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https://www.readbyqxmd.com/read/27903237/leucine-rich-repeat-kinase-2-lrrk2-regulates-%C3%AE-synuclein-clearance-in-microglia
#1
Tatsunori Maekawa, Toshikuni Sasaoka, Sadahiro Azuma, Takafumi Ichikawa, Heather L Melrose, Matthew J Farrer, Fumiya Obata
BACKGROUND: α-Synuclein (αSYN) has been genetically implicated in familial and sporadic Parkinson's disease (PD), and is associated with disease susceptibility, progression and pathology. Excess amounts of αSYN are toxic to neurons. In the brain, microglial αSYN clearance is closely related to neuronal survival. Leucine-rich repeat kinase 2 (LRRK2) is the one of the other genes implicated in familial and sporadic PD. While LRRK2 is known to be expressed in microglia, its true function remains to be elucidated...
November 30, 2016: BMC Neuroscience
https://www.readbyqxmd.com/read/27875556/mxa-is-a-novel-regulator-of-endosome-associated-transcriptional-signaling-by-bone-morphogenetic-proteins-4-and-9-bmp4-and-bmp9
#2
Huijuan Yuan, Pravin B Sehgal
There is confusion about the role that IFN-α plays in the pathogenesis of pulmonary arterial hypertension (PAH) with different investigators reporting a causative or a protective role. There is now clear evidence in PAH pathogenesis for the involvement of BMP4 and BMP9 signaling, and its disruption by mutations in BMPR2. In the present study, we investigated MxA, an IFN-α-inducible cytoplasmic dynamin-family GTPase for effects on BMP4/9 signaling, including in the presence of PAH-disease-associated mutants of BMPR2...
2016: PloS One
https://www.readbyqxmd.com/read/27867015/cmtm3-decreases-egfr-expression-and-egf-mediated-tumorigenicity-by-promoting-rab5-activity-in-gastric-cancer
#3
Wanqiong Yuan, Baocai Liu, Xiaolin Wang, Ting Li, Hui Xue, Xiaoning Mo, Shuli Yang, Shigang Ding, Wenling Han
CMTM3 (CKLF-like MARVEL transmembrane domain containing 3), a tumor suppressor gene, is involved in multiple types of malignancies. CMTM3 knockdown promotes metastasis of gastric cancer via the STAT3/Twist1/EMT signaling pathway. Strong epidermal growth factor receptor1 (EGFR) expression is significantly associated with tumor metastasis and poor outcomes of gastric cancer patients. In this paper, we show that CMTM3 suppresses epidermal growth factor (EGF)-mediated migration and STAT3 signaling, downregulates EGFR expression via accelerating EGFR degradation in gastric cancer cells...
November 17, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27852895/ras-and-rab-interactor-1-controls-neuronal-plasticity-by-coordinating-dendritic-filopodial-motility-and-ampa-receptor-turnover
#4
Zsófia Szíber, Hanna Liliom, Carlos O Oueslati Morales, Attila Ignácz, Anikó Erika Rátkai, Kornelia Ellwanger, Gisela Link, Attila Szűcs, Angelika Hausser, Katalin Schlett
Ras and Rab interactor 1 (RIN1) is predominantly expressed in the nervous system. RIN1 knockout animals have deficits in latent inhibition and fear extinction in the amygdala, suggesting a critical role for RIN1 in preventing the persistence of unpleasant memories. At the molecular level, RIN1 signals through Rab5 GTPases that control endocytosis of cell-surface receptors and Abl non-receptor tyrosine kinases that participate in actin cytoskeleton remodelling.Here, we report that RIN1 controls the plasticity of cultured mouse hippocampal neurons...
November 16, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27852225/a-functional-endosomal-pathway-is-necessary-for-lysosome-biogenesis-in-drosophila
#5
Anne-Claire Jacomin, Marie-Odile Fauvarque, Emmanuel Taillebourg
BACKGROUND: Lysosomes are the major catabolic compartment within eukaryotic cells, and their biogenesis requires the integration of the biosynthetic and endosomal pathways. Endocytosis and autophagy are the primary inputs of the lysosomal degradation pathway. Endocytosis is specifically needed for the degradation of membrane proteins whereas autophagy is responsible for the degradation of cytoplasmic components. We previously identified the deubiquitinating enzyme UBPY/USP8 as being necessary for lysosomal biogenesis and productive autophagy in Drosophila...
