1,418 results match your criteria gtpase prenylation


Mevalonate blockade in cancer cells triggers CLEC9A+ dendritic cell-mediated antitumor immunity.

Cancer Res 2021 Jul 15. Epub 2021 Jul 15.

Experiment Medicine, Sun Yat-sen University Cancer Center

Hyperactive mevalonate (MVA) metabolic activity is often observed in cancer cells, and blockade of this pathway inhibits tumor cell lipid synthesis and cell growth and enhances tumor immunogenicity. How tumor cell MVA metabolic blockade promotes antitumor immune responses, however, remains unclear. Here we show that inhibition of the MVA metabolic pathway in tumor cells elicits type 1 classical dendritic cells (cDC1)-mediated tumor recognition and antigen cross-presentation for antitumor immunity. Read More

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Production and Membrane Binding of N-Terminally Acetylated, C-Terminally Farnesylated and Carboxymethylated KRAS4b.

Methods Mol Biol 2021 ;2262:105-116

NCI RAS Initiative, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

Recombinant mammalian proteins are routinely produced in E. coli and thus lack post-translational modifications. KRAS4b is processed at both the N- and C-terminus, resulting in an acetylation of the N-terminus (at Thr, after aminopeptidase removal of the original N-term Met) and farnesylation/carboxymethylation of the C-terminal Cys (after proteolytic cleavage of the original C-terminal three amino acids, Val-Iso-Met). Read More

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Molecular and Pharmacological Characterization of the Interaction between Human Geranylgeranyltransferase Type I and Ras-Related Protein Rap1B.

Int J Mol Sci 2021 Mar 2;22(5). Epub 2021 Mar 2.

Center for Biomedical Education and Research (ZBAF), Faculty of Health, Institute of Pharmacology and Toxicology, School of Medicine, University of Witten/Herdecke, 58453 Witten, Germany.

Geranylgeranyltransferase type-I (GGTase-I) represents an important drug target since it contributes to the function of many proteins that are involved in tumor development and metastasis. This led to the development of GGTase-I inhibitors as anti-cancer drugs blocking the protein function and membrane association of e.g. Read More

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Selective axonal translation of the mRNA isoform encoding prenylated Cdc42 supports axon growth.

J Cell Sci 2021 04 15;134(7). Epub 2021 Apr 15.

Department of Biological Sciences, University of South Carolina, Columbia, SC 29208USA.

The small Rho-family GTPase Cdc42 has long been known to have a role in cell motility and axon growth. The eukaryotic Ccd42 gene is alternatively spliced to generate mRNAs with two different 3' untranslated regions (UTRs) that encode proteins with distinct C-termini. The C-termini of these Cdc42 proteins include CaaX and CCaX motifs for post-translational prenylation and palmitoylation, respectively. Read More

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The KRAS and other prenylated polybasic domain membrane anchors recognize phosphatidylserine acyl chain structure.

Proc Natl Acad Sci U S A 2021 02;118(6)

Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030;

KRAS interacts with the inner leaflet of the plasma membrane (PM) using a hybrid anchor that comprises a lysine-rich polybasic domain (PBD) and a C-terminal farnesyl chain. Electrostatic interactions have been envisaged as the primary determinant of interactions between KRAS and membranes. Here, we integrated molecular dynamics (MD) simulations and superresolution spatial analysis in mammalian cells and systematically compared four equally charged KRAS anchors: the wild-type farnesyl hexa-lysine and engineered mutants comprising farnesyl hexa-arginine, geranylgeranyl hexa-lysine, and geranylgeranyl hexa-arginine. Read More

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February 2021

The RIT1 C-terminus associates with lipid bilayers via charge complementarity.

Comput Biol Chem 2021 Apr 19;91:107437. Epub 2021 Jan 19.

Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, 87545, United States. Electronic address:

RIT1 is a member of the Ras superfamily of small GTPases involved in regulation of cellular signaling. Mutations to RIT1 are involved in cancer and developmental disorders. Like many Ras subfamily members, RIT1 is localized to the plasma membrane. Read More

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Scaffold association factor B (SAFB) is required for expression of prenyltransferases and RAS membrane association.

Proc Natl Acad Sci U S A 2020 12 30;117(50):31914-31922. Epub 2020 Nov 30.

Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016;

Inhibiting membrane association of RAS has long been considered a rational approach to anticancer therapy, which led to the development of farnesyltransferase inhibitors (FTIs). However, FTIs proved ineffective against -driven tumors. To reveal alternative therapeutic strategies, we carried out a genome-wide CRISPR-Cas9 screen designed to identify genes required for KRAS4B membrane association. Read More

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December 2020

[Therapeutic possibilities in KRAS-mutant lung adenocarcinoma].

Magy Onkol 2020 Sep 6;64(3):231-244. Epub 2020 Aug 6.

Mellkassebészeti Osztály, Országos Onkológiai Intézet, Budapest, Hungary.

KRAS mutations are the most common gain-of-function alterations in lung adenocarcinoma (LADC) in the western countries. Although the different mutations of the KRAS gene have been identified decades ago, the development of drugs targeting the KRAS protein directly have not been successful due to the lack of small molecule binding sites and the extremely high affinity to cellular GTP. Indirect strategies to inhibit KRAS (e. Read More

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September 2020

PI3K Regulatory Protein p84 Determines Mast Cell Sensitivity to Ras Inhibition-Moving Towards Cell Specific PI3K Targeting?

Front Immunol 2020 28;11:585070. Epub 2020 Oct 28.

Department of Biomedicine, University of Basel, Basel, Switzerland.

Mast cells are the major effector cells in immunoglobulin E (IgE)-mediated allergy. The high affinity IgE receptor FcRI, as well as G protein-coupled receptors (GPCRs) on the mast cell surface signals to phosphoinositide 3-kinase (PI3K) to initiate degranulation, cytokine release, and chemotaxis. PI3K is therefore considered as a target for treatment of allergic disorders. Read More

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Long-lasting Salt Bridges Provide the Anchoring Mechanism of Oncogenic Kirsten Rat Sarcoma Proteins at Cell Membranes.

J Phys Chem Lett 2020 Nov 10;11(22):9938-9945. Epub 2020 Nov 10.

Department of Physics, Technical University of Catalonia-Barcelona Tech, B4-B5 Northern Campus, Barcelona, Catalonia, Spain.

RAS proteins work as GDP-GTP binary switches and regulate cytoplasmic signaling networks that are able to control several cellular processes, playing an essential role in signal transduction pathways involved in cell growth, differentiation, and survival, so that overacting RAS signaling can lead to cancer. One of the hardest challenges to face is the design of mutation-selective therapeutic strategies. In this work, a G12D-mutated farnesylated GTP-bound Kirsten RAt sarcoma (KRAS) protein has been simulated at the interface of a DOPC/DOPS/cholesterol model anionic cell membrane. Read More

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November 2020

Cell-permeable CaaX-peptides affect K-Ras downstream signaling and promote cell death in cancer cells.

FEBS J 2021 05 7;288(9):2911-2929. Epub 2020 Nov 7.

Institute for Biochemistry, University of Cologne, Germany.

Cysteine prenylation is a post-translational modification that is used by nature to control crucial biological functions of proteins, such as membrane trafficking, signal transduction, and apoptosis. It mainly occurs in eukaryotic proteins at a C-terminal CaaX box and is mediated by prenyltransferases. Since the discovery of prenylated proteins, various tools have been developed to study the mechanisms of prenyltransferases, as well as to visualize and to identify prenylated proteins. Read More

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Pleiotropic effects of statins: A focus on cancer.

Biochim Biophys Acta Mol Basis Dis 2020 12 12;1866(12):165968. Epub 2020 Sep 12.

Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada; Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran; Research Institute of Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, Canada. Electronic address:

The statin drugs ('statins') potently inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase by competitively blocking the active site of the enzyme. Statins decrease de novo cholesterol biosynthesis and thereby reduce plasma cholesterol levels. Statins exhibit "pleiotropic" properties that are independent of their lipid-lowering effects. Read More

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December 2020

A Novel KRAS Antibody Highlights a Regulation Mechanism of Post-Translational Modifications of KRAS during Tumorigenesis.

Int J Mol Sci 2020 Sep 2;21(17). Epub 2020 Sep 2.

de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.

KRAS is a powerful oncogene responsible for the development of many cancers. Despite the great progress in understanding its function during the last decade, the study of KRAS expression, subcellular localization, and post-translational modifications remains technically challenging. Accordingly, many facets of KRAS biology are still unknown. Read More

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September 2020

NMR in integrated biophysical drug discovery for RAS: past, present, and future.

J Biomol NMR 2020 Nov 17;74(10-11):531-554. Epub 2020 Aug 17.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.

Mutations in RAS oncogenes occur in ~ 30% of human cancers, with KRAS being the most frequently altered isoform. RAS proteins comprise a conserved GTPase domain and a C-terminal lipid-modified tail that is unique to each isoform. The GTPase domain is a 'switch' that regulates multiple signaling cascades that drive cell growth and proliferation when activated by binding GTP, and the signal is terminated by GTP hydrolysis. Read More

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November 2020

Tipifarnib as a Precision Therapy for -Mutant Head and Neck Squamous Cell Carcinomas.

Mol Cancer Ther 2020 09 29;19(9):1784-1796. Epub 2020 Jul 29.

Kura Oncology, Inc., San Diego, California.

Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FTase). FTase catalyzes the posttranslational attachment of farnesyl groups to signaling proteins that are required for localization to cell membranes. Although all RAS isoforms are FTase substrates, only HRAS is exclusively dependent upon farnesylation, raising the possibility that HRAS-mutant tumors might be susceptible to tipifarnib-mediated inhibition of FTase. Read More

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September 2020

Inhibiting Protein Prenylation with Benzoxaboroles to Target Fungal Plant Pathogens.

ACS Chem Biol 2020 07 23;15(7):1930-1941. Epub 2020 Jun 23.

Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada.

Fungal pathogens pose an increasing threat to global food security through devastating effects on staple crops and contamination of food supplies with carcinogenic toxins. Widespread deployment of agricultural fungicides has increased crop yields but is driving increasingly frequent resistance to available agents and creating environmental reservoirs of drug-resistant fungi that can also infect susceptible human populations. To uncover non-cross-resistant modes of antifungal action, we leveraged the unique chemical properties of boron chemistry to synthesize novel 6-thiocarbamate benzoxaboroles with broad spectrum activity against diverse fungal plant pathogens. Read More

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Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton.

Bone 2020 10 20;139:115493. Epub 2020 Jun 20.

Garvan Institute of Medical Research, Sydney, Australia; St Vincent's Clinical School, UNSW Sydney, Australia. Electronic address:

Bisphosphonates (BP) are a class of calcium-binding drug used to prevent bone resorption in skeletal disorders such as osteoporosis and metastatic bone disease. They act by selectively targeting bone-resorbing osteoclasts and can be grouped into two classes depending on their intracellular mechanisms of action. Simple BPs cause osteoclast apoptosis after cytoplasmic conversion into toxic ATP analogues. Read More

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October 2020

Isoprenylcysteine carboxylmethyltransferase is required for the impact of mutant KRAS on TAZ protein level and cancer cell self-renewal.

Oncogene 2020 07 19;39(31):5373-5389. Epub 2020 Jun 19.

Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore.

Cancer stem cells possess the capacity for self-renewal and resistance to chemotherapy. It is therefore crucial to understand the molecular regulators of stemness in the quest to develop effective cancer therapies. TAZ is a transcription activator that promotes stem cell functions in post-development mammalian cells; suppression of TAZ activity reduces or eliminates cancer stemness in select cancers. Read More

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Current therapy of KRAS-mutant lung cancer.

