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  • oncogenic
  • The Ras family of small GTPases were originally discovered during a search for oncogenic retroviruses. (mechanobio.info)
  • Signaling through Ras GTPases regulates the activity of several transcription points including CCAAT/enhancer-binding protein (C/EBPβ) which regulates oncogenic H-RasV12-induced senescence and growth arrest. (ranscombehouseglynde.com)
  • C/EBPβ DNA binding activity is normally auto-inhibited with the N-terminal area and turned on by oncogenic Ras signaling. (ranscombehouseglynde.com)
  • Activation of C/EBPβ DNA binding by oncogenic Ras integrates the consequences of many post-translational adjustments as depicted in Fig. 8affecting LX1 and LX2) may also be involved with C/EBPβ derepression. (ranscombehouseglynde.com)
  • There are no effective K-, N-Ras, or RasGRP1 inhibitors to date and blocking oncogenic Ras signaling in the clinic remains a highly desired goal. (cam.ac.uk)
  • To succeed, we must focus on the molecular details of the RAS structure and understand at a high-resolution level how the oncogenic mutants impair function. (aacrjournals.org)
  • Structural networks of intramolecular communication between the RAS active site and membrane-interacting regions on the G-domain are disrupted in oncogenic mutants. (aacrjournals.org)
  • A) Immunoblot of lysates isolated from human HEK-HT cells stably infected with the retrovirus pBabepuro encoding the indicated N-terminal FLAG-epitope tagged oncogenic (G12V) human Ras proteins (FLAG-Ras G12V ) with an αFLAG or αtubulin antibody. (nih.gov)
  • HRAS
  • Since we found that HRAS, KRAS, and NRAS can all be SUMOylated, we propose that SUMOylation might represent a mechanism by which RAS activities are controlled. (aacrjournals.org)
  • The three major isoforms of RAS, KRAS, NRAS, and HRAS together are mutated in about 20% of human cancers, primarily in the active site at residues G12, G13, and Q61 near the γ-phosphate of the guanosine triphosphate (GTP) substrate ( Fig. 1 ). (aacrjournals.org)
  • genes
  • Nevertheless, manipulating expression or activation of each isoform yields different cellular responses and tumorigenic phenotypes, even when different ras genes are expressed from the same locus. (nih.gov)
  • We now report a novel regulatory mechanism hardwired into the very sequence of RAS genes that underlies how such similar proteins impact tumorigenesis differently. (nih.gov)
  • localization
  • Given the important roles of the small ubiquitin-related modifier (SUMO) pathway in controlling the stability, activity, or subcellular localization of key cellular regulators, we investigated here whether RAS proteins are post-translationally modified (i.e. (aacrjournals.org)
  • These nuances include distinct biochemical patterns of analog versus digital Ras activation, differences in cellular localization of Ras activation, and intricate interplays between the RasGEFs during distinct T cell developmental stages as revealed by various new mouse models. (frontiersin.org)
  • RAS is composed of the core G-domain containing the catalytic machinery and a lipidated C-terminal hypervariable region with low homology between isoforms, which tethers the G-domain to the membrane and drives localization to specific microdomains ( 7 ). (aacrjournals.org)
  • Rap1
  • While Ras is mainly localized at the plasma membrane, Rap1 has been found in different membrane compartments, depending on the cell type. (genetics.org)
  • Further, Rap1 activation appears to be stimulated by numerous exchange factors that do not act on the prototypic Ras GTPases. (genetics.org)
  • These findings strongly suggest that Rap1 plays a largely Ras-independent role in cell migration and morphogenesis. (genetics.org)
  • mutants
  • Id of Sequences in the bZIP Area Mediating Auto-inhibition To recognize components in the DBD that take part in auto-inhibition we generated a nested group of deletions that remove sequences in the C terminus and the finish from the LZ (Fig. 5and and and connections with C/EBPβ needed activation by Ras as well as the auto-inhibitory domains mutants didn't bind p300. (ranscombehouseglynde.com)
  • However none from the N-terminal auto-inhibitory domains mutants demonstrated significant arousal by p300 despite elevated Ras-induced transcriptional activity of mLX2 and ΔHelp because of their impaired auto-inhibition (find also Fig. 4and (47 -49) demonstrated which the CRD area next to the canonical LZ domains interacts using a subdomain of c-Myb to create a four-helix pack (35). (ranscombehouseglynde.com)
