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https://www.readbyqxmd.com/read/29161562/membrane-traffic-trans-golgi-tethers-leave-a%C3%A2-surprisingly-small-gap
#1
Francis A Barr
Activation and inactivation of Rab GTPases by GEFs and GAPs promotes or terminates vesicle tethering to organelles, respectively. This simple model is challenged by new evidence revealing that a catalytically inactive Rab GAP promotes rather than terminates vesicle tethering at the trans-Golgi.
November 20, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/29160307/a-non-canonical-notch-complex-regulates-adherens-junctions-and-vascular-barrier-function
#2
William J Polacheck, Matthew L Kutys, Jinling Yang, Jeroen Eyckmans, Yinyu Wu, Hema Vasavada, Karen K Hirschi, Christopher S Chen
The vascular barrier that separates blood from tissues is actively regulated by the endothelium and is essential for transport, inflammation, and haemostasis1. Haemodynamic shear stress plays a critical role in maintaining endothelial barrier function2, but how this occurs remains unknown. Here, using an engineered organotypic model of perfused microvessels and confirming in mouse models, we identify that activation of the Notch1 transmembrane receptor directly regulates vascular barrier function through a non-canonical, transcription independent signalling mechanism that drives adherens junction assembly...
November 13, 2017: Nature
https://www.readbyqxmd.com/read/29141223/gradients-of-rac1-nanoclusters-support-spatial-patterns-of-rac1-signaling
#3
Amanda Remorino, Simon De Beco, Fanny Cayrac, Fahima Di Federico, Gaetan Cornilleau, Alexis Gautreau, Maria Carla Parrini, Jean-Baptiste Masson, Maxime Dahan, Mathieu Coppey
Rac1 is a small RhoGTPase switch that orchestrates actin branching in space and time and protrusion/retraction cycles of the lamellipodia at the cell front during mesenchymal migration. Biosensor imaging has revealed a graded concentration of active GTP-loaded Rac1 in protruding regions of the cell. Here, using single-molecule imaging and super-resolution microscopy, we show an additional supramolecular organization of Rac1. We find that Rac1 partitions and is immobilized into nanoclusters of 50-100 molecules each...
November 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/29136506/a-paradoxical-tumor-suppressor-role-for-the-rac1-exchange-factor-vav1-in-t-cell-acute-lymphoblastic-leukemia
#4
Javier Robles-Valero, L Francisco Lorenzo-Martín, Mauricio Menacho-Márquez, Isabel Fernández-Pisonero, Antonio Abad, Mireia Camós, María L Toribio, Lluis Espinosa, Anna Bigas, Xosé R Bustelo
Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation...
November 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29133411/specific-inhibition-of-gpcr-independent-g-protein-signaling-by-a-rationally-engineered-protein
#5
Anthony Leyme, Arthur Marivin, Marcin Maziarz, Vincent DiGiacomo, Maria P Papakonstantinou, Prachi P Patel, Juan B Blanco-Canosa, Isha A Walawalkar, Gonzalo Rodriguez-Davila, Isabel Dominguez, Mikel Garcia-Marcos
Activation of heterotrimeric G proteins by cytoplasmic nonreceptor proteins is an alternative to the classical mechanism via G protein-coupled receptors (GPCRs). A subset of nonreceptor G protein activators is characterized by a conserved sequence named the Gα-binding and activating (GBA) motif, which confers guanine nucleotide exchange factor (GEF) activity in vitro and promotes G protein-dependent signaling in cells. GBA proteins have important roles in physiology and disease but remain greatly understudied...
November 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29132432/ac-93253-iodide-a-novel-src-inhibitor-suppresses-nsclc-progression-by-modulating-multiple-src-related-signaling-pathways
#6
Yi-Hua Lai, Sih-Yin Lin, Yu-Shan Wu, Huei-Wen Chen, Jeremy J W Chen
BACKGROUND: The tyrosine kinase Src is involved in the progression of many cancers. Moreover, inhibiting Src activity has been shown to obstruct several signaling pathways regulated by the EGFR. Thus, Src is a valuable target molecule in drug development. The purpose of this study was to identify compounds that directly or indirectly modulate Src to suppress lung cancer cell growth and motility and to investigate the molecular mechanisms underlying the effects of these compounds. METHODS: Human non-small cell lung cancer (NSCLC) cell lines (PC9, PC9/gef, A549, and H1975) with different EGFR statuses were tested by cytotoxicity and proliferation assays after AC-93253 iodide treatment...
