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Theresia E B Stradal, Sonia C P Costa
A key aspect of bacterial pathogenesis is the colonization and persistence within the host and, later on, its dissemination to new niches. During evolution, bacteria developed a myriad of virulence mechanisms to usurp the host's sophisticated defense mechanisms in order to establish their colonization niche. Elucidation of the highly dynamic and complex interactions between host and pathogens remains an important field of study. Here, we highlight the conserved manipulation of the actin cytoskeleton by some Gram-negative gastrointestinal pathogens, addressing the role of type III secreted bacterial GEFs at the different steps of pathogenesis...
October 16, 2016: Current Topics in Microbiology and Immunology
Ryan S D'Souza, James E Casanova
The IQsec/BRAG proteins are a subfamily of Arf-nucleotide exchange factors. Since their discovery almost 15 years ago, the BRAGs have been reported to be involved in diverse physiological processes from myoblast fusion, neuronal pathfinding and angiogenesis, to pathophysiological processes including X-linked intellectual disability and tumor metastasis. In this review we will address how, in each of these situations, the BRAGs are thought to regulate the surface levels of adhesive and signaling receptors. While in most cases BRAGs are thought to enhance the endocytosis of these receptors, how they achieve this remains unclear...
October 14, 2016: Small GTPases
Noah Fine, Ioannis D Dimitriou, Jacob Rullo, María José Sandí, Björn Petri, Jack Haitsma, Hisham Ibrahim, Jose La Rose, Michael Glogauer, Paul Kubes, Myron Cybulsky, Robert Rottapel
Leukocyte crawling and transendothelial migration (TEM) are potentiated by shear stress caused by blood flow. The mechanism that couples shear stress to migration has not been fully elucidated. We found that mice lacking GEF-H1 (GEF-H1(-/-)), a RhoA-specific guanine nucleotide exchange factor (GEF), displayed limited migration and recruitment of neutrophils into inflamed tissues. GEF-H1(-/-) leukocytes were deficient in in vivo crawling and TEM in the postcapillary venules. We demonstrated that although GEF-H1 deficiency had little impact on the migratory properties of neutrophils under static conditions, shear stress triggered GEF-H1-dependent spreading and crawling of neutrophils and relocalization of GEF-H1 to flotillin-2-rich uropods...
October 10, 2016: Journal of Cell Biology
Philipp Niethammer
Forces deriving from blood flow shear modulate vascular adherence and transendothelial migration of leukocytes into inflamed tissues, but the mechanisms by which shear is sensed are unclear. In this issue, Fine et al. (2016. J. Cell Biol. identify the guanosine nucleotide exchange factor GEF-H1 as critical for shear stress-induced transendothelial neutrophil migration.
October 10, 2016: Journal of Cell Biology
Max Wolff, Klaus-Martin Krönke, John Venz, Anja Kräplin, Gerhard Bühringer, Michael N Smolka, Thomas Goschke
Self-control is commonly assumed to depend on executive functions (EFs). However, it is unclear whether real-life self-control failures result from deficient EF competencies or rather reflect insufficient conflict-induced mobilization of executive control, and whether self-control depends more critically on function-specific EF competencies or general executive functioning (GEF), that is, common competencies that underlie all EFs. Here we investigated whether failure-related action versus state orientation, a personality trait related to the conflict-induced mobilization of cognitive control, moderates the effect of general and function-specific control competencies on self-control...
October 13, 2016: Journal of Experimental Psychology. General
Lianggong Ding, Ye Lei, Yanping Han, Yuhong Li, Xunming Ji, Lei Liu
As fundamental processes in mitochondrial dynamics, mitochondrial fusion, fission and transport are regulated by several core components, including Miro. As an atypical Rho-like small GTPase with high molecular mass, the exchange of GDP/GTP in Miro may require assistance from a guanine nucleotide exchange factor (GEF). However, the GEF for Miro has not been identified. While studying mitochondrial morphology in Drosophila, we incidentally observed that the loss of vimar, a gene encoding an atypical GEF, enhanced mitochondrial fission under normal physiological conditions...
October 2016: PLoS Genetics
Valentina Zamboni, Maria Armentano, Gabriella Sarò, Elisa Ciraolo, Alessandra Ghigo, Giulia Germena, Alessandro Umbach, Pamela Valnegri, Maria Passafaro, Valentina Carabelli, Daniela Gavello, Veronica Bianchi, Patrizia D'Adamo, Ivan de Curtis, Nadia El-Assawi, Alessandro Mauro, Lorenzo Priano, Nicola Ferri, Emilio Hirsch, Giorgio R Merlo
During brain development, the small GTPases Rac1/Rac3 play key roles in neuronal migration, neuritogenesis, synaptic formation and plasticity, via control of actin cytoskeleton dynamic. Their activity is positively and negatively regulated by GEFs and GAPs molecules, respectively. However their in vivo roles are poorly known. The ArhGAP15 gene, coding for a Rac-specific GAP protein, is expressed in both excitatory and inhibitory neurons of the adult hippocampus, and its loss results in the hyperactivation of Rac1/Rac3...
