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Results: 1 to 10 of 80

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The Par3 polarity protein is an exocyst receptor essential for mammary cell survival.
Ahmed SM, Macara IG
(2017) Nat Commun 8: 14867
MeSH Terms: Animals, Apoptosis, Cadherins, Cell Adhesion Molecules, Cell Line, Cell Polarity, Cell Survival, Enzyme Activation, Epithelial Cells, Female, Gene Knockdown Techniques, Golgi Apparatus, Humans, Lysine, Mammary Glands, Animal, Models, Biological, PTEN Phosphohydrolase, Phosphatidylinositol Phosphates, Phosphorylation, Protein Domains, Proto-Oncogene Proteins c-akt, Vesicular Transport Proteins, rab GTP-Binding Proteins
Show Abstract · Added April 26, 2017
The exocyst is an essential component of the secretory pathway required for delivery of basolateral proteins to the plasma membranes of epithelial cells. Delivery occurs adjacent to tight junctions (TJ), suggesting that it recognizes a receptor at this location. However, no such receptor has been identified. The Par3 polarity protein associates with TJs but has no known function in membrane traffic. We now show that, unexpectedly, Par3 is essential for mammary cell survival. Par3 silencing causes apoptosis, triggered by phosphoinositide trisphosphate depletion and decreased Akt phosphorylation, resulting from failure of the exocyst to deliver basolateral proteins to the cortex. A small region of PAR3 binds directly to Exo70 and is sufficient for exocyst docking, membrane-protein delivery and cell survival. PAR3 lacking this domain can associate with the cortex but cannot support exocyst function. We conclude that Par3 is the long-sought exocyst receptor required for targeted membrane-protein delivery.
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23 MeSH Terms
ER trapping reveals Golgi enzymes continually revisit the ER through a recycling pathway that controls Golgi organization.
Sengupta P, Satpute-Krishnan P, Seo AY, Burnette DT, Patterson GH, Lippincott-Schwartz J
(2015) Proc Natl Acad Sci U S A 112: E6752-61
MeSH Terms: Animals, COS Cells, Cercopithecus aethiops, Endoplasmic Reticulum, Golgi Apparatus, HeLa Cells, Humans, Mitosis, Phospholipases A2, Calcium-Independent, Sirolimus, Tacrolimus Binding Protein 1A, Tacrolimus Binding Proteins, rab GTP-Binding Proteins
Show Abstract · Added August 25, 2017
Whether Golgi enzymes remain localized within the Golgi or constitutively cycle through the endoplasmic reticulum (ER) is unclear, yet is important for understanding Golgi dependence on the ER. Here, we demonstrate that the previously reported inefficient ER trapping of Golgi enzymes in a rapamycin-based assay results from an artifact involving an endogenous ER-localized 13-kD FK506 binding protein (FKBP13) competing with the FKBP12-tagged Golgi enzyme for binding to an FKBP-rapamycin binding domain (FRB)-tagged ER trap. When we express an FKBP12-tagged ER trap and FRB-tagged Golgi enzymes, conditions precluding such competition, the Golgi enzymes completely redistribute to the ER upon rapamycin treatment. A photoactivatable FRB-Golgi enzyme, highlighted only in the Golgi, likewise redistributes to the ER. These data establish Golgi enzymes constitutively cycle through the ER. Using our trapping scheme, we identify roles of rab6a and calcium-independent phospholipase A2 (iPLA2) in Golgi enzyme recycling, and show that retrograde transport of Golgi membrane underlies Golgi dispersal during microtubule depolymerization and mitosis.
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13 MeSH Terms
Microtubule segment stabilization by RASSF1A is required for proper microtubule dynamics and Golgi integrity.
Arnette C, Efimova N, Zhu X, Clark GJ, Kaverina I
(2014) Mol Biol Cell 25: 800-10
MeSH Terms: Apoptosis, Cell Division, Cell Line, Transformed, Cell Polarity, Epithelial Cells, Gene Expression, Golgi Apparatus, Humans, Microtubules, Nocodazole, RNA, Small Interfering, Retinal Pigment Epithelium, Time-Lapse Imaging, Tubulin, Tubulin Modulators, Tumor Suppressor Proteins
Show Abstract · Added March 20, 2014
The tumor suppressor and microtubule-associated protein Ras association domain family 1A (RASSF1A) has a major effect on many cellular processes, such as cell cycle progression and apoptosis. RASSF1A expression is frequently silenced in cancer and is associated with increased metastasis. Therefore we tested the hypothesis that RASSF1A regulates microtubule organization and dynamics in interphase cells, as well as its effect on Golgi integrity and cell polarity. Our results show that RASSF1A uses a unique microtubule-binding pattern to promote site-specific microtubule rescues, and loss of RASSF1A leads to decreased microtubule stability. Furthermore, RASSF1A-associated stable microtubule segments are necessary to prevent Golgi fragmentation and dispersal in cancer cells and maintain a polarized cell front. These results indicate that RASSF1A is a key regulator in the fine tuning of microtubule dynamics in interphase cells and proper Golgi organization and cell polarity.
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16 MeSH Terms
Ice recovery assay for detection of Golgi-derived microtubules.
