richmond A
(1999) J Biol Chem 274: 11328-33
MeSH Terms: Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Chemokine CXCL1, Chemokines, CXC, Chemotactic Factors, Chemotaxis, Clathrin, Down-Regulation, Dynamin I, Dynamins, Endocytosis, Enzyme Activation, GTP Phosphohydrolases, Growth Substances, Humans, Intercellular Signaling Peptides and Proteins, Interleukin-8, Phosphorylation, Receptors, Chemokine, Receptors, Interleukin, Receptors, Interleukin-8B, Signal Transduction
Show Abstract · Added May 30, 2013
CXCR2 is a seven-transmembrane receptor that transduces intracellular signals in response to the chemokines interleukin-8, melanoma growth-stimulatory activity/growth-regulatory protein, and other ELR motif-containing CXC chemokines by coupling to heterotrimeric GTP-binding proteins. In this study, we explored the mechanism responsible for ligand-induced CXCR2 endocytosis. Here, we demonstrate that dynamin, a component of clathrin-mediated endocytosis, is essential for CXCR2 endocytosis and resensitization. In HEK293 cells, dynamin I K44A, a dominant-negative mutant of dynamin that inhibits the clathrin-mediated endocytosis, blocks the ligand-stimulated CXCR2 sequestration. Furthermore, co-expression of dynamin I K44A significantly delays dephosphorylation of CXCR2 after ligand stimulation, suggesting that clathrin-mediated endocytosis plays an important role in receptor dephosphorylation and resensitization. In addition, ligand-mediated receptor down-regulation is attenuated when receptor internalization is inhibited by dynamin I K44A. Interestingly, inhibition of receptor endocytosis by dynamin I K44A does not affect the CXCR2-mediated stimulation of mitogen-activated protein kinase. Most significantly, our data indicate that the ligand-stimulated receptor endocytosis is required for CXCR2-mediated chemotaxis in HEK293 cells. Taken together, our findings suggest that clathrin-mediated CXCR2 internalization is crucial for receptor endocytosis, resensitization, and chemotaxis.
2 Communities
1 Members
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22 MeSH Terms