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Small GTPases

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https://www.readbyqxmd.com/read/28696829/unraveling-a-model-of-tcl-rhoj-allosterism-using-tc10-reverse-chimeras
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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/28657426/oncogenic-ect2-signaling-regulates-rrna-synthesis-in-nsclc
#7
Verline Justilien, Kayla C Lewis, Nicole R Murray, Alan P Fields
The Rho GTPase family members Rac1, Cdc42 and RhoA play key contributory roles in the transformed phenotype of human cancers. Epithelial Cell Transforming Sequence 2 (Ect2), a guanine nucleotide exchange factor (GEF) for these Rho GTPases, has also been implicated in a variety of human cancers. We have shown that Ect2 is frequently overexpressed in both major forms of non-small cell lung cancer (NSCLC), lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC), which together make up approximately 70% of all lung cancer diagnoses...
June 28, 2017: Small GTPases
https://www.readbyqxmd.com/read/28656876/co-dependency-between-kras-addiction-and-arhgef2-promotes-an-adaptive-escape-from-mapk-pathway-inhibition
#8
Oliver A Kent, Maria-Jose Sandi, Robert Rottapel
Oncogenic KRAS engages multiple effector pathways including the MAPK cascade to promote proliferation and survival of pancreatic cancer cells. KRAS-transformed cancer cells exhibit oncogene addiction to sustained activity of RAS for maintenance of malignant phenotypes. Previously, we have shown an essential role for the RHO guanine exchange factor ARHGEF2 for growth and survival of RAS-transformed pancreatic tumors. Here, we have determined that pancreatic cancer cells demonstrating KRAS addiction are significantly dependent on expression of ARHGEF2...
June 28, 2017: Small GTPases
https://www.readbyqxmd.com/read/28650718/subversion-of-rab5-regulated-autophagy-by-the-intracellular-pathogen-ehrlichia-chaffeensis
#9
Yasuko Rikihisa
Intracellular pathogens often exploit RAB functions to establish a safe haven in which to survive and proliferate. Ehrlichia chaffeensis, an obligatory intracellular bacterium, resides in specialized membrane-bound inclusions that have early endosome-like characteristics, e.g., resident RAB5 GTPase and RAB5 effectors, including VPS34 (the catalytic subunit of class III phosphatidylinositol 3-kinase), but the inclusions lack late endosomal or lysosomal markers. Within inclusions, Ehrlichia obtains host-derived nutrients by inducing RAB5-regulated autophagy using Ehrlichia translocated factor-1 deployed by its type IV secretion system...
June 26, 2017: Small GTPases
https://www.readbyqxmd.com/read/28650698/the-rock-isoforms-differentially-regulate-the-morphological-characteristics-of-carcinoma-cells
#10
Rachel J Jerrell, Mitchell J Leih, Aron Parekh
Rho-associated kinase (ROCK) activity drives cell migration via actomyosin contractility. During invasion, individual cancer cells can transition between two modes of migration, mesenchymal and amoeboid. Changes in ROCK activity can cause a switch between these migration phenotypes which are defined by distinct morphologies. However, recent studies have shown that the ROCK isoforms are not functionally redundant as previously thought. Therefore, it is unclear whether the ROCK isoforms play different roles in regulating migration phenotypes...
June 26, 2017: Small GTPases
https://www.readbyqxmd.com/read/28644721/small-gtpases-in-plant-biotic-interactions
#11
Claudio Rivero, Soledad Traubenik, María Eugenia Zanetti, Flavio Antonio Blanco
The superfamily of small monomeric GTPases originated in a common ancestor of eukaryotic multicellular organisms and, since then, it has evolved independently in each lineage to cope with the environmental challenges imposed by their different life styles. Members of the small GTPase family function in the control of vesicle trafficking, cytoskeleton rearrangements and signaling during crucial biological processes, such as cell growth and responses to environmental cues. In this review, we discuss the emerging roles of these small GTPases in the pathogenic and symbiotic interactions established by plants with microorganisms present in their nearest environment, in which membrane trafficking is crucial along the different steps of the interaction, from recognition and signal transduction to nutrient exchange...
June 23, 2017: Small GTPases
https://www.readbyqxmd.com/read/28644713/an-unstructured-loop-that-is-critical-for-interactions-of-the-stalk-domain-of-drp1-with-saturated-phosphatidic-acid
#12
Yoshihiro Adachi, Miho Iijima, Hiromi Sesaki
Dynamin-related protein 1 (Drp1) is a dynamin superfamily GTPase, which drives membrane constriction during mitochondrial division. To mediate mitochondrial division, Drp1 is recruited to the mitochondrial outer membrane and is assembled into the division machinery. We previously showed that Drp1 interacts with phosphatidic acid (PA) and saturated phospholipids in the mitochondrial membrane, and this interaction restrains Drp1 in initiating the constriction of mitochondria. Here, we show that the role of saturated acyl chains of phospholipids is independent of their contribution to the membrane curvature or lipid packing suggesting their direct interaction with Drp1...
June 23, 2017: Small GTPases
https://www.readbyqxmd.com/read/28641070/elmo-proteins-transduce-g-protein-coupled-receptor-signal-to-control-reorganization-of-actin-cytoskeleton-in-chemotaxis-of-eukaryotic-cells
#13
Xuehua Xu, Tian Jin
Chemotaxis, which is chemoattractant-guided directional cell migration, plays major roles in recruitment of neutrophils, the metastasis of cancer cells, and the development of the model organism Dictyostelium discoideum. These cells share remarkable similarities in the signaling pathways by which they control chemotaxis. They all use a G protein-coupled receptor (GPCR)-mediated signal transduction pathway to sense the chemotactic gradient to guide cell migration. Diverse chemokines activate Rac through conserved GPCR signaling pathways...
