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Small GTPases

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https://www.readbyqxmd.com/read/28981399/the-arf-gap-and-protein-scaffold-cat1-git1-as-a-multifaceted-regulator-of-cancer-progression
#1
Sungsoo M Yoo, Richard A Cerione, Marc A Antonyak
Cool-associated tyrosine phosphorylated protein 1 (Cat1), also referred to as GPCR-kinase interacting protein 1 (Git1), is a ubiquitously expressed, multi-domain protein that is best known for regulating cell shape and migration. Cat1/Git1 functions as a GTPase activating protein (GAP) that inactivates certain members of the ADP-ribosylation factor (Arf) family of small GTPases. It is also a scaffold that brings together several signaling proteins at specific locations within the cell, ensuring their efficient activation...
October 5, 2017: Small GTPases
https://www.readbyqxmd.com/read/28980871/small-gtpases-orchestrate-cell-cell-communication-during-collective-cell-movement
#2
Anne Combedazou, Stéphanie Gayral, Nathalie Colombié, Anne Fougerat, Muriel Laffargue, Damien Ramel
Collective cell migration is a critical mechanism involved in cell movement during various physiological and pathological processes such as angiogenesis and metastasis formation. During collective movement, cells remain functionally connected and can coordinate individual cell behaviors to ensure efficient migration. A cell-cell communication process ensures this complex coordination. Although the mechanisms regulating cell-cell communication remain unclear, recent findings indicate that it is based on acto-myosin cytoskeleton tension transmission from cell to cell through adherens junctions...
October 5, 2017: Small GTPases
https://www.readbyqxmd.com/read/28972449/targeting-rock-activity-to-disrupt-and-prime-pancreatic-cancer-for-chemotherapy
#3
Claire Vennin, Nicola Rath, Marina Pajic, Michael F Olson, Paul Timpson
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease; the identification of novel targets and development of effective treatment strategies are urgently needed to improve patient outcomes. Remodeling of the pancreatic stroma occurs during PDAC development, which drives disease progression and impairs responses to therapy. The actomyosin regulatory ROCK1 and ROCK2 kinases govern cell motility and contractility, and have been suggested to be potential targets for cancer therapy, particularly to reduce the metastatic spread of tumor cells...
October 3, 2017: Small GTPases
https://www.readbyqxmd.com/read/28960175/endothelial-rhob-and-rhoc-are-dispensable-for-leukocyte-diapedesis-and-for-maintaining-vascular-integrity-during-diapedesis
#4
Lilian Schimmel, Aafke de Ligt, Simon Tol, Vivian de Waard, Jaap D van Buul
Active remodeling of the actin cytoskeleton in endothelial cells is necessary for allowing leukocytes to cross the barrier during the process of transendothelial migration (TEM). Involvement of RhoGTPases to regulate actin organization is inevitable, and we recently reported on the local function of RhoA in limiting vascular leakage during leukocyte TEM. As a follow-up we investigated here the possible involvement of two other closely-related GTPases; RhoB and RhoC, in regulating leukocyte TEM and vascular barrier maintenance...
September 29, 2017: Small GTPases
https://www.readbyqxmd.com/read/28960163/overexpression-of-ypt6-restores-invasive-filamentous-growth-and-secretory-vesicle-clustering-in-a-candida-albicans-arl1-mutant
#5
Rohan Wakade, Hayet Labbaoui, Danièle Stalder, Robert A Arkowitz, Martine Bassilana
Virulence of the human fungal pathogen Candida albicans depends on the switch from budding to filamentous growth. Deletion of the Arf GTPase Arl1 results in hyphae that are shorter as well as reduced virulence. How Arl1 is regulated during hyphal growth, a process characteristic of filamentous fungi, yet absent in S. cerevisiae, is unknown. Here, we investigated the importance of the Rab6 homolog, Ypt6, in Arl1-dependent hyphal growth and determined that YPT6 overexpression specifically rescued the hyphal growth defect of an arl1 mutant, but not the converse...