November 13, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29130930/leukocyte-rhoa-exchange-factor-arhgef1-mediates-vascular-inflammation-and-atherosclerosis
#7
Maria Luigia Carbone, Gilliane Chadeuf, Sandrine Heurtebise-Chrétien, Xavier Prieur, Thibault Quillard, Yann Goueffic, Nathalie Vaillant, Marc Rio, Laure Castan, Maxim Durand, Céline Baron-Menguy, Julien Aureille, Juliette Desfrançois, Angela Tesse, Raul M Torres, Gervaise Loirand
Abnormal activity of the renin-angiotensin-aldosterone system plays a causal role in the development of hypertension, atherosclerosis, and associated cardiovascular events such as myocardial infarction, stroke, and heart failure. As both a vasoconstrictor and a proinflammatory mediator, angiotensin II (Ang II) is considered a potential link between hypertension and atherosclerosis. However, a role for Ang II-induced inflammation in atherosclerosis has not been clearly established, and the molecular mechanisms and intracellular signaling pathways involved are not known...
November 13, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29130632/dock3-related-neurodevelopmental-syndrome-biallelic-intragenic-deletion-of-dock3-in-a-boy-with-developmental-delay-and-hypotonia
#8
Aiko Iwata-Otsubo, Alyssa L Ritter, Brooke Weckselbatt, Nicole R Ryan, David Burgess, Laura K Conlin, Kosuke Izumi
Dedicator of cytokinesis (DOCK) family are evolutionary conserved guanine nucleotide exchange factors (GEFs) for the Rho GTPases, Rac, and Cdc42. DOCK3 functions as a GEF for Rac1, and plays an important role in promoting neurite and axonal growth by stimulating actin dynamics and microtubule assembly pathways in the central nervous system. Here we report a boy with developmental delay, hypotonia, and ataxia due to biallelic DOCK3 deletion. Chromosomal single nucleotide polymorphism (SNP) microarray analysis detected a 170 kb homozygous deletion including exons 6-12 of the DOCK3 gene at 3p21...
November 12, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29125885/mir-376c-inhibits-osteoblastogenesis-by-targeting-wnt3-and-arf-gef-1-facilitated-augmentation-of-beta-catenin-transactivation
#9
Jyoti Kureel, Aijaz A John, Ravi Prakash, Divya Singh
Wnt signaling pathway plays important role in all aspects of skeletal development which include chondrogenesis, osteoblastogenesis, and osteoclastogenesis. Induction of the Wnt signaling pathway promotes bone formation while inactivation of the pathway leads to bone related disorders like osteoporosis. Wnt signaling thus has become a desired target to treat osteogenic disorders. MicroRNAs (miRNAs) represent an important category of elements that interact with Wnt signaling molecules to regulate osteogenesis...
November 10, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29124783/a-key-role-for-rac-and-pak-signaling-in-neutrophil-extracellular-traps-nets-formation-defines-a-new-potential-therapeutic-target
#10
M Gavillet, K Martinod, R Renella, D D Wagner, D A Williams
NET formation in mice (NETosis) is supported by reactive oxygen species (ROS) production by NADPH oxidase and histone hypercitrullination by peptidylarginine deiminase 4 (PAD4). Rac1 and Rac2, expressed in polymorphonuclear neutrophils (PMNs), regulate the cytoskeleton, cell shape, adhesion and migration and are also essential components of the NADPH oxidase complex. We aimed to explore the role of the Rac signaling pathway including the upstream guanosine exchange factor (GEF) activator, Vav, and a downstream effector, the p21-activated kinase, Pak, on NETosis in PMNs using a previously described flow-cytometry-based assay...
