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small GTPase Ras

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https://www.readbyqxmd.com/read/30315251/cid1067700-a-late-endosome-gtpase-rab7-receptor-antagonist-attenuates-brain-atrophy-improves-neurologic-deficits-and-inhibits-reactive-astrogliosis-in-rat-ischemic-stroke
#1
Yuan Qin, Yang He, Yong-Ming Zhu, Min Li, Yong Ni, Jin Liu, Hui-Ling Zhang
Increasing evidence suggests that Ras-related in brain 7 (Rab7), an endosome-localized small GTPase contributes to cerebral ischemic brain injury. In the present study, we investigated the role of Rab7 in ischemic stroke-induced formation of astrogliosis and glial scar. Rats were subjected to transient middle cerebral artery occlusion (tMCAO); the rats were injected with the Rab7 receptor antagonist CID1067700 (CID). Primary astrocytes were subjected to an oxygen and glucose deprivation and reoxygenation (OGD/Re) procedure; CID was added to the cell culture media...
October 12, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/30300344/ran-gtpase-an-eukaryotic-gene-novelty-is-involved-in-amphioxus-mitosis
#2
Ugo Coppola, Filomena Caccavale, Marta Scelzo, Nicholas D Holland, Filomena Ristoratore, Salvatore D'Aniello
Ran (ras-related nuclear protein) is a small GTPase belonging to the RAS superfamily that is specialized in nuclear trafficking. Through different accessory proteins, Ran plays key roles in several processes including nuclear import-export, mitotic progression and spindle assembly. Consequently, Ran dysfunction has been linked to several human pathologies. This work illustrates the high degree of amino acid conservation of Ran orthologues across evolution, reflected in its conserved role in nuclear trafficking...
2018: PloS One
https://www.readbyqxmd.com/read/30288957/filamin-a-as-a-balance-between-erk-smad-activities-during-cardiac-valve-development
#3
Katelynn Toomer, Kimberly Sauls, Diana Fulmer, Lilong Guo, Kelsey Moore, Janiece Glover, Rebecca Stairley, Joyce Bischoff, Robert A Levine, Russell A Norris
Mitral valve prolapse (MVP) affects 2.4% of the population and has poorly understood etiology. Recent genetic studies have begun to unravel the complexities of MVP and through these efforts, mutations in the FLNA (Filamin-A) gene were identified as disease causing. Our in vivo and in vitro studies have validated these genetic findings and have revealed FLNA as a central regulator of valve morphogenesis. The mechanisms by which FLNA mutations result in myxomatous mitral valve disease are currently unknown, but may involve proteins previously associated with mutated regions of the FLNA protein, such as the small GTPase signaling protein, R-Ras...
October 5, 2018: Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology
https://www.readbyqxmd.com/read/30287508/ras-variant-signalling
#4
REVIEW
Stephanie P Mo, Judy M Coulson, Ian A Prior
RAS proteins are small GTPases that regulate signalling networks that control cellular proliferation and survival. They are frequently mutated in cancer and a commonly occurring group of developmental disorders called RASopathies. We discuss recent findings describing how RAS isoforms and different activating mutations differentially contribute to normal and disease-associated biology and the mechanisms that have been proposed to underpin this.
October 3, 2018: Biochemical Society Transactions
https://www.readbyqxmd.com/read/30282804/structural-basis-of-inactivation-of-ras-and-rap1-small-gtpases-by-ras-rap1-specific-endopeptidase-from-the-sepsis-causing-pathogen-vibrio-vulnificus
#5
Song Yee Jang, Jungwon Hwang, Byoung Sik Kim, Eun-Young Lee, Byung-Ha Oh, Myung Hee Kim
Multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are secreted by Gram-negative bacteria and function as primary virulence-promoting macromolecules that deliver multiple cytopathic and cytotoxic effector domains into the host cytoplasm. Among these effectors, Ras/Rap1-specific endopeptidase (RRSP) catalyzes the sequence-specific cleavage of the switch I region of the cellular substrates Ras and Rap1 that are crucial for host innate immune defenses during infection. To dissect the molecular basis underpinning RRSP-mediated substrate inactivation, we determined the crystal structure of an RRSP from the sepsis-causing bacterial pathogen Vibrio vulnificus ( Vv RRSP)...