Cancer Metastasis Rev 2020 12;39(4):1159-1177

Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Rath Gyorgy u. 7-9, Budapest, 1122, Hungary.

KRAS mutations are the most frequent gain-of-function alterations in patients with lung adenocarcinoma (LADC) in the Western world. Although they have been identified decades ago, prior efforts to target KRAS signaling with single-agent therapeutic approaches such as farnesyl transferase inhibitors, prenylation inhibition, impairment of KRAS downstream signaling, and synthetic lethality screens have been unsuccessful. Moreover, the role of KRAS oncogene in LADC is still not fully understood, and its prognostic and predictive impact with regards to the standard of care therapy remains controversial. Read More

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December 2020

Prenylation of Axonally Translated Rac1 Controls NGF-Dependent Axon Growth.

Dev Cell 2020 06 12;53(6):691-705.e7. Epub 2020 Jun 12.

Department of Biology, Johns Hopkins University, 3400 N. Charles St, 227 Mudd Hall, Baltimore, MD 21218, USA. Electronic address:

Compartmentalized signaling is critical for cellular organization and specificity of functional outcomes in neurons. Here, we report that post-translational lipidation of newly synthesized proteins in axonal compartments allows for short-term and autonomous responses to extrinsic cues. Using conditional mutant mice, we found that protein prenylation is essential for sympathetic axon innervation of target organs. Read More

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Purification of Farnesylated hGBP1 and Characterization of Its Polymerization and Membrane Binding.

Methods Mol Biol 2020 ;2159:67-81

Physical Chemistry I, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Bochum, Germany.

The human guanylate-binding protein 1 (hGBP1) is the best characterized isoform of the seven human GBPs belonging to the superfamily of dynamin-like proteins (DLPs). As known for other DLPs, hGBP1 also exhibits antiviral and antimicrobial activity within the cell. hGBP 1, like hGBPs 2 and 5, carries a CAAX motive at the C-terminus leading to isoprenylation in the living cells. Read More

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K-Ras prenylation as a potential anticancer target.

Cancer Metastasis Rev 2020 12;39(4):1127-1141

Department of Thoracic Surgery, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany.

KRAS is one of the most commonly mutated oncogene and a negative predictive factor for a number of targeted therapies. Therefore, the development of targeting strategies against mutant KRAS is urgently needed. One potential strategy involves disruption of K-Ras membrane localization, which is necessary for its proper function. Read More

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December 2020

A conserved and regulated mechanism drives endosomal Rab transition.

Elife 2020 05 11;9. Epub 2020 May 11.

University of Osnabrück, Department of Biology/Chemistry, Biochemistry section, Osnabrück, Germany.

Endosomes and lysosomes harbor Rab5 and Rab7 on their surface as key proteins involved in their identity, biogenesis, and fusion. Rab activation requires a guanine nucleotide exchange factor (GEF), which is Mon1-Ccz1 for Rab7. During endosome maturation, Rab5 is replaced by Rab7, though the underlying mechanism remains poorly understood. Read More

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A Non-Canonical Calmodulin Target Motif Comprising a Polybasic Region and Lipidated Terminal Residue Regulates Localization.

Int J Mol Sci 2020 Apr 15;21(8). Epub 2020 Apr 15.

Princess Margaret Cancer Centre, University Health Network, 101 College St., Toronto, ON M5G 1L7, Canada.

Calmodulin (CaM) is a Ca-sensor that regulates a wide variety of target proteins, many of which interact through short basic helical motifs bearing two hydrophobic 'anchor' residues. CaM comprises two globular lobes, each containing a pair of EF-hand Ca-binding motifs that form a Ca-induced hydrophobic pocket that binds an anchor residue. A central flexible linker allows CaM to accommodate diverse targets. Read More

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Calmodulin disrupts plasma membrane localization of farnesylated KRAS4b by sequestering its lipid moiety.