October 7, 2016: Scientific Reports
Xia Li, Tetsuro Ohmori, Kaoru Irie, Yuichi Kimura, Yasuyuki Suda, Tomoaki Mizuno, Kenji Irie
Ccr4, a component of the Ccr4-Not cytoplasmic deadenylase complex, is known to be required for the cell wall integrity (CWI) pathway in the budding yeast Saccharomyces cerevisiae. However, it is not fully understood how Ccr4 and other components of the Ccr4-Not complex regulate the CWI pathway. Previously, we showed that Ccr4 functions in the CWI pathway together with Khd1 RNA binding protein. Ccr4 and Khd1 modulate a signal from Rho1 small GTPase in the CWI pathway by regulating the expression of ROM2 mRNA and LRG1 mRNA, encoding a guanine nucleotide exchange factor (GEF) and a GTPase-activating protein (GAP) for Rho1, respectively...
September 2016: MSphere
Tao Liu, Hongyu Li, Wanjin Hong, Weiping Han
ADP-ribosylation factor (ARF) family of guanine-nucleotide binding (G) proteins regulates organelle biogenesis, structure and trafficking. The functions of ARF proteins are tightly controlled by guanine nucleotide exchange factors (GEFs) containing a conserved SEC7 domain. Based on sequence similarity to BIG/GBF of the Arf-GEF family, we recently identified brefeldin A-inhibited guanine nucleotide exchange protein 3 (BIG3) as a novel ARF GEF protein with a non-functional catalytic motif in the SEC7 domain. BIG3 is mainly expressed in pancreatic islets and brain...
October 1, 2016: Journal of Neurochemistry
Anna Bagnato, Laura Rosanò
Metastatization is a complex multistep process requiring fine-tuned regulated cytoskeleton re-modeling, mediated by the cross-talk of actin with interacting partners, such as the Rho GTPases. Our expanding knowledge of invadopodia, small invasive membrane protrusions composed of a core of F-actin, actin regulators and actin-binding proteins, and hotspots for secretion of extracellular matrix (ECM) proteinases, contributes to clarify critical steps of the metastatic program. Growth factor receptors and their intermediate signaling molecules, along with matrix adhesion and rigidity, pH and hypoxia, act as drivers of cytoskeleton changes and invadopodia formation...
October 3, 2016: Small GTPases
Olivier Calvayrac, Anne Pradines, Gilles Favre
Metastatic dissemination is the cause of death in the vast majority of cancers, including lung cancers. In order to metastasize, tumor cells must undergo a well-known series of changes, however the molecular details of how they manage to overcome the barriers at each stage remain incomplete. One critical step is acquiring the ability to migrate through the extracellular matrix. Loss of expression of the RAS-related small GTPase RHOB is a common feature of lung cancer progression, and we recently reported that this induces an epithelial-to-mesenchymal transition (EMT) that is dependent on SLUG overexpression and E-Cadherin inhibition and is characterized by 3-dimensional cell shape reorganization and the increased invasiveness of bronchial cells...
September 27, 2016: Small GTPases
Zhanna Lipatova, Uddalak Majumdar, Nava Segev
Ypt/Rab GTPases, key regulators of intracellular trafficking pathways, are activated by guanine-nucleotide exchange factors (GEFs). Here, we identify a novel GEF complex, TRAPP IV, which regulates Ypt1-mediated autophagy. In the yeast Saccharomyces cerevisiae, Ypt1 GTPase is required for the initiation of secretion and autophagy, suggesting that it regulates these two distinct pathways. However, whether these pathways are coordinated by Ypt1 and by what mechanism, is still unknown. TRAPP is a conserved modular complex that acts as a Ypt/Rab GEF...
September 26, 2016: Genetics
Philip R Goody
Evidence and arguments are summarized that suggest that intrinsic (tryptophan) protein fluorescence provides an excellent and convenient signal for monitoring both GEF (guanine nucleotide exchange factor) and GAP (GTPase activating protein) activity of a large number of small GTPases. In addition, post-translational modifications of Rab proteins occurring in a region known to be a hot spot for such modifications also lead to fluorescence changes that can be accurately monitored in a time-dependent manner. It is suggested that intrinsic fluorescence should be the first method chosen for monitoring such reactions of tryptophan-containing small GTPases...