  • The use of Ras effector-loop mutants indicated that signalling via multiple Ras-effectors is necessary for the maximum activation of transcription. (ncl.ac.uk)
  • Targeting posttranslational modifications at the C-terminus is discussed by Cox and colleagues ( 3 ) in this CCR Focus series, while alternative strategies focused on altered metabolic pathways driven by RAS mutants and synthetic lethality approaches are reviewed by Kimmelman ( 4 ) and Downward ( 5 ), respectively. (aacrjournals.org)
  • small
  • In these cascades, small GTPases help link cell surface receptors to the actin cytoskeleton, guide interaction with other cells and the extracellular matrix, and direct the delivery and internalization of lipids and proteins. (thermofisher.com)
  • TcsL belongs to the large clostridial glucosylating toxin (LCGT) family which inactivates small GTPases by glucosylation with uridine-diphosphate (UDP)-glucose as a cofactor. (mdpi.com)
  • biochemical
  • Results from biochemical and molecular studies indicated that the SUMO-E3 ligase PIASγ specifically interacts with RAS and promotes its SUMOylation. (aacrjournals.org)
  • Such a distribution can be ascertained by biochemical fractionation, which shows Ras-GRF1 in both soluble and particulate fractions, its proportions vary depending on the cell type. (atlasgeneticsoncology.org)
  • Structural and biochemical analysis of Ras-effector signaling via RalGDS. (embl-heidelberg.de)
  • hydrolysis
  • We next established that RasGRP1 overexpression results in a constitutively high GTP -loading rate of Ras, which is constantly counterbalanced by hydrolysis of RasGTP 2. (cam.ac.uk)
  • glucosylation
  • Release of these proinflammatory responses is positively regulated by Ras-GTPases, which leads to the hypothesis that Ras glucosylation by glucosylating toxins results in (at least) reduced proinflammatory responses. (frontiersin.org)
  • Against this background, data on toxin-catalyzed Ras glucosylation are required to estimate of pro-inflammatory effect of the glucosylating toxins. (frontiersin.org)
  • Furthermore, the glucosylation of (H/K/N)Ras was detected in TcdA-(not TcdB)-treated cells, as analyzed exploiting immunoblot analysis using the Ras glucosylation-sensitive 27H5 antibody. (frontiersin.org)
  • Under these conditions, (H/K/N)Ras glucosylation by TcdA was detected. (frontiersin.org)
  • In contrast, TcdB-catalyzed (H/K/N)Ras glucosylation was detected by neither MRM analysis, immunoblot analysis nor [14C]glucosylation in a cell-free system. (frontiersin.org)
  • RasGEFs
  • Ras GTPases are activated by RasGEFs (guanine nucleotide exchange factors). (cam.ac.uk)
  • Ras guanine nucleotide exchange factors (RasGEFs) catalyze GTP loading of Ras and play a pivotal role in regulating receptor-ligand induced Ras activity. (frontiersin.org)
  • Early on it was recognized that Ras activation is critical for T cell development and that the RasGEFs play an important role herein. (frontiersin.org)
  • In many instances, the exact nature of these nuances in Ras activation or how these may result from fine-tuning of the RasGEFs is not understood. (frontiersin.org)
  • Multiple, yet distinct lipid products are generated following T cell receptor (TCR) stimulation and bind to different domains in the RasGRP and SOS RasGEFs to facilitate the activation of the membrane-anchored Ras GTPases. (frontiersin.org)
  • In this review we highlight how different lipid-based elements are generated by various enzymes downstream of the TCR and other receptors and how these dynamic and interrelated lipid products may fine-tune Ras activation by RasGEFs in developing T cells. (frontiersin.org)
  • In both the Ras·GDP and Ras·GTP states the nucleotide is very tightly bound ( 2 - 4 ) and for Ras activation to occur Ras guanine nucleotide exchange factors (RasGEFs) need to loosen the grip of Ras on the bound nucleotide, stabilizing nucleotide-free Ras that stochastically but preferentially associates with GTP, because GTP is present in the cell in higher concentrations than GDP ( 5 ). (frontiersin.org)
  • pathways
  • Signal transduction pathways involving RAS are illustrated in McCormick's overview of this CCR Focus series ( 2 ). (aacrjournals.org)
  • Many observations have indicated that Ras transmits signals from cell surface receptors into multiple pathways via direct interaction with different effectors in mammalian cells. (embl-heidelberg.de)
  • activation
  • Moreover, SUMOylation of RAS appeared to be associated with its activation. (aacrjournals.org)