November 10, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29121646/the-phosphomimetic-mutation-of-syndecan-4-binds-and-inhibits-tiam1-modulating-rac1-activity-in-pdz-interaction-dependent-manner
#11
Aniko Keller-Pinter, Bettina Ughy, Monika Domoki, Aladar Pettko-Szandtner, Tamas Letoha, Jozsef Tovari, Jozsef Timar, Laszlo Szilak
The small GTPases of the Rho family comprising RhoA, Rac1 and Cdc42 function as molecular switches controlling several essential biochemical pathways in eukaryotic cells. Their activity is cycling between an active GTP-bound and an inactive GDP-bound conformation. The exchange of GDP to GTP is catalyzed by guanine nucleotide exchange factors (GEFs). Here we report a novel regulatory mechanism of Rac1 activity, which is controlled by a phosphomimetic (Ser179Glu) mutant of syndecan-4 (SDC4). SDC4 is a ubiquitously expressed transmembrane, heparan sulfate proteoglycan...
2017: PloS One
https://www.readbyqxmd.com/read/29121260/an-arf-gap-promotes-endocytosis-and-hyphal-growth-of-ashbya-gossypii
#12
Therese Oscarsson, Andrea Walther, Klaus B Lengeler, Jürgen Wendland
The ADP-ribosylation factor (ARF) family of GTPases are highly conserved from yeast to human and regulate vesicle budding. Sec7 domain containing proteins stimulate the guanine nucleotide exchange on Arf proteins while ARF-GTPase activating proteins stimulate the hydrolysis of GTP. Since vesicle trafficking is important for hyphal growth we studied the A. gossypii homolog of S. cerevisiae ARF3 along with its putative GEF and GAP encoded by YEL1 and GTS1, respectively. Deletion of YEL1 had no discernible phenotype and deletion of ARF3 had only a minor defect in vacuolar fusion...
November 7, 2017: FEMS Microbiology Letters
https://www.readbyqxmd.com/read/29118104/conditional-deletion-of-ric-8b-in-olfactory-sensory-neurons-leads-to-olfactory-impairment
#13
Cleiton F Machado, Maíra H Nagai, Cassandra S Lyra, Thiago M Reis-Silva, André Machado Xavier, Isaias Glezer, Luciano F Felicio, Bettina Malnic
The olfactory system can discriminate a vast number of odorants. This ability derives from the existence of a large family of odorant receptors expressed in the cilia of the olfactory sensory neurons. Odorant receptors signal through the olfactory-specific G-protein subunit, Gαolf. Ric-8b, a guanine nucleotide exchange factor, interacts with Gαolf and can amplify odorant receptor signal transduction in vitro To explore the function of Ric-8b in vivo, we generated a tissue specific knockout mouse by crossing OMP-Cre transgenic mice to Ric-8b floxed mice...
November 8, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29107538/hybrid-structure-of-the-raga-c-ragulator-mtorc1-activation-complex
#14
Ming-Yuan Su, Kyle L Morris, Do Jin Kim, Yangxue Fu, Rosalie Lawrence, Goran Stjepanovic, Roberto Zoncu, James H Hurley
The lysosomal membrane is the locus for sensing cellular nutrient levels, which are transduced to mTORC1 via the Rag GTPases and the Ragulator complex. The crystal structure of the five-subunit human Ragulator at 1.4 Å resolution was determined. Lamtor1 wraps around the other four subunits to stabilize the assembly. The Lamtor2:Lamtor3 dimer stacks upon Lamtor4:Lamtor5 to create a platform for Rag binding. Hydrogen-deuterium exchange was used to map the Rag binding site to the outer face of the Lamtor2:Lamtor3 dimer and to the N-terminal intrinsically disordered region of Lamtor1...
October 25, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29106825/recurrent-de-novo-mutations-disturbing-the-gtp-gdp-binding-pocket-of-rab11b-cause-intellectual-disability-and-a-distinctive-brain-phenotype
#15
Ideke J C Lamers, Margot R F Reijnders, Hanka Venselaar, Alison Kraus, Sandra Jansen, Bert B A de Vries, Gunnar Houge, Gyri Aasland Gradek, Jieun Seo, Murim Choi, Jong-Hee Chae, Ineke van der Burgt, Rolph Pfundt, Stef J F Letteboer, Sylvia E C van Beersum, Simone Dusseljee, Han G Brunner, Dan Doherty, Tjitske Kleefstra, Ronald Roepman
The Rab GTPase family comprises ∼70 GTP-binding proteins, functioning in vesicle formation, transport and fusion. They are activated by a conformational change induced by GTP-binding, allowing interactions with downstream effectors. Here, we report five individuals with two recurrent de novo missense mutations in RAB11B; c.64G>A; p.Val22Met in three individuals and c.202G>A; p.Ala68Thr in two individuals. An overlapping neurodevelopmental phenotype, including severe intellectual disability with absent speech, epilepsy, and hypotonia was observed in all affected individuals...