September 29, 2017: Small GTPases
https://www.readbyqxmd.com/read/28960134/differential-requirement-of-rab22a-for-the-recruitment-of-er-derived-proteins-to-phagosomes-and-endosomes-in-dendritic-cells
#6
Cristina Croce, Luis S Mayorga, Ignacio Cebrian
The recruitment of endoplasmic reticulum (ER) components to dendritic cell (DC) phagosomes and endosomes is a crucial event to achieve efficient cross-presentation of exogenous antigens. We have previously identified the small GTPase Rab22a as a key regulator of MHC-I trafficking and antigen cross-presentation by DCs. In this study we show that low expression of Rab22a does not prevent the normal delivery of ER-derived proteins to DC phagosomes. In contrast, the presence of these proteins was diminished in endosomes labelled with a fluid phase marker...
September 29, 2017: Small GTPases
https://www.readbyqxmd.com/read/28949796/rhoa-rhob-and-rhoc-differentially-regulate-endothelial-barrier-function
#7
Manon C A Pronk, Jan S M van Bezu, Geerten P van Nieuw Amerongen, Victor W M van Hinsbergh, Peter L Hordijk
RhoGTPases are known regulators of intracellular actin dynamics that are important for maintaining endothelial barrier function. RhoA is most extensively studied as a key regulator of endothelial barrier function, however the function of the 2 highly homologous family-members (> 88%) RhoB and RhoC in endothelial barrier function is still poorly understood. This study aimed to determine whether RhoA, RhoB and RhoC have overlapping or distinct roles in barrier function and permeability in resting and activated endothelium...
September 26, 2017: Small GTPases
https://www.readbyqxmd.com/read/28877029/impairments-in-age-dependent-ubiquitin-proteostasis-and-structural-integrity-of-selective-neurons-by-uncoupling-ran-gtpase-from-the-ran-binding-domain-3-of-ranbp2-and-identification-of-novel-mitochondrial-isoforms-of-ubiquitin-conjugating-enzyme-e2i-ubc9-and
#8
Hemangi Patil, Dosuk Yoon, Reshma Bhowmick, Yunfei Cai, Kyoung-In Cho, Paulo A Ferreira
The Ran-binding protein 2 (Ranbp2/Nup358) is a cytoplasmic and peripheral nucleoporin comprised of 4 Ran-GTP-binding domains (RBDs) that are interspersed among diverse structural domains with multifunctional activities. Our prior studies found that the RBD2 and RBD3 of Ranbp2 control mitochondrial motility independently of Ran-GTP-binding in cultured cells, whereas loss of Ran-GTP-binding to RBD2 and RBD3 are essential to support cone photoreceptor development and the survival of mature retinal pigment epithelium (RPE) in mice...
September 6, 2017: Small GTPases
https://www.readbyqxmd.com/read/28876998/meiosis-specific-localization-of-the-exocytic-rab-ypt2-in-fission-yeast
#9
Kazuki Imada, Taro Nakamura
Fission yeast Ypt2, an orthologue of the mammalian small GTPase Rab8, is responsible for post-Golgi membrane trafficking. During meiosis, Ypt2 localizes at the spindle pole body (SPB), where it regulates de novo biogenesis of the spore plasma membrane. Recruitment of Ypt2 to the SPB is dependent on its meiosis-specific GDP/GTP exchange factor (GEF), the SPB-resident protein Spo13. Here we have examined the SPB recruitment of Ypt2 by Spo13. The GEF activity of Spo13 was required, but not essential for recruitment...
September 6, 2017: Small GTPases
https://www.readbyqxmd.com/read/28696829/unraveling-a-model-of-tcl-rhoj-allosterism-using-tc10-reverse-chimeras
#10
Rebecca R Florke, Grace T Young, Michael J Hamann
In addition to the classical regulation of GTPase activity by effector proteins, investigating the variations in the amino acid sequence and structures of GTPases often provides insights into regulatory mechanisms that are more GTPase-specific. TCL/RhoJ is a Rho GTPase most closely related to Cdc42 and TC10; however, its nucleotide exchange activity is distinctly influenced by N-terminal amino acids 17-20 and the more distal amino acids 121-129. In this short study, we have further explored the differences between TCL and its homologue TC10 and show that its unique mode of allosteric regulation requires broader diversification of its amino acid sequence than previously appreciated...