  • The activated Ras sets off a signal transduction pathway which ends up with the activation of the MAP kinase ERK1 , which translocates to the nucleus to induce gene expression. (mechanobio.info)
  • A growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases. (nih.gov)
  • Oddly enough the naturally taking place LIP isoform (153-297) shown almost undetectable binding activity and was refractory to Ras activation (Fig. 2 and evaluation from the C/EBPβ series. (ranscombehouseglynde.com)
  • More recent work has revealed that nuances in Ras activation appear to significantly impact T cell development and selection. (frontiersin.org)
  • Activation of Ras is regulated by the balance of opposing actions of two classes of Ras regulatory enzymes. (frontiersin.org)
  • The DH domain also mediates in Ras-GRF dimerization that ensues upon activation. (atlasgeneticsoncology.org)
  • cancers
  • The development of strategies to target these novel sites will add a fresh direction in the quest to conquer RAS-driven cancers. (aacrjournals.org)
  • See all articles in this CCR Focus section, "Targeting RAS-Driven Cancers. (aacrjournals.org)
  • TcsL
  • H/K/N)Ras are presented to be glucosylated by TcsL and TcdA but by neither TcdB isoform tested. (frontiersin.org)
  • Notably, TcsL modifies Rac and Ras GTPases, leading to drastic alteration of the actin cytoskeleton and cell viability. (mdpi.com)
  • TcsL-cat binding to PS facilitates a high enzymatic activity towards membrane-anchored Ras by about three orders of magnitude as compared to Ras in solution. (mdpi.com)
  • effector
  • The structure of the complex of Ras with the Ras-binding domain of its effector RalGDS (RGS-RBD), the first genuine Ras-effector complex, has been solved by X-ray crystallography. (embl-heidelberg.de)
  • Identification of PLC210, a Caenorhabditis elegans phospholipase C, as a putative effector of Ras. (embl-heidelberg.de)
  • In the nematode Caenorhabditis elegans, LIN-45 Raf has been identified by genetic analyses as an effector of LET-60 Ras. (embl-heidelberg.de)
  • These results strongly suggest that PLC210 belongs to a novel class of PI-PLC, which is a putative effector of Ras. (embl-heidelberg.de)
  • Identification of Nore1 as a potential Ras effector. (embl-heidelberg.de)
  • family
  • Ras family members are involved in many cellular processes. (mechanobio.info)
  • Given their origin, members of the Ras family are commonly associated with cancer. (mechanobio.info)
  • Over the past 5 years, approximately 20 novel Ras-family GEFs have been identified and characterized. (nih.gov)
  • This review discusses the structure and function of the catalytic or CDC25 homology domain common to almost all Ras-family GEFs. (nih.gov)
  • Here we report a bead-based flow cytometric assay that quantitatively measures the nucleotide binding properties of glutathione-S-transferase (GST) chimeras for prototypical Ras family members Rab7 and Rho. (unm.edu)
  • and a d bl- h omology (DH) region, which exhibits GEF activity towards Rho family GTPases, in particular Rac-1 . (atlasgeneticsoncology.org)
  • differences
  • In sum, the flow cytometric assay can be used to measure nucleotide binding properties of GTPases in real time and to quantitatively assess differences between GTPases. (unm.edu)
  • These differences could have an effect on stabilization of conformational states of interest in attenuating signaling through RAS. (aacrjournals.org)
  • regulatory
  • Although this canonical cycle is the regulatory holy grail for RAS and related GTPases, a high-resolution view reveals variations that embellish and complement this cycle based on detailed structural features. (aacrjournals.org)
  • residues
  • This domain, which could be narrowed down to 100 amino acid residues, associated in vitro with human Ha-Ras in a GTP-dependent manner and competed with yeast adenylyl cyclase for binding Ha-Ras. (embl-heidelberg.de)
  • cell
  • In 2013, we described a cancer Ras-signal driven by overexpression of the RasGEF RasGRP1 in pediatric T-cell acute lymphoblastic leukemia (TALL) patients and murine models 1. (cam.ac.uk)
  • bind
  • Recent success in the discovery of compounds that bind RAS and inhibit signaling has fueled renewed enthusiasm, and in-depth understanding of the structure and function of RAS has opened new avenues for direct targeting. (aacrjournals.org)
  • activity
  • This augmentation occurred only in the current presence of Ras did and signaling not affect basal C/EBPβ activity. (ranscombehouseglynde.com)
  • The TGFβ 1 -induced β-catenin phosphorylation was also dependent on PI3-kinase and Ras activity. (biologists.org)