The Experts below are selected from a list of 75921 Experts worldwide ranked by ideXlab platform
Yi Zheng - One of the best experts on this subject based on the ideXlab platform.
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Rho GTPase-activating Proteins in Cancer
The Rho GTPases in Cancer, 2009Co-Authors: Matthew Grogg, Yi ZhengAbstract:Rho GTPases are involved in a variety of cellular functions and require strict regulation to insure proper signaling. As negative regulators of the Rho Proteins, Rho GTPase-activating Proteins (GAPs) also play critical roles in cytoskeleton regulation, cell-cycle control, gene expression, and normal development. The sheer number and multidomain structural feature of known RhoGAPs are indicative of the importance of such regulation. Among an array of the possible functions, the role RhoGAPs play in cell proliferation, cell migration, and morphogenesis make them likely candidates in tumorigenesis and tumor progression. With the identification of several guanine-nucleotide exchange factors (GEFs) as oncogenes it has been inferred that RhoGAPs may function in some capacity as tumor suppressors. This appears to be the case with several Rho GAPs (e.g., DLC-1 and β2-chimaerin); however, other RhoGAPs seem to play positive and/or negative roles in different cancers (e.g., p190 RhoGAP). While current data offer no steadfast rule for the RhoGAP involvement in cancer, the significance of RhoGAPs has been established, and some of the GAPs may provide useful targets for future cancer therapy.
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Rho GTPase-activating Proteins in cell regulation
Trends in cell biology, 2003Co-Authors: Sun Young Moon, Yi ZhengAbstract:Rho family small GTPases serve as molecular switches involved in the regulation of diverse cellular functions including various cytoskeleton-related events and gene transcription. The Rho GTPase-activating Proteins (RhoGAPs) are one of the major classes of regulators of Rho GTPases found in all eukaryotes that are crucial in cell cytoskeletal organization, growth, differentiation, neuronal development and synaptic functions. Recent studies have implicated them as specific negative regulators of Rho protein signalling pathways and provided insight into how the RhoGAP-catalysed GTPase-activating reaction might proceed. Progress has also been made in understanding how various intracellular signals might converge on or diverge from RhoGAPs leading to their tight regulation or GAP-independent function.
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Regulation of RhoA GTP hydrolysis by the GTPase-activating Proteins p190, p50RhoGAP, Bcr, and 3BP-1.
Biochemistry, 1998Co-Authors: Baolin Zhang, Yi ZhengAbstract:The small GTP-binding protein RhoA becomes inactivated by hydrolyzing bound GTP to GDP through its intrinsic GTPase activity which is further stimulated by a family of Rho GTPase-activating protein...
Alfred G Gilman - One of the best experts on this subject based on the ideXlab platform.
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A G protein γ subunit-like domain shared between RGS11 and other RGS Proteins specifies binding to Gβ5 subunits
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Bryan E. Snow, Andrejs M Krumins, Alfred G Gilman, Sheu Fen Lee, Mark A. Wall, Stephen Chung, Joan Mangion, Sudha Arya, David P. SiderovskiAbstract:Regulators of G protein signaling (RGS) Proteins act as GTPase-activating Proteins (GAPs) toward the α subunits of heterotrimeric, signal-transducing G Proteins. RGS11 contains a G protein γ subunit-like (GGL) domain between its Dishevelled/Egl-10/Pleckstrin and RGS domains. GGL domains are also found in RGS6, RGS7, RGS9, and the Caenorhabditis elegans protein EGL-10. Coexpression of RGS11 with different Gβ subunits reveals specific interaction between RGS11 and Gβ5. The expression of mRNA for RGS11 and Gβ5 in human tissues overlaps. The Gβ5/RGS11 heterodimer acts as a GAP on Gαo, apparently selectively. RGS Proteins that contain GGL domains appear to act as GAPs for Gα Proteins and form complexes with specific Gβ subunits, adding to the combinatorial complexity of G protein-mediated signaling pathways.