July 11, 2017: Small GTPases
https://www.readbyqxmd.com/read/28696827/isolation-of-rab5-positive-endosomes-reveals-a-new-mitochondrial-degradation-pathway-utilized-by-bnip3-and-parkin
#11
Babette C Hammerling, Sarah E Shires, Leonardo J Leon, Melissa Q Cortez, Åsa B Gustafsson
Degradation of mitochondria is an important cellular quality control mechanism mediated by two distinct pathways: one involving Parkin-mediated ubiquitination and the other dependent on mitophagy receptors. It is known that mitochondria are degraded by the autophagy pathway; however, we recently reported that the small GTPase Rab5 and early endosomes also participate in Parkin-mediated mitochondrial clearance. Here, we have developed a protocol to isolate Rab5-positive vesicles from cells for proteomics analysis and provide additional data confirming that mitophagy regulators and mitochondrial proteins are present in these vesicles...
July 11, 2017: Small GTPases
https://www.readbyqxmd.com/read/28696821/multifaceted-role-of-smcr8-as-autophagy-regulator
#12
Jennifer Jung, Christian Behrends
Through autophagy intracellular material is engulfed by double membrane vesicles and delivered to lysosomes for degradation. This process requires Rab GTPases, Rab GAPs and Rab GEFs for proper membrane trafficking, since they control vesicle budding, targeting and fusion. Deregulation of autophagy contributes to several human diseases including cancer, bacterial or viral infections and neurodegeneration. This review focuses on the complex roles of the newly identified protein SMCR8 and its interaction partners during formation and maturation of autophagosomes as well as regulation of lysosomal function and further discusses their implication in neurodegenerative diseases such as ALS and FTD...
July 11, 2017: Small GTPases
https://www.readbyqxmd.com/read/28696820/viral-interactions-with-host-cell-rab-gtpases
#13
Paul Spearman
Viruses are obligate intracellular parasites that utilize cellular machinery for many aspects of their replication cycles. Enveloped viruses generally rely upon host vesicular trafficking machinery to direct their structural proteins and genomes to sites of virus replication, assembly, and budding. Rab GTPases have been implicated in the replication of many important viral pathogens infecting humans. This review provides a summary of virus-Rab protein interactions, with a particular focus on the role of Rab-related trafficking pathways on late events in the lifecycle of herpesviruses and of HIV-1...
July 11, 2017: Small GTPases
https://www.readbyqxmd.com/read/28692342/targeting-the-%C3%AE-4-%C3%AE-5-interface-of-ras-results-in-multiple-levels-of-inhibition
#14
Russell Spencer-Smith, Lie Li, Sheela Prasad, Akiko Koide, Shohei Koide, John P O'Bryan
Generation of RAS-targeted therapeutics has long been considered a "holy grail" in cancer research. However, a lack of binding pockets on the surface of RAS and its picomolar affinity for guanine nucleotides have made isolation of inhibitors particularly challenging. We recently described a monobody, termed NS1, that blocks RAS signaling and oncogenic transformation. NS1 binds to the α4-β6-α5 interface of H-RAS and K-RAS thus preventing RAS dimerization and nanoclustering, which in turn prevents RAS-stimulated dimerization and activation of RAF...
July 10, 2017: Small GTPases
https://www.readbyqxmd.com/read/28682649/targeting-ras-signaling-in-aml-ralb-is-a-small-gtpase-with-big-potential
#15
Emily J Pomeroy, Craig E Eckfeldt
Acute myeloid leukemia (AML) is a devastating malignancy for which novel treatment approaches are desperately needed. Ras signaling is an attractive therapeutic target for AML because a large proportion of AMLs have mutations in NRAS, KRAS, or genes that activate Ras signaling, and key Ras effectors are activated in virtually all AML patient samples. This has inspired efforts to develop Ras-targeted treatment strategies for AML. Due to the inherent difficulty and disappointing efficacy of targeting Ras proteins directly, many have focused on inhibiting Ras effector pathways...