October 3, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/30279169/the-bacterial-ras-rap1-site-specific-endopeptidase-rrsp-cleaves-ras-through-an-atypical-mechanism-to-disrupt-ras-erk-signaling
#6
Marco Biancucci, George Minasov, Avik Banerjee, Alfa Herrera, Patrick J Woida, Matthew B Kieffer, Lakshman Bindu, Maria Abreu-Blanco, Wayne F Anderson, Vadim Gaponenko, Andrew G Stephen, Matthew Holderfield, Karla J F Satchell
The Ras-extracellular signal-regulated kinase pathway is critical for controlling cell proliferation, and its aberrant activation drives the growth of various cancers. Because many pathogens produce toxins that inhibit Ras activity, efforts to develop effective Ras inhibitors to treat cancer could be informed by studies of Ras inhibition by pathogens. Vibrio vulnificus causes fatal infections in a manner that depends on multifunctional autoprocessing repeats-in-toxin, a toxin that releases bacterial effector domains into host cells...
October 2, 2018: Science Signaling
https://www.readbyqxmd.com/read/30271600/rasal3-preferentially-stimulates-gtp-hydrolysis-of-the-rho-family-small-gtpase-rac2
#7
Yoonjae Shin, Yong Woo Kim, Hyemin Kim, Nakyoung Shin, Tae Sung Kim, Taeg Kyu Kwon, Jang Hyun Choi, Jong-Soo Chang
Members of the Ras superfamily of small G-proteins serve as molecular switches of intracellular signaling pathways. Rac2 is a Rho subfamily GTPase switch that is specifically expressed in hematopoietic cells and regulates AKT activation in cell signaling. Ras activating protein-like 3 (RASAL3) is the recently identified Ras GTPase activating protein (GAP) that is also specifically expressed in hematopoietic cells and stimulates p21ras GTPase activity. The restricted expression of both Rac2 and RASAL3 suggests that they may serve critical roles in hematopoietic cell signaling...
September 2018: Biomedical Reports
https://www.readbyqxmd.com/read/30261690/ovarian-tumor-microenvironment-signaling-convergence-on-the-rac1-gtpase
#8
REVIEW
Laurie G Hudson, Jennifer M Gillette, Huining Kang, Melanie R Rivera, Angela Wandinger-Ness
The tumor microenvironment for epithelial ovarian cancer is complex and rich in bioactive molecules that modulate cell-cell interactions and stimulate numerous signal transduction cascades. These signals ultimately modulate all aspects of tumor behavior including progression, metastasis and therapeutic response. Many of the signaling pathways converge on the small GTPase Ras-related C3 botulinum toxin substrate (Rac)1. In addition to regulating actin cytoskeleton remodeling necessary for tumor cell adhesion, migration and invasion, Rac1 through its downstream effectors, regulates cancer cell survival, tumor angiogenesis, phenotypic plasticity, quiescence, and resistance to therapeutics...
September 27, 2018: Cancers
https://www.readbyqxmd.com/read/30257933/ras-dependent-cell-fate-decisions-are-reinforced-by-the-rap-1-small-gtpase-in-caenorhabditis-elegans
#9
Neal R Rasmussen, Daniel J Dickinson, David J Reiner
The notoriety of the small GTPase Ras as the most mutated oncoprotein has led to a well-characterized signaling network largely conserved across metazoans. Yet the role of its close relative Rap1 (Ras Proximal), which shares 100% identity between their core effector binding sequences, remains unclear. A long-standing controversy in the field is whether Rap1 also functions to activate the canonical Ras effector, the S/T kinase Raf. We used the developmentally simpler Caenorhabditis elegans , which lacks the extensive paralog redundancy of vertebrates, to examine the role of RAP-1 in two distinct LET-60/Ras-dependent cell fate patterning events: induction of 1° vulval precursor cell (VPC) fate and of the excretory duct cell...
September 26, 2018: Genetics
https://www.readbyqxmd.com/read/30241678/structural-and-biophysical-characterization-of-rab5a-from-leishmania-donovani
#10
Diva Maheshwari, Rahul Yadav, Ruchir Rastogi, Anupam Jain, Sarita Tripathi, Amitabha Mukhopadhyay, Ashish Arora
Leishmania donovani possess two isoforms of Rab5 (Rab5a and Rab5b), which are involved in fluid phase and receptor-mediated endocytosis, respectively. We have characterized the solution structure and dynamics of a stabilized truncated LdRab5a mutant. For the purpose of NMR structure determination, protein stability was enhanced by systematically introducing various deletions and mutations. Deletion of hypervariable C-terminal and the 20 residues LdRab5a specific insert slightly enhanced the stability, which was further improved by C107S mutation...
