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https://www.readbyqxmd.com/read/29743203/the-parkinson-s-disease-vps35-d620n-mutation-enhances-lrrk2-mediated-rab-protein-phosphorylation-in-mouse-and-human
#1
Rafeeq Mir, Francesca Tonelli, Pawel Lis, Thomas Macartney, Nicole K Polinski, Terina N Martinez, Meng-Yun Chou, Andrew J M Howden, Theresa König, Christoph Hotzy, Ivan Milenkovic, Thomas Brücke, Alexander Zimprich, Esther Sammler, Dario R Alessi
Missense mutations in the LRRK2 and VPS35 genes result in autosomal dominant Parkinson's disease. The VPS35 gene encodes for the cargo-binding component of the retromer complex, while LRRK2 modulates vesicular trafficking by phosphorylating a subgroup of Rab proteins. Pathogenic mutations in LRRK2 increase its kinase activity. It is not known how the only thus far described pathogenic VPS35 mutation, [D620N] exerts its effects. We reveal that the VPS35[D620N] knock-in mutation, strikingly elevates LRRK2 mediated phosphorylation of Rab8A, Rab10 and Rab12 in mouse embryonic fibroblasts...
May 9, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29669912/insulin-induced-exocytosis-regulates-the-cell-surface-level-of-low-density-lipoprotein-related-protein-1-in-m%C3%A3-ller-glial-cells
#2
Virginia Actis Dato, Rubén A Grosso, María C Sánchez, Claudio M Fader, Gustavo A Chiabrando
Low-density lipoprotein (LDL) receptor-related protein-1 (LRP1) is expressed in retinal Müller glial cells (MGCs) and regulates intracellular translocation to the plasma membrane (PM) of the membrane proteins involved in cellular motility and activity. Different functions of MGCs may be influenced by insulin, including the removal of extracellular glutamate in the retina. In the present work, we investigated whether insulin promotes LRP1 translocation to the PM in the Müller glial-derived cell line MIO-M1...
April 18, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29579237/acid-ceramidase-inhibition-ameliorates-%C3%AE-synuclein-accumulation-upon-loss-of-gba1-function
#3
Myung Jong Kim, Sohee Jeon, Lena F Burbulla, Dimitri Krainc
GBA1 encodes the lysosomal enzyme β-glucocerebrosidase (GCase) which converts glucosylceramide into ceramide and glucose. Mutations in GBA1 lead to Gaucher's disease and are a major risk factor for Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), synucleinopathies characterized by accumulation of intracellular α-synuclein. In this study, we examined whether decreased ceramide that is observed in GCase-deficient cells contributes to α-synuclein accumulation. We demonstrated that deficiency of GCase leads to a reduction of C18-ceramide species and altered intracellular localization of Rab8a, a small GTPase implicated in secretory autophagy, that contributed to impaired secretion of α-synuclein and accumulation of intracellular α-synuclein...
March 22, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29482628/lrrk2-mediated-rab8a-phosphorylation-promotes-lipid-storage
#4
Miao Yu, Muhammad Arshad, Wenmin Wang, Dongyu Zhao, Li Xu, Linkang Zhou
BACKGROUND: Several mutations in leucine rich repeat kinase 2 (LRRK2) gene have been associated with pathogenesis of Parkinson's disease (PD), a neurodegenerative disorder marked by resting tremors, and rigidity, leading to Postural instability. It has been revealed that mutations that lead to an increase of kinase activity of LRRK2 protein are significantly associated with PD pathogenesis. Recent studies have shown that some Rab GTPases, especially Rab8, serve as substrates of LRRK2 and undergo phosphorylation in its switch II domain upon interaction...