June 22, 2017: Small GTPases
https://www.readbyqxmd.com/read/28641032/targeting-rho-gtpase-effector-p21-activated-kinase-4-pak4-suppresses-p-bad-microrna-drug-resistance-axis-leading-to-inhibition-of-pancreatic-ductal-adenocarcinoma-proliferation
#14
Ramzi M Mohammad, Yiwei Li, Irfana Muqbil, Amro Aboukameel, William Senapedis, Erkan Baloglu, Yosef Landesman, Philip A Philip, Asfar S Azmi
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and therapy resistant malignancy. Mutant K-Ras, found in >90% of refractory PDAC, acts as a molecular switch activating Rho GTPase signaling that in turn promotes a plethora of pro-survival molecules and oncogenic microRNAs. We investigated the impact of Rho GTPase effector protein p21 activated kinase 4 (PAK4) inhibition on pro-survival p-Bad and oncogenic miRNA signaling. We demonstrate that the dual NAMPT and PAK4 modulators (KPT-9274 and KPT-9307) inhibit PDAC cell proliferation through down-regulation of Bad phosphorylation and up-regulation tumor suppressive miRNAs (miR-145, let-7c, let-7d, miR-34c, miR320 and miR-100)...
June 22, 2017: Small GTPases
https://www.readbyqxmd.com/read/28636467/normal-epithelial-cells-trigger-epha2-dependent-rasv12-cell-repulsion-at-the-single-cell-level
#15
William Hill, Catherine Hogan
Epithelial cells expressing oncogenic Ras (RasV12) are detected by normal neighbors and are often extruded from tissues. We recently demonstrated that differential EphA2 signaling drives the segregation of mutant cells from normal monolayers via cell repulsion and increased RasV12 cell contractility. EphA2 signaling on RasV12 cells is triggered by ephrin-A ligands presented by normal cells. Here, we show that normal epithelial cells trigger the repulsion and enhanced contractility of Ras-transformed epithelial cells at the single cell level...
June 21, 2017: Small GTPases
https://www.readbyqxmd.com/read/28632996/taking-control-hijacking-of-rab-gtpases-by-intracellular-bacterial-pathogens
#16
Stefania Spanò, Jorge E Galán
Intracellular bacterial pathogens survive and replicate within specialized eukaryotic cell organelles. To establish their intracellular niches these pathogens have adopted sophisticated strategies to control intracellular membrane trafficking. Since Rab-family GTPases are critical regulators of endocytic and secretory membrane trafficking events, many intracellular pathogens have evolved specific mechanisms to modulate or hijack Rab GTPases dynamics and trafficking functions. One such strategy is the delivery of bacterial effectors through specialized machines to specifically target Rab GTPases...
June 20, 2017: Small GTPases
https://www.readbyqxmd.com/read/28632994/role-of-the-small-gtpase-rap1-in-signal-transduction-cell-dynamics-and-bacterial-infection
#17
Hubert Hilbi, Arjan Kortholt
Rap1 belongs to the Ras family of small GTPases, which are involved in a multitude of cellular signal transduction pathways and have extensively been linked to cancer biogenesis and metastasis. The small GTPase is activated in response to various extracellular and intracellular cues. Rap1 has conserved functions in Dictyostelium discoideum amoeba and mammalian cells, which are important for cell polarity, substrate and cell-cell adhesion and other processes that involve the regulation of cytoskeletal dynamics...
June 20, 2017: Small GTPases
https://www.readbyqxmd.com/read/28632992/targeting-the-rhogtpase-rock-pathway-for-the-treatment-of-vhl-hif-pathway-driven-cancers
#18
Jordan M Thompson, Jaime Landman, Olga V Razorenova
The loss of the von Hippel-Lindau (VHL) tumor-suppressor is a major driver of Clear Cell Renal Cell Carcinoma (CC-RCC) resulting in the stabilization and overactivation of hypoxia inducible factors (HIFs). ROCK 1 is a well-known protein serine/threonine kinase which is recognized as having a role in cancer including alterations in cell motility, metastasis and angiogenesis. As a function of the later effect, we recently investigated and identified a synthetic lethal interaction between VHL loss and ROCK1 inhibition in CC-RCC that is dependent on HIF overactivation...
June 20, 2017: Small GTPases
https://www.readbyqxmd.com/read/28632484/rab-gtpases-and-their-interacting-protein-partners-structural-insights-into-rab-functional-diversity
#19
Olena Pylypenko, Hussein Hammich, I-Mei Yu, Anne Houdusse
Rab molecular switches are key players in defining membrane identity and regulating intracellular trafficking events in eukaryotic cells. In spite of their global structural similarity, Rab-family members acquired particular features that allow them to perform specific cellular functions. The overall fold and local sequence conservations enable them to utilize a common machinery for prenylation and recycling; while individual Rab structural differences determine interactions with specific partners such as GEFs, GAPs and effector proteins...
June 20, 2017: Small GTPases
https://www.readbyqxmd.com/read/28628388/coordination-of-ampa-receptor-trafficking-by-rab-gtpases
#20
Angelika Hausser, Katalin Schlett
Synaptic connections in the brain are continuously weakened or strengthened in response to changes in neuronal activity. This process, known as synaptic plasticity, is the cellular basis for learning and memory, and is thought to be altered in several neuronal disorders. An important aspect of synaptic plasticity is the tightly controlled trafficking and synaptic targeting of the AMPA-type glutamate receptors, which are the major mediators of fast excitatory transmission in the brain. This review addresses the role of Rab GTPases in AMPA receptor trafficking in neurons under basal conditions and during activity-induced synaptic plasticity, especially during long-term potentiation (LTP) and long-term depression (LTD)...
June 19, 2017: Small GTPases
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