December 15, 2016: Analytical Biochemistry
Fausto Andres Ortiz-Morea, Daniel V Savatin, Wim Dejonghe, Rahul Kumar, Yu Luo, Maciej Adamowski, Jos Van den Begin, Keini Dressano, Guilherme Pereira de Oliveira, Xiuyang Zhao, Qing Lu, Annemieke Madder, Jiří Friml, Daniel Scherer de Moura, Eugenia Russinova
The Arabidopsis thaliana endogenous elicitor peptides (AtPeps) are released into the apoplast after cellular damage caused by pathogens or wounding to induce innate immunity by direct binding to the membrane-localized leucine-rich repeat receptor kinases, PEP RECEPTOR1 (PEPR1) and PEPR2. Although the PEPR-mediated signaling components and responses have been studied extensively, the contributions of the subcellular localization and dynamics of the active PEPRs remain largely unknown. We used live-cell imaging of the fluorescently labeled and bioactive pep1 to visualize the intracellular behavior of the PEPRs in the Arabidopsis root meristem...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
Raquel B Haga, Anne J Ridley
Rho GTPases are well known for their roles in regulating cell migration, and also contribute to a variety of other cellular responses. They are subdivided into two groups: typical and atypical. The typical Rho family members, including RhoA, Rac1 and Cdc42, cycle between an active GTP-bound and inactive GDP-bound conformation, and are regulated by GEFs, GAPs and GDIs, whereas atypical Rho family members have amino acid substitutions that alter their ability to interact with GTP/GDP and hence are regulated by different mechanisms...
September 14, 2016: Small GTPases
Kazuhiro Kashiwagi, Takuhiro Ito, Shigeyuki Yokoyama
Eukaryotic translation initiation factor 2B (eIF2B), a heterodecameric complex of two sets of the α-, β-, γ-, δ- and ε-subunits, is the guanine nucleotide exchange factor (GEF) specific for eIF2, a heterotrimeric G protein consisting of the α-, β- and γ-subunits. The eIF2 protein binds GTP on the γ-subunits and delivers an initiator methionyl-tRNA (Met-tRNAi (M) (et) ) to the ribosome. The GEF activity of eIF2B is inhibited by stress-induced phosphorylation of Ser51 in the α-subunit of eIF2, which leads to lower amounts of active eIF2 and a limited quantity of Met-tRNAi (M) (et) for the ribosome, resulting in global repression of translation...
September 14, 2016: FEBS Journal
Vijay Gupta, Deepali Bhandari, Anthony Leyme, Nicolas Aznar, Krishna K Midde, I-Chung Lo, Jason Ear, Ingrid Niesman, Inmaculada López-Sánchez, Juan Bautista Blanco-Canosa, Mark von Zastrow, Mikel Garcia-Marcos, Marilyn G Farquhar, Pradipta Ghosh
We previously showed that guanine nucleotide-binding (G) protein α subunit (Gα)-interacting vesicle-associated protein (GIV), a guanine-nucleotide exchange factor (GEF), transactivates Gα activity-inhibiting polypeptide 1 (Gαi) proteins in response to growth factors, such as EGF, using a short C-terminal motif. Subsequent work demonstrated that GIV also binds Gαs and that inactive Gαs promotes maturation of endosomes and shuts down mitogenic MAPK-ERK1/2 signals from endosomes. However, the mechanism and consequences of dual coupling of GIV to two G proteins, Gαi and Gαs, remained unknown...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
Y Komiya, Y Onodera, M Kuroiwa, S Nomimura, Y Kubo, J-M Nam, K Kajiwara, S Nada, C Oneyama, H Sabe, M Okada
Epithelial tumor cells often acquire malignant properties, such as invasion/metastasis and uncontrolled cell growth, by undergoing epithelial-mesenchymal transition (EMT). However, the mechanisms by which EMT contributes to malignant progression remain elusive. Here we show that the Rho guanine nucleotide exchange factor (GEF) ARHGEF5 promotes tumor malignancy in a manner dependent on EMT status. We previously identified ARHGEF5, a member of the Dbl family of GEFs, as a multifunctional mediator of Src-induced cell invasion and tumor growth...
2016: Oncogenesis
Mei Yang, Chen Liang, Kunchithapadam Swaminathan, Stephanie Herrlinger, Fan Lai, Ramin Shiekhattar, Jian-Fu Chen
The intronic GGGGCC hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) is a prevalent genetic abnormality identified in both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) is a protein with unclear functions. We report that C9ORF72 is a component of a multiprotein complex containing SMCR8, WDR41, and ATG101 (an important regulator of autophagy). The C9ORF72 complex displays guanosine triphosphatase (GTPase) activity and acts as a guanosine diphosphate-guanosine 5'-triphosphate (GDP-GTP) exchange factor (GEF) for RAB39B...
September 2016: Science Advances
Atsuko Kimura, Kazuhiko Namekata, Xiaoli Guo, Chikako Harada, Takayuki Harada
Glaucoma is a neurodegenerative disease of the eye and it is one of the major causes of blindness. Glaucoma is usually associated with elevated intraocular pressure (IOP) and the current therapy focuses on reduction of IOP. However, neuroprotective strategies could also be beneficial for treatment of glaucoma because the pathology of the disease involves retinal ganglion cell (RGC) death and damage to the optic nerve. Dedicator of cytokinesis 3 (Dock3) is an atypical guanine exchange factor (GEF) that belongs to a family of Dock proteins, Dock1-11...
September 9, 2016: Histology and Histopathology
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