February 27, 2018: Lipids in Health and Disease
https://www.readbyqxmd.com/read/29396404/the-ciliopathy-protein-talpid3-kiaa0586-acts-upstream-of-rab8-activation-in-zebrafish-photoreceptor-outer-segment-formation-and-maintenance
#5
Irene Ojeda Naharros, Flavia B Cristian, Jingjing Zang, Matthias Gesemann, Philip W Ingham, Stephan C F Neuhauss, Ruxandra Bachmann-Gagescu
Ciliopathies are human disorders caused by dysfunction of primary cilia, ubiquitous microtubule-based organelles involved in signal transduction. Cilia are anchored inside the cell through basal bodies (BBs), modified centrioles also acting as microtubule-organization centers. Photoreceptors (PRs) are sensory neurons, whose primary cilium forms a highly specialized compartment called the outer segment (OS) responsible for sensing incoming light. Thus, ciliopathies often present with retinal degeneration. Mutations in KIAA0586/TALPID3 (TA3) cause Joubert syndrome, in which 30% of affected individuals develop retinal involvement...
February 2, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29374787/rab27a-facilitates-human-parainfluenza-virus-type-2-growth-by-promoting-cell-surface-transport-of-envelope-proteins
#6
Keisuke Ohta, Yusuke Matsumoto, Machiko Nishio
Human parainfluenza virus type 2 (hPIV-2) proteins and genomes newly synthesized in the cytoplasm need to be transported to the plasma membrane where budding occurs. This mechanism, where Rab proteins regulate intracellular traffic by switching between GTP-bound active form and GDP-bound inactive form, is not fully understood. mRNA and protein expression levels of Rab8a, Rab11a, and Rab27a are not altered by hPIV-2 infection. hPIV-2 growth is affected by depletion of Rab27a but not Rab8a and Rab11a. Overexpression of a constitutively active mutant of Rab27a Q78L promotes the cell surface levels of fusion (F) and hemagglutinin-neuraminidase (HN) proteins in hPIV-2-infected cells without affecting viral mRNA levels...
April 2018: Medical Microbiology and Immunology
https://www.readbyqxmd.com/read/29357897/parkinson-disease-associated-mutations-in-lrrk2-cause-centrosomal-defects-via-rab8a-phosphorylation
#7
Jesús Madero-Pérez, Elena Fdez, Belén Fernández, Antonio J Lara Ordóñez, Marian Blanca Ramírez, Patricia Gómez-Suaga, Dieter Waschbüsch, Evy Lobbestael, Veerle Baekelandt, Angus C Nairn, Javier Ruiz-Martínez, Ana Aiastui, Adolfo López de Munain, Pawel Lis, Thomas Comptdaer, Jean-Marc Taymans, Marie-Christine Chartier-Harlin, Alexandria Beilina, Adriano Gonnelli, Mark R Cookson, Elisa Greggio, Sabine Hilfiker
BACKGROUND: Mutations in LRRK2 are a common genetic cause of Parkinson's disease (PD). LRRK2 interacts with and phosphorylates a subset of Rab proteins including Rab8a, a protein which has been implicated in various centrosome-related events. However, the cellular consequences of such phosphorylation remain elusive. METHODS: Human neuroblastoma SH-SY5Y cells stably expressing wildtype or pathogenic LRRK2 were used to test for polarity defects in the context of centrosomal positioning...
January 23, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29297744/tgfb1-is-secreted-through-an-unconventional-pathway-dependent-on-the-autophagic-machinery-and-cytoskeletal-regulators
#8
Julian Nüchel, Sushmita Ghatak, Alexandra V Zuk, Anja Illerhaus, Matthias Mörgelin, Katrin Schönborn, Katrin Blumbach, Sara A Wickström, Thomas Krieg, Gerhard Sengle, Markus Plomann, Beate Eckes
TGFB1 (transforming growth factor beta 1) is a potent cytokine playing a driving role in development, fibrosis and cancer. It is synthesized as prodomain-growth factor complex that requires tethering to LTBP (latent transforming growth factor beta binding protein) for efficient secretion into the extracellular space. Upon release, this large latent complex is sequestered by anchorage to extracellular matrix (ECM) networks, from which the mature growth factor needs to be activated in order to reach its receptors and initiate signaling...