July 6, 2017: Small GTPases
https://www.readbyqxmd.com/read/27715448/membrane-orientation-dynamics-of-lipid-modified-small-gtpases
#16
Priyanka Prakash, Alemayehu A Gorfe
Lipid-modified GTPases in the Ras superfamily that mediate a variety of cell signaling processes were thought to be passively anchored to membranes. However, an increasing number of recent studies are finding that membrane binding of these proteins is hardly a passive process, and it involves the soluble catalytic domain as well as the lipid anchor. The catalytic domain adopts multiple orientations on the membrane surface due to internal fluctuations that are modulated by activation status and mutations. Distinct orientation preferences among small GTPases likely lead to differential signaling outcomes, as downstream effectors can sense different orientations...
July 3, 2017: Small GTPases
https://www.readbyqxmd.com/read/27494456/c9orf72-is-a-gdp-gtp-exchange-factor-for-rab8-and-rab39-and-regulates-autophagy
#17
Camille Corbier, Chantal Sellier
Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS-FTD) are devastating neurodegenerative disease affecting motoneurons from the spinal chord and neurons from the frontal and temporal cortex, respectively. The most common genetic cause for ALS-FTD is an expansion of GGGGCC repeats within the first intron of the C9ORF72 gene. However, little is known on the function of C9ORF72. Recently, other and we found that C9ORF72 forms a stable complex with the SMCR8 and WDR41 proteins. This complex acts as a GDP/GTP exchange factor for the small RAB GTPases Rab8a and Rab39b...
July 3, 2017: Small GTPases
https://www.readbyqxmd.com/read/27470417/endocytosis-regulates-membrane-localization-and-function-of-the-fusogen-eff-1
#18
Ksenia Smurova, Benjamin Podbilewicz
Cell fusion is essential for sexual reproduction and formation of muscles, bones, and placenta. Two families of cell fusion proteins (Syncytins and FFs) have been identified in eukaryotes. Syncytins have been shown to form the giant syncytial trophoblasts in the placenta. The FFs are essential to fuse cells in the skin, reproductive, excretory, digestive and nervous systems in nematodes. EFF-1 (Epithelial Fusion Failure 1), a member of the FF family, is a type I membrane glycoprotein that is essential for most cell fusions in C...
July 3, 2017: Small GTPases
https://www.readbyqxmd.com/read/27458755/functional-implication-of-dclk1-and-dclk1-expressing-cells-in-cancer
#19
C Benedikt Westphalen, Michael Quante, Timothy C Wang
Doublecortin like kinase protein 1 (Dclk1) is a microtubule-associated protein with C-terminal serine/threonine kinase domain. Originally designated Doublecortin and CaM kinase-like 1 protein (Dcamkl1) or KIAA0369, Dclk1 was first described as a marker for radial glia cells in the context of microtubule polymerization and neuronal migration, possibly contributing to early neurogenesis. Additionally, Dclk1 was proposed as a marker of quiescent gastrointestinal and pancreatic stem cells, but in recent years has been recognized as a marker for tuft cells in the gastrointestinal tract...
July 3, 2017: Small GTPases
https://www.readbyqxmd.com/read/27442895/rac1-in-human-diseases-the-therapeutic-potential-of-targeting-rac1-signaling-regulatory-mechanisms
#20
Hadir Marei, Angeliki Malliri
Abnormal Rac1 signaling is linked to a number of debilitating human diseases, including cancer, cardiovascular diseases and neurodegenerative disorders. As such, Rac1 represents an attractive therapeutic target, yet the search for effective Rac1 inhibitors is still underway. Given the adverse effects associated with Rac1 signaling perturbation, cells have evolved several mechanisms to ensure the tight regulation of Rac1 signaling. Thus, characterizing these mechanisms can provide invaluable information regarding major cellular events that lead to aberrant Rac1 signaling...
July 3, 2017: Small GTPases
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