November 16, 2016: BMC Cell Biology
https://www.readbyqxmd.com/read/27835596/cd99-triggering-induces-methuosis-of-ewing-sarcoma-cells-through-igf-1r-ras-rac1-signaling
#6
Maria Cristina Manara, Mario Terracciano, Caterina Mancarella, Marika Sciandra, Clara Guerzoni, Michela Pasello, Andrea Grilli, Nicoletta Zini, Piero Picci, Mario P Colombo, Andrea Morrione, Katia Scotlandi
CD99 is a cell surface molecule that has emerged as a novel target for Ewing sarcoma (EWS), an aggressive pediatric bone cancer. This report provides the first evidence of methuosis in EWS, a non-apoptotic form of cell death induced by an antibody directed against the CD99 molecule. Upon mAb triggering, CD99 induces an IGF-1R/RAS/Rac1 complex, which is internalized into RAB5-positive endocytic vacuoles. This complex is then dissociated, with the IGF-1R recycling to the cell membrane while CD99 and RAS/Rac1 are sorted into immature LAMP-1-positive vacuoles, whose excessive accumulation provokes methuosis...
November 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27814354/scribbled-optimizes-bmp-signaling-through-its-receptor-internalization-to-the-rab5-endosome-and-promote-robust-epithelial-morphogenesis
#7
Jinghua Gui, Yunxian Huang, Osamu Shimmi
Epithelial cells are characterized by apical-basal polarity. Intrinsic factors underlying apical-basal polarity are crucial for tissue homeostasis and have often been identified to be tumor suppressors. Patterning and differentiation of epithelia are key processes of epithelial morphogenesis and are frequently regulated by highly conserved extrinsic factors. However, due to the complexity of morphogenesis, the mechanisms of precise interpretation of signal transduction as well as spatiotemporal control of extrinsic cues during dynamic morphogenesis remain poorly understood...
November 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27798239/phosphatidylinositol-4-kinase-ii%C3%AE-negatively-regulates-invadopodia-formation-and-suppresses-an-invasive-cellular-phenotype
#8
Ganiyu Olabanji Alli-Balogun, Christina A Gewinner, Ruth Jacobs, Janos Kriston-Vizi, Mark G Waugh, Shane Minogue
The type II PI 4-kinases enzymes synthesise the lipid phosphatidylinositol 4-phosphate (PI(4)P) which has been detected at the Golgi complex and endosomal compartments, and which recruits clathrin adaptors. Despite common mechanistic similarities between the isoforms, the extent of their redundancy is unclear.We found that depletion of PI4KIIα and PI4KIIβ using siRNA led to actin remodelling. Depletion of PI4KIIβ also induced the formation of invadopodia containing membrane type I matrix metalloproteinase (MT1-MMP)...
October 26, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27793976/vps34-regulates-rab7-and-late-endocytic-trafficking-through-recruitment-of-the-gtpase-activating-protein-armus
#9
Nadia Jaber, Noor Mohd-Naim, Ziqing Wang, Jennifer L DeLeon, Seong Kim, Hua Zhong, Namratha Sheshadri, Zhixun Dou, Aimee L Edinger, Guangwei Du, Vania M M Braga, Wei-Xing Zong
The class III phosphoinositide 3-kinase (PI3K) Vps34 (also known as PIK3C3 in mammals) produces phosphatidylinositol 3-phosphate [PI(3)P] on both early and late endosome membranes to control membrane dynamics. We used Vps34-deficient cells to delineate whether Vps34 has additional roles in endocytic trafficking. In Vps34(-/-) mouse embryonic fibroblasts (MEFs), transferrin recycling and EEA1 membrane localization were unaffected despite elevated Rab5-GTP levels. Strikingly, a large increase in Rab7-GTP levels, an accumulation of enlarged late endosomes, and decreased EGFR degradation were observed in Vps34-deficient cells...
December 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27764233/escrt-i-protein-tsg101-plays-a-role-in-the-post-macropinocytic-trafficking-and-infection-of-endothelial-cells-by-kaposi-s-sarcoma-associated-herpesvirus
#10
Binod Kumar, Dipanjan Dutta, Jawed Iqbal, Mairaj Ahmed Ansari, Arunava Roy, Leela Chikoti, Gina Pisano, Mohanan Valiya Veettil, Bala Chandran
Kaposi's sarcoma-associated herpesvirus (KSHV) binding to the endothelial cell surface heparan sulfate is followed by sequential interactions with α3β1, αVβ3 and αVβ5 integrins and Ephrin A2 receptor tyrosine kinase (EphA2R). These interactions activate host cell pre-existing FAK, Src, PI3-K and RhoGTPase signaling cascades, c-Cbl mediated ubiquitination of receptors, recruitment of CIB1, p130Cas and Crk adaptor molecules, and membrane bleb formation leading to lipid raft dependent macropinocytosis of KSHV into human microvascular dermal endothelial (HMVEC-d) cells...