October 23, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29101098/regulation-of-cortical-stability-by-rhogef3-in-mitotic-sensory-organ-precursor-cells-in-drosophila
#16
Lydie Couturier, Khalil Mazouni, Fred Bernard, Charlotte Besson, Elodie Reynaud, François Schweisguth
In epithelia, mitotic cells round up and push against their neighbors to divide. Mitotic rounding results from increased assembly of F-actin and cortical recruitment of Myosin II, leading to increased cortical stability. Whether this process is developmentally regulated is not well known. Here, we examined the regulation of cortical stability in Sensory Organ precursor cells (SOPs) in the Drosophila pupal notum. SOPs differed in apical shape and actomyosin dynamics from their epidermal neighbors prior to division and appeared to have a more rigid cortex at mitosis...
November 3, 2017: Biology Open
https://www.readbyqxmd.com/read/29097023/vav1-friend-and-foe-of-cancer
#17
Fukun Guo, Yi Zheng
A recent study shows that the protumorigenic guanine nucleotide exchange factor (GEF) Vav1 functions as a tumor suppressor in T cell acute lymphoblastic leukemia (T-ALL) through its ability to complex with the Cbl-b ubiquitin ligase and the intracellular domain of Notch1 (ICN1) and to promote ICN1 degradation. Vav1can act as a double-edged sword in tumorigenesis.
December 2017: Trends in Cell Biology
https://www.readbyqxmd.com/read/29089502/allosteric-inhibition-of-the-guanine-nucleotide-exchange-factor-dock5-by-a-small-molecule
#18
Yann Ferrandez, Wenhua Zhang, François Peurois, Lurlène Akendengué, Anne Blangy, Mahel Zeghouf, Jacqueline Cherfils
Rac small GTPases and their GEFs of the DOCK family are pivotal checkpoints in development, autoimmunity and bone homeostasis, and their abnormal regulation is associated to diverse pathologies. Small molecules that inhibit their activities are therefore needed to investigate their functions. Here, we characterized the mechanism of inhibition of human DOCK5 by C21, a small molecule that inhibits mouse Dock5 in cells and blocks bone degradation in mice models of osteoporosis. We showed that the catalytic DHR2 domain of DOCK5 has a high basal GEF activity in the absence of membranes which is not regulated by a simple feedback loop...
October 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29089384/the-guanine-nucleotide-exchange-factor-arf-like-protein-13b-is-essential-for-assembly-of-the-mouse-photoreceptor-transition-zone-and-outer-segment
#19
Christin Hanke-Gogokhia, Zhijian Wu, Ali Sharif, Hussein Yazigi, Jeanne M Frederick, Wolfgang Baehr
ARL13b is a small GTPase that functions as a guanosine nucleotide exchange factor (GEF) for ARL3-GDP. ARL13b is located exclusively in photoreceptor outer segments (OS) presumably anchored to discs by palmitoylation, whereas ARL3 is an inner segment cytoplasmic protein. Hypomorphic mutations affecting the ARL13b G‑domain inactivate GEF activity and lead to Joubert Syndrome (JS) in human. However, the molecular mechanisms in ARL13b mutation-induced JS, particularly the function of primary cilia, are still incompletely understood...
October 31, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29074966/mutation-specific-mechanisms-of-hyperactivation-of-noonan-syndrome-sos-molecules-detected-with-single-molecule-imaging-in-living-cells
#20
Yuki Nakamura, Nobuhisa Umeki, Mitsuhiro Abe, Yasushi Sako
Noonan syndrome (NS) is a congenital hereditary disorder associated with developmental and cardiac defects. Some patients with NS carry mutations in SOS, a guanine nucleotide exchange factor (GEF) for the small GTPase RAS. NS mutations have been identified not only in the GEF domain, but also in various domains of SOS, suggesting that multiple mechanisms disrupt SOS function. In this study, we examined three NS mutations in different domains of SOS to clarify the abnormality in its translocation to the plasma membrane, where SOS activates RAS...
October 26, 2017: Scientific Reports
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