2018: Autophagy
https://www.readbyqxmd.com/read/29281629/loss-of-function-of-the-ciliopathy-protein-cc2d2a-disorganizes-the-vesicle-fusion-machinery-at-the-periciliary-membrane-and-indirectly-affects-rab8-trafficking-in-zebrafish-photoreceptors
#9
Irene Ojeda Naharros, Matthias Gesemann, José M Mateos, Gery Barmettler, Austin Forbes, Urs Ziegler, Stephan C F Neuhauss, Ruxandra Bachmann-Gagescu
Ciliopathies are human disorders caused by dysfunction of primary cilia, ubiquitous organelles involved in transduction of environmental signals such as light sensation in photoreceptors. Concentration of signal detection proteins such as opsins in the ciliary membrane is achieved by RabGTPase-regulated polarized vesicle trafficking and by a selective barrier at the ciliary base, the transition zone (TZ). Dysfunction of the TZ protein CC2D2A causes Joubert/Meckel syndromes in humans and loss of ciliary protein localization in animal models, including opsins in retinal photoreceptors...
December 2017: PLoS Genetics
https://www.readbyqxmd.com/read/29167152/rab27b-requirement-for-stretch-induced-exocytosis-in-bladder-umbrella-cells
#10
Luciana I Gallo, Marianela G Dalghi, Dennis R Clayton, Wily G Ruiz, Puneet Khandelwal, Gerard Apodaca
Umbrella cells, which must maintain a tight barrier, modulate their apical surface area during bladder filling by exocytosis of an abundant, subapical pool of discoidal- and/or fusiform-shaped vesicles (DFVs). Despite the importance of this trafficking event for bladder function, the pathways that promote DFV exocytosis remain to be identified. We previously showed that DFV exocytosis depends in part on a RAB11A-RAB8A-MYO5B network, but RAB27B is also reported to be associated with DFVs, and knockout mice lacking RAB27B have fewer DFVs...
March 1, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29127256/development-of-phospho-specific-rab-protein-antibodies-to-monitor-in-vivo-activity-of-the-lrrk2-parkinson-s-disease-kinase
#11
Pawel Lis, Sophie Burel, Martin Steger, Matthias Mann, Fiona Brown, Federico Diez, Francesca Tonelli, Janice L Holton, Philip Winglok Ho, Shu-Leong Ho, Meng-Yun Chou, Nicole K Polinski, Terina N Martinez, Paul Davies, Dario R Alessi
Mutations that activate the LRRK2 (leucine-rich repeat protein kinase 2) protein kinase predispose to Parkinson's disease, suggesting that LRRK2 inhibitors might have therapeutic benefit. Recent work has revealed that LRRK2 phosphorylates a subgroup of 14 Rab proteins, including Rab10, at a specific residue located at the centre of its effector-binding switch-II motif. In the present study, we analyse the selectivity and sensitivity of polyclonal and monoclonal phospho-specific antibodies raised against nine different LRRK2-phosphorylated Rab proteins (Rab3A/3B/3C/3D, Rab5A/5B/5C, Rab8A/8B, Rab10, Rab12, Rab29[T71], Rab29[S72], Rab35 and Rab43)...
January 2, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29125462/systematic-proteomic-analysis-of-lrrk2-mediated-rab-gtpase-phosphorylation-establishes-a-connection-to-ciliogenesis
#12
Martin Steger, Federico Diez, Herschel S Dhekne, Pawel Lis, Raja S Nirujogi, Ozge Karayel, Francesca Tonelli, Terina N Martinez, Esben Lorentzen, Suzanne R Pfeffer, Dario R Alessi, Matthias Mann
We previously reported that Parkinson's disease (PD) kinase LRRK2 phosphorylates a subset of Rab GTPases on a conserved residue in their switch-II domains (Steger et al., 2016) (PMID: 26824392). Here, we systematically analyzed the Rab protein family and found 14 of them (Rab3A/B/C/D, Rab5A/B/C, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43) to be specifically phosphorylated by LRRK2, with evidence for endogenous phosphorylation for ten of them (Rab3A/B/C/D, Rab8A/B, Rab10, Rab12, Rab35 and Rab43). Affinity enrichment mass spectrometry revealed that the primary ciliogenesis regulator, RILPL1 specifically interacts with the LRRK2-phosphorylated forms of Rab8A and Rab10, whereas RILPL2 binds to phosphorylated Rab8A, Rab10, and Rab12...