October 2, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/30237463/o-glcnacylation-on-rab3a-attenuates-its-effects-on-mitochondrial-oxidative-phosphorylation-and-metastasis-in-hepatocellular-carcinoma
#11
Weicheng Wu, Xixi Zheng, Jing Wang, Tianxiao Yang, Wenjuan Dai, Shushu Song, Lan Fang, Yilin Wang, Jianxin Gu
Rab3A is a small Ras-like GTPase critical for membrane traffic. Although the functions of Rab3A have been reported in several cancers, the roles of Rab3A in hepatocellular carcinoma (HCC) have never been determined. To investigate the potential roles of Rab3A in HCC progression, we first determined Rab3A levels in HCC tissues and observed upregulated mRNA and protein levels of Rab3A in most tumor tissues. However, in vitro data showed that decreasing Rab3A in most HCC cell lines conferred no significant effects and overexpressing Rab3A in PLC/PRF/5 cells even inhibited migration and invasion...
September 20, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/30233567/a-small-gtpase-rhoa-inhibits-bacterial-infection-through-integrin-mediated-phagocytosis-in-invertebrates
#12
Ji-Dong Xu, Meng-Qi Diao, Guo-Juan Niu, Xian-Wei Wang, Xiao-Fan Zhao, Jin-Xing Wang
The Ras GTPase superfamily, including more than 100 members, plays a vital role in a number of cellular processes, such as cytoskeleton recombination, gene expression, and signaling pathway regulation. Some members of the superfamily participate in innate immunity in animals. However, there have been few studies of RhoA on this aspect. In the present study, we identified a RhoA GTPase in the shrimp Marsupenaeus japonicus and named it Mj RhoA. Expression of MjRhoA was significantly upregulated in hemocytes and heart of shrimp challenged with Vibrio anguillarum ...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/30228185/the-small-gtpase-rab28-is-required-for-phagocytosis-of-cone-outer-segments-by-the-murine-retinal-pigmented-epithelium
#13
Guoxin Ying, Karsten Boldt, Marius Ueffing, Cecilia D Gerstner, Jeanne M Frederick, Wolfgang Baehr
Rab28, a member of the RAS oncogene family is a ubiquitous, farnesylated, small GTPase of unknown function present in photoreceptors and the retinal pigmented epithelium (RPE). Nonsense mutations of the human RAB28 gene cause recessive cone-rod dystrophy 18 (CRD18), characterized by macular hyperpigmentation, progressive loss of visual acuity, RPE atrophy and severely attenuated cone and rod electroretinography (ERG) responses. In an attempt to elucidate the disease-causing mechanism, we generated Rab28-/- mice by deleting exon 3 and truncating Rab28 after exon 2...
September 18, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/30221743/identification-of-key-genes-and-associated-pathways-in-kit-pdgfra-wild%C3%A2-type-gastrointestinal-stromal-tumors-through-bioinformatics-analysis
#14
Wen-Jie Wang, Hong-Tao Li, Jian-Ping Yu, Yu-Min Li, Xiao-Peng Han, Peng Chen, Wen-Wen Yu, Wei-Kai Chen, Zuo-Yi Jiao, Hong-Bin Liu
Gastrointestinal stromal tumors (GISTs) are the most common type of mesenchymal tumor in the gastrointestinal tract. The present study aimed to identify the potential candidate biomarkers that may be involved in the pathogenesis and progression of v‑kit Hardy‑Zuckerman 4 feline sarcoma viral oncogene homolog (KIT)/platelet‑derived growth factor receptor α (PDGFRA) wild‑type GISTs. A joint bioinformatics analysis was performed to identify the differentially expressed genes (DEGs) in wild‑type GIST samples compared with KIT/PDGFRA mutant GIST samples...
September 5, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/30191377/rab23-promotes-hepatocellular-carcinoma-cell-migration-via-rac1-tgf-%C3%AE-signaling
#15
Li Zhang, Bingqiang Zhang, Wenxian You, Pan Li, Youlin Kuang
Rab23 is a member of Ras-related small GTPase family, which plays a critical role in the progression of wide range of tumors. However, its biological function in hepatocellular carcinoma still remains unclear. Here, we investigated the effects of Rab23 on proliferation and migration in hepatocellular carcinoma cell and its potential mechanisms. We found over-expression of Rab23 promoted the Hep3B hepatocellular carcinoma cell migration, which could be reversed by Rab23 silencing. Rab23 induced Rac1 activation and followed progression of epithelial-mesenchymal transition (EMT) along with upregulation of N-cadherin, snail as well as vimentin and downregulation of E-cadherin via upregulating Transforming Growth Factor-β (TGF-β)...