Grimaldi AD, Fomicheva M, Kaverina I
(2013) Methods Cell Biol 118: 401-15
MeSH Terms: Biological Transport, Cell Line, Centrosome, Golgi Apparatus, Humans, Ice, Microscopy, Confocal, Microscopy, Fluorescence, Microtubule-Organizing Center, Microtubules, Tubulin
Show Abstract · Added March 20, 2014
Proper organization of the microtubule cytoskeleton is essential for many cellular processes including maintenance of Golgi organization and cell polarity. Traditionally, the centrosome is considered to be the major microtubule organizing center (MTOC) of the cell; however, microtubule nucleation can also occur through centrosome-independent mechanisms. Recently, the Golgi has been described as an additional, centrosome-independent, MTOC with distinct cellular functions. Golgi-derived microtubules contribute to the formation of an asymmetric microtubule network, control Golgi organization, and support polarized trafficking and directed migration in motile cells. In this chapter, we present an assay using recovery from ice treatment to evaluate the potential of the Golgi, or other MTOCs, to nucleate microtubules. This technique allows for clear separation of distinct MTOCs and observation of newly nucleated microtubules at these locations, which are normally obscured by the dense microtubule network present at steady-state conditions. This type of analysis is important for discovery and characterization of noncentrosomal MTOCs and, ultimately, understanding of their unique cellular functions.
Copyright © 2013 Elsevier Inc. All rights reserved.
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11 MeSH Terms
Auto-inhibition of Drs2p, a yeast phospholipid flippase, by its carboxyl-terminal tail.
Zhou X, Sebastian TT, Graham TR
(2013) J Biol Chem 288: 31807-15
MeSH Terms: Biological Transport, Active, Calcium-Transporting ATPases, Golgi Apparatus, Phosphatidylinositol Phosphates, Protein Structure, Tertiary, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Show Abstract · Added January 20, 2015
Drs2p, a yeast type IV P-type ATPase (P4-ATPase), or flippase, couples ATP hydrolysis to phosphatidylserine translocation and the establishment of membrane asymmetry. A previous study has shown that affinity-purified Drs2p, possessing an N-terminal tandem affinity purification tag (TAPN-Drs2), retains ATPase and translocase activity, but Drs2p purified using a C-terminal tag (Drs2-TAPC) was inactive. In this study, we show that the ATPase activity of N-terminally purified Drs2p associates primarily with a proteolyzed form of Drs2p lacking the C-terminal cytosolic tail. Truncation of most of the Drs2p C-terminal tail sequence activates its ATPase activity by ∼4-fold. These observations are consistent with the hypothesis that the C-terminal tail of Drs2p is auto-inhibitory to Drs2p activity. Phosphatidylinositol 4-phosphate (PI(4)P) has been shown to positively regulate Drs2p activity in isolated Golgi membranes through interaction with the C-terminal tail. In proteoliposomes reconstituted with purified, N-terminally TAP-tagged Drs2p, both ATPase and flippase activity were significantly higher in the presence of PI(4)P. In contrast, PI(4)P had no significant effect on the activity of a truncated form of Drs2p, which lacked the C-terminal tail. This work provides the first direct evidence, in a purified system, that a phospholipid flippase is subject to auto-inhibition by its C-terminal tail, which can be relieved by a phosphoinositide to stimulate flippase activity.
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7 MeSH Terms
Golgi as an MTOC: making microtubules for its own good.
Zhu X, Kaverina I
(2013) Histochem Cell Biol 140: 361-7
MeSH Terms: Golgi Apparatus, Humans, Microtubule-Organizing Center, Microtubules
Show Abstract · Added December 10, 2013
In cells, microtubules (MTs) are nucleated at MT-organizing centers (MTOCs). The centrosome-based MTOCs organize radial MT arrays, which are often not optimal for polarized trafficking. A recently discovered subset of non-centrosomal MTs nucleated at the Golgi has proven to be indispensable for the Golgi organization, post-Golgi trafficking and cell polarity. Here, we summarize the history of this discovery, known molecular prerequisites of MT nucleation at the Golgi and unique functions of Golgi-derived MTs.
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4 MeSH Terms
In vitro and in vivo studies of the antiparasitic activity of sterol 14α-demethylase (CYP51) inhibitor VNI against drug-resistant strains of Trypanosoma cruzi.
