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small GTPase Ras

Susan M Hiatt, Matthew B Neu, Ryne C Ramaker, Andrew A Hardigan, Jeremy W Prokop, Miroslava Hancarova, Darina Prchalova, Marketa Havlovicova, Jan Prchal, Viktor Stranecky, Dwight K C Yim, Zöe Powis, Boris Keren, Caroline Nava, Cyril Mignot, Marlene Rio, Anya Revah-Politi, Parisa Hemati, Nicholas Stong, Alejandro D Iglesias, Sharon F Suchy, Rebecca Willaert, Ingrid M Wentzensen, Patricia G Wheeler, Lauren Brick, Mariya Kozenko, Anna C E Hurst, James W Wheless, Yves Lacassie, Richard M Myers, Gregory S Barsh, Zdenek Sedlacek, Gregory M Cooper
Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase...
November 30, 2018: PLoS Genetics
Tuomo Ketomäki, Maria Vähätupa, Ulrike May, Toini Pemmari, Ella Ruikka, Jussi Hietamo, Pirkka Kaipiainen, Harlan Barker, Seppo Parkkila, Hannele Uusitalo-Järvinen, Tero A H Järvinen
Wounds close by keratinocytes migrating from the edge of the wound and re-epithelializing the epidermis. It has been proposed that the major stimuli for wound closure are blood-derived growth factors, chemokines, and cytokines. The small GTPase R-Ras, a known integrin activator, also regulates vascular permeability during angiogenesis, and blood vessels lacking R-Ras leak plasma proteins constantly. We explored whether the access to blood-derived proteins influences skin wound healing in R-Ras knockout (KO) mice...
November 29, 2018: Experimental Dermatology
Javad Alizadeh, Shahla Shojaei, Simone da Silva Rosa, Adel Rezaei Moghadam, Amir A Zeki, Mohammad Hashemi, Marek J Los, Joseph W Gordon, Saeid Ghavami
The Rho GTPase family belongs to the Ras superfamily and includes approximately 20 members in humans. Rho GTPases are important in the regulation of diverse cellular functions, including cytoskeletal dynamics, cell motility, cell polarity, axonal guidance, vesicular trafficking, and cell cycle control. Changes in Rho GTPase signaling play an essential regulatory role in many pathological conditions, such as cancer, central nervous system diseases, and immune system-dependent diseases. The posttranslational modification of Rho GTPases (i...
November 11, 2018: Journal of Visualized Experiments: JoVE
Ze-Yi Zheng, Jing Li, Fuhai Li, Yanqiao Zhu, Kemi Cui, Stephen T Wong, Eric C Chang, Yi-Hua Liao
Ras GTPases are powerful drivers for tumorigenesis, but directly targeting Ras for treating cancer remains challenging. The growth and transforming activity of the aggressive basal-like breast cancer (BLBC) are driven by N-Ras. To target N-Ras in BLBC, this study screened existing pharmacologically active compounds for the new ability to induce N-Ras degradation, which led to the identification of flunarizine (FLN), previously approved for treating migraine and epilepsy. The FLN-induced N-Ras degradation was not affected by a 26S-proteasome inhibitor...
November 16, 2018: Scientific Reports
Ming Huang, Yinsheng Wang
Development of tamoxifen resistance remains a tremendous challenge for the treatment of estrogen-receptor (ER)-positive breast cancer. Small GTPases of the Ras superfamily play crucial roles in intracellular trafficking and cell signaling, and aberrant small-GTPase signaling is implicated in many types of cancer. In this study, we employed a targeted, quantitative proteomic approach that relies on stable-isotope labeling by amino acids in cell culture (SILAC), gel fractionation, and scheduled multiple-reaction-monitoring (MRM) analysis, to assess the differential expression of small GTPases in MCF-7 and the paired tamoxifen-resistant breast cancer cells...
November 30, 2018: Analytical Chemistry
Stella Liong, Gillian Barker, Martha Lappas
Heightened placental inflammation and dysfunction are commonly associated in pregnant obese women compared to their pregnant lean counterparts. The small GTPase superfamily members known as the rat sarcoma viral oncogene homolog (Ras) proteins, in particular, the K-Ras and H-Ras isoforms, have been implicated to regulate inflammation. The aims were to determine the placental Ras expression and activity with maternal obesity and its role in regulating placental inflammation. Human placenta was obtained at term Caesarean section from lean and obese pregnant women to determine the effect of maternal obesity on Ras protein expression and activity...
2018: Mediators of Inflammation
Akil A Puckerin, Donald D Chang, Zunaira Shuja, Papiya Choudhury, Joachim Scholz, Henry M Colecraft
Genetically encoded inhibitors for voltage-dependent Ca2+ (CaV ) channels (GECCIs) are useful research tools and potential therapeutics. Rad/Rem/Rem2/Gem (RGK) proteins are Ras-like G proteins that potently inhibit high voltage-activated (HVA) Ca2+ (CaV 1/CaV 2 family) channels, but their nonselectivity limits their potential applications. We hypothesized that nonselectivity of RGK inhibition derives from their binding to auxiliary CaV β-subunits. To investigate latent CaV β-independent components of inhibition, we coexpressed each RGK individually with CaV 1 (CaV 1...