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p115 RhoGEF, a GTPase activating protein for Gα12 and Gα13
Science (New York N.Y.), 1998Co-Authors: Tohru Kozasa, Alfred G Gilman, Xuejun Jiang, Matthew J. Hart, Pamela M. Sternweis, William D. Singer, Gideon BollagAbstract:Members of the regulators of G protein signaling (RGS) family stimulate the intrinsic guanosine triphosphatase (GTPase) activity of the α subunits of certain heterotrimeric guanine nucleotide–binding Proteins (G Proteins). The guanine nucleotide exchange factor (GEF) for Rho, p115 RhoGEF, has an amino-terminal region with similarity to RGS Proteins. Recombinant p115 RhoGEF and a fusion protein containing the amino terminus of p115 had specific activity as GTPase activating Proteins toward the α subunits of the G Proteins G12 and G13, but not toward members of the Gs, Gi, or Gqsubfamilies of Gα Proteins. This GEF may act as an intermediary in the regulation of Rho Proteins by G13 and G12.
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rgs4 and gaip are gtpase activating Proteins for gqα and block activation of phospholipase cβ by γ thio gtp gqα
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: John R Hepler, Alfred G Gilman, David M Berman, Tohru KozasaAbstract:RGS Proteins constitute a newly appreciated and large group of negative regulators of G protein signaling. Four members of the RGS family act as GTPase-activating Proteins (GAPs) with apparent specificity for members of the Giα subfamily of G protein subunits. We demonstrate here that two RGS Proteins, RGS4 and GAIP, also act as GAPs for Gqα, the Gα protein responsible for activation of phospholipase Cβ. Furthermore, these RGS Proteins block activation of phospholipase Cβ by guanosine 5′-(3-O-thio)triphosphate-Gqα. GAP activity does not explain this effect, which apparently results from occlusion of the binding site on Gα for effector. Inhibitory effects of RGS Proteins on G protein-mediated signaling pathways can be demonstrated by simple mixture of RGS4 or GAIP with plasma membranes.
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the gtpase activating protein rgs4 stabilizes the transition state for nucleotide hydrolysis
Journal of Biological Chemistry, 1996Co-Authors: David M Berman, Tohru Kozasa, Alfred G GilmanAbstract:Abstract RGS Proteins constitute a newly appreciated group of negative regulators of G protein signaling. Discovered by genetic screens in yeast, worms, and other organisms, two mammalian RGS Proteins, RGS4 and GAIP, act as GTPase-activating Proteins for members of the Gi family of G protein α subunits. We have purified recombinant RGS4 to homogeneity and demonstrate that it acts catalytically to stimulate GTP hydrolysis by Gi Proteins. Furthermore, RGS4 stabilizes the transition state for GTP hydrolysis, as evidenced by its high affinity for the GDP-AlF4−-bound forms of Goα and Giα and its relatively low affinity for the GTPγS- and GDP-bound forms of these Proteins. Consequently, RGS4 is most likely not a downstream effector for activated Gα subunits. All members of the Gi subfamily of Proteins tested are substrates for RGS4 (including Gtα and Gzα); the protein has lower affinity for Gqα, and it does not stimulate the GTPase activity of Gsα or G12α.
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gaip and rgs4 are gtpase activating Proteins for the gi subfamily of g protein α subunits
Cell, 1996Co-Authors: David M Berman, Thomas M Wilkie, Alfred G GilmanAbstract:Abstract A novel class of regulators of G protein signaling (RGS) Proteins has been identified recently. Genetic evidence suggests that RGS Proteins inhibit G protein–mediated signaling at the level of the receptor–G protein interaction or the G protein α subunit itself. We have found that two RGS family members, GAIP and RGS4, are GTPase-activating Proteins (GAPs), accelerating the rate of GTP hydrolysis by G iα1 at least 40-fold. All G i subfamily members assayed were substrates for these GAPs; G sα was not. RGS4 activates the GTPase activity of certain G iα1 mutants (e.g., R178C), but not others (e.g., Q204L). The GAP activity of RGS Proteins is consistent with their proposed role as negative regulators of G protein–mediated signaling.