October 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27760128/enrichment-of-phosphatidylethanolamine-in-viral-replication-compartments-via-co-opting-the-endosomal-rab5-small-gtpase-by-a-positive-strand-rna-virus
#11
Kai Xu, Peter D Nagy
Positive-strand RNA viruses build extensive membranous replication compartments to support replication and protect the virus from antiviral responses by the host. These viruses require host factors and various lipids to form viral replication complexes (VRCs). The VRCs built by Tomato bushy stunt virus (TBSV) are enriched with phosphatidylethanolamine (PE) through a previously unknown pathway. To unravel the mechanism of PE enrichment within the TBSV replication compartment, in this paper, the authors demonstrate that TBSV co-opts the guanosine triphosphate (GTP)-bound active form of the endosomal Rab5 small GTPase via direct interaction with the viral replication protein...
October 2016: PLoS Biology
https://www.readbyqxmd.com/read/27758863/mesenchymal-stromal-cell-derived-extracellular-vesicles-promote-myeloid-biased-multipotent-hematopoietic-progenitor-expansion-via-toll-like-receptor-engagement
#12
Natalya A Goloviznina, Santhosh Chakkaramakkil Verghese, Young Me Yoon, Oleh Taratula, Daniel L Marks, Peter Kurre
Mesenchymal stromal cells (MSC) present in the bone marrow (BM) microenvironment secrete cytokines and angiogenic factors that support the maintenance and regenerative expansion of hematopoietic stem and progenitor cells (HSPC). Here, we tested the hypothesis that extracellular vesicles (EVs) released by MSC contribute to the paracrine crosstalk that shapes hematopoietic function. We systematically characterized EV release by murine stromal cells and demonstrate that MSC-derived EVs prompt a loss of HSPC quiescence with concomitant expansion of murine myeloid progenitors...
October 7, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27715385/progress-of-endocytic-chrn-to-autophagic-degradation-is-regulated-by-rab5-gtpase-and-t145-phosphorylation-of-sh3glb1-at-mouse-neuromuscular-junctions-in-vivo
#13
Franziska Wild, Muzamil Majid Khan, Tatjana Straka, Rüdiger Rudolf
Endocytosed nicotinic acetylcholine receptors (CHRN) are degraded via macroautophagy/autophagy during atrophic conditions and are accompanied by the autophagic regulator protein SH3GLB1. The present study addressed the functional role of SH3GLB1 on CHRN trafficking and its implementation. We found an augmented ratio of total SH3GLB1 to threonine-145 phosphorylated SH3GLB1 (SH3GLB1:p-SH3GLB1) under conditions of increased CHRN vesicle numbers. Overexpression of T145 phosphomimetic (T145E) and phosphodeficient (T145A) mutants of SH3GLB1, was found to either slow down or augment the processing of endocytic CHRN vesicles, respectively...
December 2016: Autophagy
https://www.readbyqxmd.com/read/27681439/deepn-as-an-approach-for-batch-processing-of-yeast-2-hybrid-interactions
#14
Natasha Pashkova, Tabitha A Peterson, Venkatramanan Krishnamani, Patrick Breheny, Mark Stamnes, Robert C Piper
We adapted the yeast 2-hybrid assay to simultaneously uncover multiple transient protein interactions within a single screen by using a strategy termed DEEPN (dynamic enrichment for evaluation of protein networks). This approach incorporates high-throughput DNA sequencing and computation to follow competition among a plasmid population encoding interacting partners. To demonstrate the capacity of DEEPN, we identify a wide range of ubiquitin-binding proteins, including interactors that we verify biochemically...