November 10, 2017: ELife
https://www.readbyqxmd.com/read/29089333/electrical-pulse-stimulation-induces-glut4-glucose-transporter-translocation-in-c2c12-myotubes-that-depends-on-rab8a-rab13-and-rab14
#13
Zhu Li, Yingying Yue, Fang Hu, Chang Zhang, Xiaofang Ma, Nana Li, Lihong Qiu, Maolong Fu, Liming Chen, Zhi Yao, Philip J Bilan, Amira Klip, Wenyan Niu
The signals mobilizing GLUT4 to the plasma membrane in response to muscle contraction are less known than those elicited by insulin. This disparity is undoubtedly due to lack of suitable in vitro models to study skeletal muscle contraction. We generated C2C12 myotubes stably expressing HA-tagged GLUT4 (C2C12-GLUT4 HA) that contract in response to electrical pulse stimulation (EPS) and investigated molecular mechanisms regulating GLUT4 HA. EPS (60min, 20V, 1Hz, 24ms pulses at 976ms intervals) elicited a gain in surface GLUT4 HA (GLUT4 translocation) comparably to insulin or 5-amino imidazole-4-carboxamide ribonucleotide (AICAR)...
October 31, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29044157/facilitating-identification-of-minimal-protein-binding-domains-by-cross-linking-mass-spectrometry
#14
Qingyang Liu, Sanne Remmelzwaal, Albert J R Heck, Anna Akhmanova, Fan Liu
Characterization of protein interaction domains is crucial for understanding protein functions. Here we combine cross-linking mass spectrometry (XL-MS) with deletion analysis to accurately locate minimal protein interaction domains. As a proof of concept, we investigated in detail the binding interfaces of two protein assemblies: the complex formed by MICAL3, ELKS and Rab8A, which is involved in exocytosis, and the complex of SLAIN2, CLASP2 and ch-TOG, which controls microtubule dynamics. We found that XL-MS provides valuable information to efficiently guide the design of protein fragments that are essential for protein interaction...
October 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29024942/loss-of-myosin-vb-in-colorectal-cancer-is-a-strong-prognostic-factor-for-disease-recurrence
#15
Elisabeth Letellier, Martine Schmitz, Aurélien Ginolhac, Fabien Rodriguez, Pit Ullmann, Komal Qureshi-Baig, Sonia Frasquilho, Laurent Antunes, Serge Haan
BACKGROUND: Selecting the most beneficial treatment regimens for colorectal cancer (CRC) patients remains challenging due to a lack of prognostic markers. Members of the Myosin family, proteins recognised to have a major role in trafficking and polarisation of cells, have recently been reported to be closely associated with several types of cancer and might thus serve as potential prognostic markers in the context of CRC. METHODS: We used a previously established meta-analysis of publicly available gene expression data to analyse the expression of different members of the Myosin V family, namely MYO5A, 5B, and 5C, in CRC...
November 21, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28883094/integrin-%C3%AE-8-and-pcdh15-act-as-a-complex-to-regulate-cilia-biogenesis-in-sensory-cells
#16
Linda Goodman, Marisa Zallocchi
The way an organism perceives its surroundings depends on sensory systems and the highly specialized cilia present in the neurosensory cells. Here, we describe the existence of an integrin α8 (Itga8) and protocadherin-15a (Pcdh15a) ciliary complex in neuromast hair cells in a zebrafish model. Depletion of the complex via downregulation or loss-of-function mutation leads to a dysregulation of cilia biogenesis and endocytosis. At the molecular level, removal of the complex blocks the access of Rab8a into the cilia as well as normal recruitment of ciliary cargo by centriolar satellites...