Sci Signal 2020 03 31;13(625). Epub 2020 Mar 31.

Princess Margaret Cancer Center, University Health Network, Toronto, Ontario M5G 1L7, Canada.

KRAS4b is a small guanosine triphosphatase (GTPase) protein that regulates several signal transduction pathways that underlie cell proliferation, differentiation, and survival. KRAS4b function requires prenylation of its C terminus and recruitment to the plasma membrane, where KRAS4b activates effector proteins including the RAF family of kinases. The Ca-sensing protein calmodulin (CaM) has been suggested to regulate the localization of KRAS4b through direct, Ca-dependent interaction, but how CaM and KRAS4b functionally interact is controversial. Read More

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Targeting and signaling of Rho of plants guanosine triphosphatases require synergistic interaction between guanine nucleotide inhibitor and vesicular trafficking.

J Integr Plant Biol 2020 Oct 16;62(10):1484-1499. Epub 2020 Apr 16.

State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, Tai'an, 271018, China.

Most eukaryotic cells are polarized. Common toolbox regulating cell polarization includes Rho guanosine triphosphatases (GTPases), in which spatiotemporal activation is regulated by a plethora of regulators. Rho of plants (ROPs) are the only Rho GTPases in plants. Read More

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October 2020

Targeting Kras -mutant cancer with a mutation-specific inhibitor.

J Intern Med 2020 08 7;288(2):183-191. Epub 2020 Apr 7.

Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.

The RAS genes, which include H, N, and KRAS, comprise the most frequently mutated family of oncogenes in cancer. Mutations in KRAS - such as the G12C mutation - are found in most pancreatic, half of colorectal and a third of lung cancer cases and is thus responsible for a substantial proportion of cancer deaths. Consequently, KRAS has been the subject of exhaustive drug-targeting efforts over the past 3-4 decades. Read More

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Stochastic activation and bistability in a Rab GTPase regulatory network.

Proc Natl Acad Sci U S A 2020 03 11;117(12):6540-6549. Epub 2020 Mar 11.

Institute of Science and Technology Austria, 3400 Klosterneuburg, Austria;

The eukaryotic endomembrane system is controlled by small GTPases of the Rab family, which are activated at defined times and locations in a switch-like manner. While this switch is well understood for an individual protein, how regulatory networks produce intracellular activity patterns is currently not known. Here, we combine in vitro reconstitution experiments with computational modeling to study a minimal Rab5 activation network. Read More

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Interferon inducible GBPs restrict Burkholderia thailandensis motility induced cell-cell fusion.

PLoS Pathog 2020 03 9;16(3):e1008364. Epub 2020 Mar 9.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.

Innate immunity responds to pathogens by producing alarm signals and activating pathways that make host cells inhospitable for pathogen replication. The intracellular bacterium Burkholderia thailandensis invades the cytosol, hijacks host actin, and induces cell fusion to spread to adjacent cells, forming multinucleated giant cells (MNGCs) which promote bacterial replication. We show that type I interferon (IFN) restricts macrophage MNGC formation during B. Read More

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The balance of protein farnesylation and geranylgeranylation during the progression of nonalcoholic fatty liver disease.

J Biol Chem 2020 04 5;295(15):5152-5162. Epub 2020 Mar 5.

State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China

Protein prenylation is an essential posttranslational modification and includes protein farnesylation and geranylgeranylation using farnesyl diphosphate or geranylgeranyl diphosphate as substrates, respectively. Geranylgeranyl diphosphate synthase is a branch point enzyme in the mevalonate pathway that affects the ratio of farnesyl diphosphate to geranylgeranyl diphosphate. Abnormal geranylgeranyl diphosphate synthase expression and activity can therefore disrupt the balance of farnesylation and geranylgeranylation and alter the ratio between farnesylated and geranylgeranylated proteins. Read More

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