November 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Eduardo Garrido, Juan Lázaro, Montserrat Jaumot, Neus Agell, Jaime Rubio-Martinez
K-Ras, one of the most common small GTPases of the cell, still presents many riddles, despite the intense efforts to unveil its mysteries. Such is the case of its interaction with Calmodulin, a small acidic protein known for its role as a calcium ion sensor. Although the interaction between these two proteins and its biological implications have been widely studied, a model of their interaction has not been performed. In the present work we analyse this intriguing interaction by computational means. To do so, both conventional molecular dynamics and scaled molecular dynamics have been used...
October 2018: PLoS Computational Biology
Tony G Walsh, Yong Li, Andreas Wersäll, Alastair W Poole
Our understanding of fundamental biological processes within platelets is continually evolving. A critical feature of platelet biology relates to the intricate uptake, packaging and release of bioactive cargo from storage vesicles, essential in mediating a range of classical (haemostasis/thrombosis) and non-classical (regeneration/inflammation/metastasis) roles platelets assume. Pivotal to the molecular control of these vesicle trafficking events are the small GTPases of the Ras superfamily, which function as spatially distinct, molecular switches controlling essential cellular processes...
October 26, 2018: Platelets
Kent Sakai, Shuichi Nagashima, Tetsuji Wakabayashi, Bayasgalan Tumenbayar, Hiroko Hayakawa, Morisada Hayakawa, Tadayoshi Karasawa, Ken Ohashi, Hisataka Yamazaki, Akihito Takei, Shoko Takei, Daisuke Yamamuro, Manabu Takahashi, Hiroaki Yagyu, Jun-Ichi Osuga, Masafumi Takahashi, Shin-Ichi Tominaga, Shun Ishibashi
Objective- Inhibition of HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is atheroprotective primarily by decreasing plasma LDL (low-density lipoprotein)-cholesterol. However, it is unknown whether inhibition of HMGCR in myeloid cells contributes to this atheroprotection. We sought to determine the role of myeloid HMGCR in the development of atherosclerosis. Approach and Results- We generated mice with genetically reduced Hmgcr in myeloid cells ( Hmgcr m- /m - ) using LysM (Cre) and compared various functions of their macrophages to those of Hmgcr fl/fl control mice...
November 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Wenjing Xu, Erika S Wittchen, Samantha L Hoopes, Lucia Stefanini, Keith Burridge, Kathleen M Caron
Objective- Maintenance of lymphatic permeability is essential for normal lymphatic function during adulthood, but the precise signaling pathways that control lymphatic junctions during development are not fully elucidated. The Gs -coupled AM (adrenomedullin) signaling pathway is required for embryonic lymphangiogenesis and the maintenance of lymphatic junctions during adulthood. Thus, we sought to elucidate the downstream effectors mediating junctional stabilization in lymphatic endothelial cells. Approach and Results- We knocked-down both Rap1A and Rap1B isoforms in human neonatal dermal lymphatic cells (human lymphatic endothelial cells) and genetically deleted the mRap1 gene in lymphatic endothelial cells by producing 2 independent, conditional Rap1a/b knockout mouse lines...
October 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Matthew C Stout, Paul M Campbell
RAS is the most commonly mutated driver of tumorigenesis, seen in about 30% of all cancer cases. There is a subset of tumors termed RAS-driven cancers in which RAS mutation or overactivation is evident, including as much as 95% in pancreatic and 50% in colon cancer. RAS is a family of small membrane bound GTPases that act as a signaling node to control both normal and cancer biology. Since the discovery of RAS' overall prominence in many tumor types and specifically in RAS-dependent cancers, it has been an obvious therapeutic target for drug development...
December 2018: Biochemical Pharmacology
Lei Xie, Li-Yan Li, Duo Zheng, Yang-Min Xie, Xiu-E Xu, Li-Hua Tao, Lian-Di Liao, Ying-Hua Xie, Yin-Wei Cheng, Li-Yan Xu, En-Min Li
Invasion and metastasis are critical pathological and mortal processes in esophageal squamous cell carcinoma (ESCC). Novel drugs, targeting the two cancer migration stages, will augment the treatment options for ESCC therapy and improve overall survival. A novel natural macrolide F806 specifically promotes apoptosis of various ESCC cells. However, whether F806 can inhibit metastasis of ESCC cells needs further evaluation. Here, our data showed that F806 inhibits dynamic F-actin assembly and then suppresses the migration of ESCC cells in vitro and their invasion and metastasis in vivo...
2018: BioMed Research International
Tamara Zoranovic, Jan Manent, Lee Willoughby, Ricardo Matos de Simoes, John E La Marca, Sofya Golenkina, Xia Cuiping, Susanne Gruber, Belinda Angjeli, Elisabeth Eva Kanitz, Shane J F Cronin, G Gregory Neely, Andreas Wernitznig, Patrick O Humbert, Kaylene J Simpson, Constantine S Mitsiades, Helena E Richardson, Josef M Penninger
Oncogenic mutations in the small GTPase Ras contribute to ~30% of human cancers. However, Ras mutations alone are insufficient for tumorigenesis, therefore it is paramount to identify cooperating cancer-relevant signaling pathways. We devised an in vivo near genome-wide, functional screen in Drosophila and discovered multiple novel, evolutionarily-conserved pathways controlling Ras-driven epithelial tumorigenesis. Human gene orthologs of the fly hits were significantly downregulated in thousands of primary tumors, revealing novel prognostic markers for human epithelial tumors...
October 2018: PLoS Genetics
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
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
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
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 19, 2018: Biochemical Society Transactions
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)...
November 23, 2018: Journal of Biological Chemistry
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
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