November 1, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28720835/exophagy-of-annexin-a2-via-rab11-rab8a-and-rab27a-in-ifn-%C3%AE-stimulated-lung-epithelial-cells
#17
Ying-Da Chen, Yi-Ting Fang, Yi-Lin Cheng, Chiou-Feng Lin, Li-Jin Hsu, Shu-Ying Wang, Robert Anderson, Chih-Peng Chang, Yee-Shin Lin
Annexin A2 (ANXA2), a phospholipid-binding protein, has multiple biological functions depending on its cellular localization. We previously demonstrated that IFN-γ-triggered ANXA2 secretion is associated with exosomal release. Here, we show that IFN-γ-induced autophagy is essential for the extracellular secretion of ANXA2 in lung epithelial cells. We observed colocalization of ANXA2-containing autophagosomes with multivesicular bodies (MVBs) after IFN-γ stimulation, followed by exosomal release. IFN-γ-induced exophagic release of ANXA2 could not be observed in ATG5-silenced or mutant RAB11-expressing cells...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28714518/regulation-of-tubular-recycling-endosome-biogenesis-by-the-p53-micall1-pathway
#18
Yukie Takahashi, Chizu Tanikawa, Takafumi Miyamoto, Makoto Hirata, Guanxiong Wang, Koji Ueda, Tsunehiko Komatsu, Koichi Matsuda
p53, one of the most frequently mutated genes in colon cancer, suppresses cancer development through transactivation of its targets. Herein, we conducted a comprehensive analysis of the p53 downstream pathway in colorectal cancer by using multi-omics analysis. Mass spectrometric analysis of HCT116 p53+/+ and HCT116 p53-/- cells treated with adriamycin identified 124 proteins increased by DNA damage in a p53-dependent manner. Further screening using a cDNA microarray and the TCGA database revealed MICALL1 as a novel p53 target, and we identified functional p53 binding motifs located approximately 3000 base pairs upstream of the MICALL1 gene...
August 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28696211/rab8a-deficiency-in-skeletal-muscle-causes-hyperlipidemia-and-hepatosteatosis-by-impairing-muscle-lipid-uptake-and-storage
#19
Qiaoli Chen, Ping Rong, Dijin Xu, Sangsang Zhu, Liang Chen, Bingxian Xie, Qian Du, Chao Quan, Yang Sheng, Tong-Jin Zhao, Peng Li, Hong Yu Wang, Shuai Chen
Skeletal muscle absorbs long-chain fatty acids (LCFAs) that are either oxidized in mitochondria or temporarily stored as triglycerides in lipid droplets (LDs). So far, it is still not fully understood how lipid uptake and storage are regulated in muscle and whether these are important for whole-body lipid homeostasis. Here we show that the small GTPase Rab8a regulates lipid uptake and storage in skeletal muscle. Muscle-specific Rab8a deletion caused hyperlipidemia and exacerbated hepatosteatosis induced by a high-fat diet...
September 2017: Diabetes
https://www.readbyqxmd.com/read/28602209/update-on-glut4-vesicle-traffic-a-cornerstone-of-insulin-action
#20
REVIEW
Javier R Jaldin-Fincati, Martin Pavarotti, Scott Frendo-Cumbo, Philip J Bilan, Amira Klip
Glucose transport is rate limiting for dietary glucose utilization by muscle and fat. The glucose transporter GLUT4 is dynamically sorted and retained intracellularly and redistributes to the plasma membrane (PM) by insulin-regulated vesicular traffic, or 'GLUT4 translocation'. Here we emphasize recent findings in GLUT4 translocation research. The application of total internal reflection fluorescence microscopy (TIRFM) has increased our understanding of insulin-regulated events beneath the PM, such as vesicle tethering and membrane fusion...
August 2017: Trends in Endocrinology and Metabolism: TEM
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