September 6, 2018: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/30158598/ras-dva-small-gtpases-lost-during-evolution-of-amniotes-regulate-regeneration-in-anamniotes
#16
Anastasiya S Ivanova, Daria D Korotkova, Galina V Ermakova, Natalia Yu Martynova, Andrey G Zaraisky, Maria B Tereshina
In contrast to amniotes (reptiles, birds and mammals), anamniotes (fishes and amphibians) can effectively regenerate body appendages such as fins, limbs and tails. Why such a useful capability was progressively lost in amniotes remains unknown. As we have hypothesized recently, one of the reasons for this could be loss of some genes regulating the regeneration in evolution of amniotes. Here, we demonstrate the validity of this hypothesis by showing that genes of small GTPases Ras-dva1 and Ras-dva2, that had been lost in a stepwise manner during evolution of amniotes and disappeared completely in placental mammals, are important for regeneration in anamniotes...
August 29, 2018: Scientific Reports
https://www.readbyqxmd.com/read/30158581/the-expression-and-function-of-rasal2-in-renal-cell-carcinoma-angiogenesis
#17
Ke Hui, Yangyang Yue, Shiqi Wu, Yanan Gu, Bing Guan, Xinyang Wang, Jer-Tsong Hsieh, Luke S Chang, Dalin He, Kaijie Wu
Patients with renal cell carcinoma (RCC) often develop resistance to antivascular drugs and eventually succumb to disease. However, the underlying molecular mechanism remains poorly understood. In this study, we demonstrated that RASAL2, a RAS GTPase-activating protein, played a tumor-suppressive role in RCC by targeting tumor angiogenesis. Firstly, we showed that RASAL2 was frequently epigenetically silenced in RCC, and its loss was negatively correlated with overall survival of RCC patients. Furthermore, we discovered that RASAL2 could inhibit RCC angiogenesis in vitro and in vivo...
August 29, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/30113035/-mutations-in-the-effector-domain-of-rhov-gtpase-impair-its-binding-to-pak1-protein-kinase
#18
I V Korobko, M V Shepelev
Atypical RhoV GTPase (Chp/Wrch-2) is a member of the human Rho GTPase family, which belongs to the superfamily of Ras-related small GTPases. The biological functions of RhoV, regulation of its activity, and mechanisms of its action remain largely unexplored. Rho GTPases regulate a wide range of cellular processes by interacting with protein targets called effectors. Several putative RhoV effectors have been identified, including protein kinases of the Pak (p21-activated kinase) family: Pak1, Pak2, Pak4, and Pak6...
July 2018: Molekuliarnaia Biologiia
https://www.readbyqxmd.com/read/30104724/ras-nucleotide-cycling-underlies-the-shp2-phosphatase-dependence-of-mutant-braf-nf1-and-ras-driven-cancers
#19
Robert J Nichols, Franziska Haderk, Carlos Stahlhut, Christopher J Schulze, Golzar Hemmati, David Wildes, Christos Tzitzilonis, Kasia Mordec, Abby Marquez, Jason Romero, Tientien Hsieh, Aubhishek Zaman, Victor Olivas, Caroline McCoach, Collin M Blakely, Zhengping Wang, Gert Kiss, Elena S Koltun, Adrian L Gill, Mallika Singh, Mark A Goldsmith, Jacqueline A M Smith, Trever G Bivona
Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E -driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRASG12C )...
September 2018: Nature Cell Biology
https://www.readbyqxmd.com/read/30097772/gtpases-rac1-and-ras-signaling-from-endosomes
#20
Francesc Tebar, Carlos Enrich, Carles Rentero, Thomas Grewal
The endocytic compartment is not only the functional continuity of the plasma membrane but consists of a diverse collection of intracellular heterogeneous complex structures that transport, amplify, sustain, and/or sort signaling molecules. Over the years, it has become evident that early, late, and recycling endosomes represent an interconnected vesicular-tubular network able to form signaling platforms that dynamically and efficiently translate extracellular signals into biological outcome. Cell activation, differentiation, migration, death, and survival are some of the endpoints of endosomal signaling...
2018: Progress in Molecular and Subcellular Biology
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