The Experts below are selected from a list of 4293 Experts worldwide ranked by ideXlab platform
Channing J Der - One of the best experts on this subject based on the ideXlab platform.
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Ras and RHO family GTPase mutations in cancer: twin sons of different mothers?
Critical reviews in biochemistry and molecular biology, 2020Co-Authors: Richard G. Hodge, Antje Schaefer, Sarah V. Howard, Channing J DerAbstract:The Ras and RHO family comprise two major branches of the Ras Superfamily of small GTPases. These proteins function as regulated molecular switches and control cytoplasmic signaling networks that r...
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Facile real time detection of membrane colocalization of Ras Superfamily GTPase proteins in living cells
2018Co-Authors: Luke Wang, Channing J Der, Tikvah K. Hayes, Margie N. Sutton, Robert C. Bast, Frank Mccormick, Geoffrey M. WahlAbstract:Members of the Ras family of GTPases (KRas4A, KRas4B, HRas, and NRas) are the most frequently mutated oncogenes in human cancers. The CAAX motif in the C-terminal hypervariable region (HVR-CAAX domain) contains the cysteine residue that is critical for protein prenylation that enables Ras protein membrane localization, homodimer/oligomer formation, and activation of effector signaling and oncogenic activity. However, it remains unclear if Ras can interact with other prenylated proteins, and if so, how this impacts Ras function. Here we use a newly developed quantifiable Recombinase enhanced Bimolecular LucifeRase Complementation strategy (ReBiL2.0) to investigate some of the requirements for Ras Superfamily small GTPase protein interactions, and whether this requires cell membrane localization. ReBiL enables such analyses to be done at physiologic expression levels in living cells. Our results confirm that the C-terminal prenylated HVR-CAAX domain is sufficient to direct KRas and heterologous proteins to colocalize in the cell membrane. We discovered that KRas also colocalizes with a subset of small GTPase Superfamily members including RAC1, RAC2 and DIRas3 in a prenylation-dependent manner. KRas colocalization or co-clustering with heterologous proteins can impact KRas downstream signaling. ReBiL2.0 thus provides a rapid, simple and straightforward method to identify and characterize the colocalization of membrane-associated proteins and to discover agonists and antagonists thereof.
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inhibitors of the Ras Superfamily g proteins
2013Co-Authors: Fuyuhiko Tamanoi, Channing J DerAbstract:Targeted toward researchers in biochemistry, molecular and cell biology, pharmacology, and cancer, this is the second part of The Enzymes' volumes that discuss inhibitors of the Ras Superfamily G-proteins. Key features: contributions from leading authorities; and informs and updates on all the latest developments in the field.
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Lipid Modification of Ras Superfamily GTPases: Not Just Membrane Glue
Protein Prenylation PART A, 2011Co-Authors: Emily J. Chenette, Channing J DerAbstract:Publisher Summary This chapter discusses the process, regulation, and biological consequence of lipid modification of Ras Superfamily small GTPases, with a focus on the role of isoprenoid modification of the Rho and Rab family members. The activity of Ras-related GTPases supports a myriad of physiological and pathophysiological cellular events. Guanine nucleotide binding and hydrolysis regulate Ras-mediated signaling, which governs binding to and activation of downstream effector proteins. However, the subcellular localization of active Ras proteins—and hence the identity of nearby effector and regulatory proteins—can determine the biological outcome of these signaling events. In addition to the diversification of different Ras Superfamily GTPase branches by their control by unique regulators and their activation of distinct effectors, their biological roles are further diversified by their posttranslational modification by isoprenoid and fatty acid lipids. Together with other CAAX-signaled and additional posttranslational modifications and (phosphorylation, ubiquitination, SUMOylation), further diversification of the subcellular localization and biological roles of otherwise highly structurally and biochemically related small GTPases can be achieved. These modifications dictate distinct biological functions by impacting the spatiotemporal localization and activity of small GTPases.
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Ras Superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?
Nature reviews. Cancer, 2010Co-Authors: Dominico Vigil, Kent L Rossman, Jacqueline Cherfils, Channing J DerAbstract:There is now considerable and increasing evidence for a causal role for aberrant activity of the Ras Superfamily of small GTPases in human cancers. These GTPases function as GDP-GTP-regulated binary switches that control many fundamental cellular processes. A common mechanism of GTPase deregulation in cancer is the deregulated expression and/or activity of their regulatory proteins, guanine nucleotide exchange factors (GEFs) that promote formation of the active GTP-bound state and GTPase-activating proteins (GAPs) that return the GTPase to its GDP-bound inactive state. In this Review, we assess the association of GEFs and GAPs with cancer and their druggability for cancer therapeutics.
Alfonso Valencia - One of the best experts on this subject based on the ideXlab platform.