September 27, 2016: Cell Reports
https://www.readbyqxmd.com/read/27607061/tau-tubulin-kinase-ttbk2-sensitivity-of-glutamate-receptor-gluk2
#15
Kristina Nieding, Veronika Matschke, Sven G Meuth, Florian Lang, Guiscard Seebohm, Nathalie Strutz-Seebohm
BACKGROUND/AIMS: Inherited, autosomal dominant spinocerebellar ataxia type 11 (SCA11) is caused by loss of function mutations of TTBK2 (tau tubulin kinase 2). Mutations observed in patients with SCA11 include truncated TTBK2(450). The present study explored the possibility that TTBK2 influences the function of the glutamate receptor GluK2. METHODS: GluK2 was expressed in Xenopus oocytes without and with additional expression of wild type TTBK2, the truncated mutant TTBK2(450), or the kinase dead mutants TTBK2(KD) and TTBK2(450/KD)...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27595600/regulated-endosomal-trafficking-of-diacylglycerol-lipase-alpha-dagl%C3%AE-generates-distinct-cellular-pools-implications-for-endocannabinoid-signaling
#16
Ya Zhou, Fiona V Howell, Oleg O Glebov, David Albrecht, Gareth Williams, Patrick Doherty
Diacylglycerol lipase alpha (DAGLα) generates the endocannabinoid (eCB) 2-arachidonylglycerol (2-AG) that regulates the proliferation and differentiation of neural stem cells and serves as a retrograde signaling lipid at synapses. Nothing is known about the dynamics of DAGLα expression in cells and this is important as it will govern where 2-AG can be made and released. We have developed a new construct to label DAGLα at the surface of live cells and follow its trafficking. In hippocampal neurons a cell surface pool of DAGLα co-localizes with Homer, a postsynaptic density marker...
October 2016: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/27574541/the-multiple-roles-of-rab9-in-the-endolysosomal-system
#17
Ana Kucera, Oddmund Bakke, Cinzia Progida
The small GTPase Rab9 has long been described as a protein that mediates endosome-to-trans-Golgi Network (TGN) transport, and specifically mannose-6-phospate receptor (MPR) recycling. However, studies have challenged this view by showing that Rab9 also is connected to sorting pathways toward the endolysosomal compartments. We recently characterized the spatio-temporal dynamics of Rab9 and, by using live cell imaging, we showed that it enters the endosomal pathway together with CI-MPR at the transition stage between early, Rab5-positive, and late, Rab7a-positive, endosomes...
July 2016: Communicative & Integrative Biology
https://www.readbyqxmd.com/read/27559127/the-ccz1-mon1-rab7-module-and-rab5-control-distinct-steps-of-autophagy
#18
Krisztina Hegedűs, Szabolcs Takáts, Attila Boda, András Jipa, Péter Nagy, Kata Varga, Attila L Kovács, Gábor Juhász
The small GTPase Rab5 promotes recruitment of the Ccz1-Mon1 guanosine exchange complex to endosomes to activate Rab7, which facilitates endosome maturation and fusion with lysosomes. How these factors function during autophagy is incompletely understood. Here we show that autophagosomes accumulate due to impaired fusion with lysosomes upon loss of the Ccz1-Mon1-Rab7 module in starved Drosophila fat cells. In contrast, autophagosomes generated in Rab5-null mutant cells normally fuse with lysosomes during the starvation response...
October 15, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27559088/rab5-and-its-effector-fhf-contribute-to-neuronal-polarity-through-dynein-dependent-retrieval-of-somatodendritic-proteins-from-the-axon
#19
Xiaoli Guo, Ginny G Farías, Rafael Mattera, Juan S Bonifacino
An open question in cell biology is how the general intracellular transport machinery is adapted to perform specialized functions in polarized cells such as neurons. Here we illustrate this adaptation by elucidating a role for the ubiquitous small GTPase Ras-related protein in brain 5 (Rab5) in neuronal polarity. We show that inactivation or depletion of Rab5 in rat hippocampal neurons abrogates the somatodendritic polarity of the transferrin receptor and several glutamate receptor types, resulting in their appearance in the axon...
September 6, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27556945/an-endosomal-tether-undergoes-an-entropic-collapse-to-bring-vesicles-together
#20
David H Murray, Marcus Jahnel, Janelle Lauer, Mario J Avellaneda, Nicolas Brouilly, Alice Cezanne, Hernán Morales-Navarrete, Enrico D Perini, Charles Ferguson, Andrei N Lupas, Yannis Kalaidzidis, Robert G Parton, Stephan W Grill, Marino Zerial
An early step in intracellular transport is the selective recognition of a vesicle by its appropriate target membrane, a process regulated by Rab GTPases via the recruitment of tethering effectors. Membrane tethering confers higher selectivity and efficiency to membrane fusion than the pairing of SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) alone. Here we address the mechanism whereby a tethered vesicle comes closer towards its target membrane for fusion by reconstituting an endosomal asymmetric tethering machinery consisting of the dimeric coiled-coil protein EEA1 (refs 6, 7) recruited to phosphatidylinositol 3-phosphate membranes and binding vesicles harbouring Rab5...
August 24, 2016: Nature
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