Soeiro Mde N, de Souza EM, da Silva CF, Batista Dda G, Batista MM, Pavão BP, Araújo JS, Aiub CA, da Silva PB, Lionel J, Britto C, Kim K, Sulikowski G, Hargrove TY, Waterman MR, Lepesheva GI
(2013) Antimicrob Agents Chemother 57: 4151-63
MeSH Terms: 14-alpha Demethylase Inhibitors, Animals, Chagas Disease, Drug Resistance, Endoplasmic Reticulum, Golgi Apparatus, Imidazoles, Male, Mice, Microscopy, Electron, Transmission, Nitroimidazoles, Oxadiazoles, Protozoan Proteins, Sterol 14-Demethylase, Thiazoles, Triazoles, Trypanocidal Agents, Trypanosoma cruzi
Show Abstract · Added March 7, 2014
Chagas disease affects more than 10 million people worldwide, and yet, as it has historically been known as a disease of the poor, it remains highly neglected. Two currently available drugs exhibit severe toxicity and low effectiveness, especially in the chronic phase, while new drug discovery has been halted for years as a result of a lack of interest from pharmaceutical companies. Although attempts to repurpose the antifungal drugs posaconazole and ravuconazole (inhibitors of fungal sterol 14α-demethylase [CYP51]) are finally in progress, development of cheaper and more efficient, preferably Trypanosoma cruzi-specific, chemotherapies would be highly advantageous. We have recently reported that the experimental T. cruzi CYP51 inhibitor VNI cures with 100% survival and 100% parasitological clearance both acute and chronic murine infections with the Tulahuen strain of T. cruzi. In this work, we further explored the potential of VNI by assaying nitro-derivative-resistant T. cruzi strains, Y and Colombiana, in highly stringent protocols of acute infection. The data show high antiparasitic efficacy of VNI and its derivative (VNI/VNF) against both forms of T. cruzi that are relevant for mammalian host infection (bloodstream and amastigotes), with the in vivo potency, at 25 mg/kg twice a day (b.i.d.), similar to that of benznidazole (100 mg/kg/day). Transmission electron microscopy and reverse mutation tests were performed to explore cellular ultrastructural and mutagenic aspects of VNI, respectively. No mutagenic potential could be seen by the Ames test at up to 3.5 μM, and the main ultrastructural damage induced by VNI in T. cruzi was related to Golgi apparatus and endoplasmic reticulum organization, with membrane blebs presenting an autophagic phenotype. Thus, these preliminary studies confirm VNI as a very promising trypanocidal drug candidate for Chagas disease therapy.
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18 MeSH Terms
The Scribble polarity protein stabilizes E-cadherin/p120-catenin binding and blocks retrieval of E-cadherin to the Golgi.
Lohia M, Qin Y, Macara IG
(2012) PLoS One 7: e51130
MeSH Terms: Animals, Cadherins, Catenins, Cell Nucleus, Cell Polarity, Endocytosis, Golgi Apparatus, Humans, Lysosomes, Madin Darby Canine Kidney Cells, Membrane Proteins, Models, Biological, Protein Binding, Protein Stability, Protein Transport, Vesicular Transport Proteins
Show Abstract · Added March 20, 2014
Several polarity proteins, including Scribble (Scrb) have been implicated in control of vesicle traffic, and in particular the endocytosis of E-cadherin, but through unknown mechanisms. We now show that depletion of Scrb enhances endocytosis of E-cadherin by weakening the E-cadherin-p120catenin interaction. Unexpectedly, however, the internalized E-cadherin is not degraded but accumulates in the Golgi apparatus. Silencing p120-catenin causes degradation of E-cadherin in lysosomes, but degradation is blocked by the co-depletion of Scrb, which diverts the internalized E-cadherin to the Golgi. Loss of Scrb also enhances E-cadherin binding to retromer components, and retromer is required for Golgi accumulation of Scrb, and E-cadherin stability. These data identify a novel and unanticipated function for Scrb in blocking retromer-mediated diversion of E-cadherin to the Golgi. They provide evidence that polarity proteins can modify the intracellular itinerary for endocytosed membrane proteins.
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16 MeSH Terms
Human embryonic stem cells: living on the edge.
Gama V, Deshmukh M
(2012) Cell Cycle 11: 3905-6
MeSH Terms: Apoptosis, Caspases, Cell Differentiation, Cytochromes c, DNA Damage, Embryonic Stem Cells, Golgi Apparatus, Humans, Mitochondria, bcl-2-Associated X Protein
Added October 26, 2015
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10 MeSH Terms
Modulation of Golgi-associated microtubule nucleation throughout the cell cycle.
Maia AR, Zhu X, Miller P, Gu G, Maiato H, Kaverina I
(2013) Cytoskeleton (Hoboken) 70: 32-43
MeSH Terms: Cell Cycle, Cell Line, Flow Cytometry, G1 Phase, G2 Phase, Golgi Apparatus, Humans, Microscopy, Fluorescence, Microtubules, Mitosis
Show Abstract · Added February 3, 2014
A microtubule (MT) subpopulation that emanates from Golgi membrane has been recently shown to comprise a significant part of MT network in interphase cells. In this study, we address whether Golgi membrane, which is being extensively remodeled throughout the cell cycle, retains its ability to nucleate MTs at diverse cell cycle stages. Live cell imaging and immunofluorescence microscopy reveals that Golgi-derived MTs form at multiple stages of the cell cycle, including G(1), G(2), and distinct phases of mitosis. However, the capacity of Golgi to nucleate MTs in mitosis is strongly down-regulated as compared with interphase, indicating that this property is cell cycle regulated. We demonstrate that Golgi-derived MTs are indispensable for efficient Golgi assembly in telophase, and speculate that these noncentrosomal MTs may hold specific functions at other cell cycle stages.
Copyright © 2012 Wiley Periodicals, Inc.
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10 MeSH Terms