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Evolution of the Ras Superfamily of GTPases
Ras Superfamily Small G Proteins: Biology and Mechanisms 1, 2014Co-Authors: Ana M. Rojas, Alfonso ValenciaAbstract:The Ras Superfamily of small GTPases illustrates a large functional diversification in the context of a preserved structural framework and a prototypic GTP-binding site. The Ras Superfamily of small GTP-binding proteins is essential to regulate the cellular organization and signaling in cells. Members of this Superfamily contain a structurally and mechanistically preserved GTP-binding core, with considerable functional and sequence divergence. In this chapter we review the evolutionary structure of the Superfamily at the organism and sequence level, presenting a representative tree that reflects the history of the Ras Superfamily including crucial evolutionary time points and detailed trees for the Rho, Ras, Rab, Arf, and Ran families. Based on this information we discuss some of the complex relationships between the evolution of proteins and the acquisition of distinctive cellular functions.
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the Ras protein Superfamily evolutionary tree and role of conserved amino acids
Journal of Cell Biology, 2012Co-Authors: Ana M. Rojas, Gloria Fuentes, Antonio Rausell, Alfonso ValenciaAbstract:The Ras Superfamily is a fascinating example of functional diversification in the context of a preserved structural framework and a prototypic GTP binding site. Thanks to the availability of complete genome sequences of species representing important evolutionary branch points, we have analyzed the composition and organization of this Superfamily at a greater level than was previously possible. Phylogenetic analysis of gene families at the organism and sequence level revealed complex relationships between the evolution of this protein Superfamily sequence and the acquisition of distinct cellular functions. Together with advances in computational methods and structural studies, the sequence information has helped to identify features important for the recognition of molecular partners and the functional specialization of different members of the Ras Superfamily.
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Evolution: The Ras protein Superfamily: Evolutionary tree and role of conserved amino acids
The Journal of cell biology, 2012Co-Authors: Ana M. Rojas, Gloria Fuentes, Antonio Rausell, Alfonso ValenciaAbstract:The Ras Superfamily is a fascinating example of functional diversification in the context of a preserved structural framework and a prototypic GTP binding site. Thanks to the availability of complete genome sequences of species representing important evolutionary branch points, we have analyzed the composition and organization of this Superfamily at a greater level than was previously possible. Phylogenetic analysis of gene families at the organism and sequence level revealed complex relationships between the evolution of this protein Superfamily sequence and the acquisition of distinct cellular functions. Together with advances in computational methods and structural studies, the sequence information has helped to identify features important for the recognition of molecular partners and the functional specialization of different members of the Ras Superfamily.
Ana M. Rojas - One of the best experts on this subject based on the ideXlab platform.
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Evolution of the Ras Superfamily of GTPases
Ras Superfamily Small G Proteins: Biology and Mechanisms 1, 2014Co-Authors: Ana M. Rojas, Alfonso ValenciaAbstract:The Ras Superfamily of small GTPases illustrates a large functional diversification in the context of a preserved structural framework and a prototypic GTP-binding site. The Ras Superfamily of small GTP-binding proteins is essential to regulate the cellular organization and signaling in cells. Members of this Superfamily contain a structurally and mechanistically preserved GTP-binding core, with considerable functional and sequence divergence. In this chapter we review the evolutionary structure of the Superfamily at the organism and sequence level, presenting a representative tree that reflects the history of the Ras Superfamily including crucial evolutionary time points and detailed trees for the Rho, Ras, Rab, Arf, and Ran families. Based on this information we discuss some of the complex relationships between the evolution of proteins and the acquisition of distinctive cellular functions.
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the Ras protein Superfamily evolutionary tree and role of conserved amino acids
Journal of Cell Biology, 2012Co-Authors: Ana M. Rojas, Gloria Fuentes, Antonio Rausell, Alfonso ValenciaAbstract:The Ras Superfamily is a fascinating example of functional diversification in the context of a preserved structural framework and a prototypic GTP binding site. Thanks to the availability of complete genome sequences of species representing important evolutionary branch points, we have analyzed the composition and organization of this Superfamily at a greater level than was previously possible. Phylogenetic analysis of gene families at the organism and sequence level revealed complex relationships between the evolution of this protein Superfamily sequence and the acquisition of distinct cellular functions. Together with advances in computational methods and structural studies, the sequence information has helped to identify features important for the recognition of molecular partners and the functional specialization of different members of the Ras Superfamily.
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Evolution: The Ras protein Superfamily: Evolutionary tree and role of conserved amino acids
The Journal of cell biology, 2012Co-Authors: Ana M. Rojas, Gloria Fuentes, Antonio Rausell, Alfonso ValenciaAbstract:The Ras Superfamily is a fascinating example of functional diversification in the context of a preserved structural framework and a prototypic GTP binding site. Thanks to the availability of complete genome sequences of species representing important evolutionary branch points, we have analyzed the composition and organization of this Superfamily at a greater level than was previously possible. Phylogenetic analysis of gene families at the organism and sequence level revealed complex relationships between the evolution of this protein Superfamily sequence and the acquisition of distinct cellular functions. Together with advances in computational methods and structural studies, the sequence information has helped to identify features important for the recognition of molecular partners and the functional specialization of different members of the Ras Superfamily.
Atle M. Bones - One of the best experts on this subject based on the ideXlab platform.
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the crystal structure of arabidopsis thaliana rac7 rop9 the first Ras Superfamily gtpase from the plant kingdom
Phytochemistry, 2006Co-Authors: Christopher Gravningen Sørmo, Ingar Leiros, Tore Brembu, Per Winge, Atle M. BonesAbstract:Arabidopsis thaliana RAC/ROP GTPases constitute a plant specific Rho GTPase family in the Ras Superfamily, which has been implicated in numerous pivotal signalling cascades in plants. Research has shown that plants in some cases have evolved different modes of regulating Rho GTPase activity as compared to the equivalent systems in animals and yeast. In order to gain structural insight into plant signaling at the molecular level, we have determined the first crystal structure of a RAC-like GTPase belonging to the Ras Superfamily from the plant kingdom. The structure of AtRAC7/ROP9 bound to GDP was solved at a resolution of 1.78 A. We have found that the structure of plant Rho GTPases is based upon a conserved G-domain architecture, but structural differences were found concerning the insert region and switch II region of the protein.
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The crystal structure of Arabidopsis thaliana RAC7/ROP9: The first Ras Superfamily GTPase from the plant kingdom
Phytochemistry, 2006Co-Authors: Christopher Gravningen Sørmo, Ingar Leiros, Tore Brembu, Per Winge, Atle M. BonesAbstract:Arabidopsis thaliana RAC/ROP GTPases constitute a plant specific Rho GTPase family in the Ras Superfamily, which has been implicated in numerous pivotal signalling cascades in plants. Research has shown that plants in some cases have evolved different modes of regulating Rho GTPase activity as compared to the equivalent systems in animals and yeast. In order to gain structural insight into plant signaling at the molecular level, we have determined the first crystal structure of a RAC-like GTPase belonging to the Ras Superfamily from the plant kingdom. The structure of AtRAC7/ROP9 bound to GDP was solved at a resolution of 1.78 A. We have found that the structure of plant Rho GTPases is based upon a conserved G-domain architecture, but structural differences were found concerning the insert region and switch II region of the protein.
Kent L Rossman - One of the best experts on this subject based on the ideXlab platform.
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Ras Superfamily gefs and gaps validated and tractable targets for cancer therapy
Nature Reviews Cancer, 2010Co-Authors: Dominico Vigil, Jacqueline Cherfils, Kent L RossmanAbstract:Certain members of the Ras Superfamily of small GTPases are commonly deregulated in human cancers, but how can we target them? This Review explores the association of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that regulate GTPases with cancer and discusses whether they can be effectively targeted therapeutically.
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Ras Superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?
Nature reviews. Cancer, 2010Co-Authors: Dominico Vigil, Kent L Rossman, Jacqueline Cherfils, Channing J DerAbstract:There is now considerable and increasing evidence for a causal role for aberrant activity of the Ras Superfamily of small GTPases in human cancers. These GTPases function as GDP-GTP-regulated binary switches that control many fundamental cellular processes. A common mechanism of GTPase deregulation in cancer is the deregulated expression and/or activity of their regulatory proteins, guanine nucleotide exchange factors (GEFs) that promote formation of the active GTP-bound state and GTPase-activating proteins (GAPs) that return the GTPase to its GDP-bound inactive state. In this Review, we assess the association of GEFs and GAPs with cancer and their druggability for cancer therapeutics.
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Signaling interplay in Ras Superfamily function.
Current biology : CB, 2005Co-Authors: Natalia Mitin, Kent L Rossman, Channing J DerAbstract:Ras proteins function as signaling hubs that are activated by convergent signaling pathways initiated by extracellular stimuli. Activated Ras in turn regulates a diversity of downstream cytoplasmic signaling cascades. Ras proteins are founding members of a large Superfamily of small GTPases that have significant sequence and biochemical similarities. Recent observations have established a complex signaling interplay between Ras and other members of the family. A key biochemical mechanism facilitating this crosstalk involves guanine nucleotide exchange factors (GEFs), which serve as regulators and effectors, as well as signaling integrators, of Ras signaling.
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the Ras Superfamily at a glance
Journal of Cell Science, 2005Co-Authors: Krister Wennerberg, Kent L RossmanAbstract:The Ras Superfamily of small guanosine triphosphatases (GTPases) comprise over 150 human members (Table S1 in [supplementary material][1]), with evolutionarily conserved orthologs found in Drosophila, C. elegans, S. cerevisiae, S. pombe, Dictyostelium and plants ([Colicelli, 2004][2]). The Ras
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Established and emerging fluorescence-based assays for G-protein function: Ras-Superfamily GTPases.
Combinatorial chemistry & high throughput screening, 2003Co-Authors: Rafael Rojas, Kent L Rossman, Randall J. Kimple, David P. Siderovski, John SondekAbstract:Ras and Rho GTPases are signaling proteins that regulate a variety of physiological events and are intimately linked to the progression of cancer. Recently, a variety of fluorescence-based assays have been refined to monitor activation of these GTPases. This review summarizes current fluorescence-based techniques for studying Ras Superfamily GTPases with an emphasis on practical examples and high-throughput applications. These techniques are not only useful for biochemical characterization of Ras Superfamily members, but will also facilitate the discovery of small molecule therapeutics designed to inhibit signal transduction mediated by GTPases.