Henry I Mosberg - One of the best experts on this subject based on the ideXlab platform.
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structure based design synthesis and pharmacologic evaluation tf peptide rgs4 inhibitors
Journal of Peptide Research, 2008Co-Authors: Huailing Zhong, John R Omnaas, Richard R Neubig, Henry I MosbergAbstract:: Regulators of G-protein signaling (RGS) Proteins form a multifunctional signaling family. A key role of RGS Proteins is binding to the G-protein Galpha-subunit and acting as GTPase-activating Proteins (GAPs), thereby rapidly terminating G protein-coupled receptor (GPCR) signaling. Using the published RGS4-Gialpha1 X-ray structure we have designed and synthesized a series of cyclic peptides, modeled on the Gialpha Switch I region, that inhibit RGS4 GAP activity. These compounds should prove useful for elucidating RGS-mediated activity and serve as a starting point for the development of a novel class of therapeutic agent.
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structure based design synthesis and activity of peptide inhibitors of rgs4 gap activity
Methods in Enzymology, 2004Co-Authors: Huailing Zhong, John R Omnaas, Richard R Neubig, Henry I MosbergAbstract:One of the principal roles of the multifunctional regulator of G-protein signaling (RGS) Proteins is to terminate G-protein-coupled receptor (GPCR) signaling by binding to the G-protein Gα subunit, thus acting as GTPase-activating Proteins (GAPs). In principle, then, selective inhibitors of this GAP function would have potential as therapeutic agents, as they could be used to augment the effects of endogenous or exogenous GPCR agonists. Using the published RGS4-Giα1 X-ray structure, we have designed and synthesized a series of cyclic peptides, modeled on the Giα switch I region, that inhibit RGS4 GAP activity, presumably by blocking the interaction between RGS4 and Giα1. These compounds should prove useful for elucidating RGS-mediated activity and serve as a starting point for the development of a novel class of therapeutic agent.
Klaus Scheffzek - One of the best experts on this subject based on the ideXlab platform.
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Ras-Specific GTPase-activating Proteins-Structures, Mechanisms, and Interactions.
Cold Spring Harbor perspectives in medicine, 2019Co-Authors: Klaus Scheffzek, Giridhar ShivalingaiahAbstract:Ras-specific GTPase-activating Proteins (RasGAPs) down-regulate the biological activity of Ras Proteins by accelerating their intrinsic rate of GTP hydrolysis, basically by a transition state stabilizing mechanism. Oncogenic Ras is commonly not sensitive to RasGAPs caused by interference of mutants with the electronic or steric requirements of the transition state, resulting in up-regulation of activated Ras in respective cells. RasGAPs are modular Proteins containing a helical catalytic RasGAP module surrounded by smaller domains that are frequently involved in the subcellular localization or contributing to regulatory features of their host Proteins. In this review, we summarize current knowledge about RasGAP structure, mechanism, regulation, and dual-substrate specificity and discuss in some detail neurofibromin, one of the most important negative Ras regulators in cellular growth control and neuronal function.
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Inhibition and termination of physiological responses by GTPase activating Proteins.
Physiological reviews, 2012Co-Authors: Erzsébet Ligeti, Stefan Welti, Klaus ScheffzekAbstract:Physiological processes are strictly organized in space and time. However, in cell physiology research, more attention is given to the question of space rather than to time. To function as a signal, environmental changes must be restricted in time; they need not only be initiated but also terminated. In this review, we concentrate on the role of one specific protein family involved in biological signal termination. GTPase activating Proteins (GAPs) accelerate the endogenously low GTP hydrolysis rate of monomeric guanine nucleotide-binding Proteins (GNBPs), limiting thereby their prevalence in the active, GTP-bound form. We discuss cases where defective or excessive GAP activity of specific Proteins causes significant alteration in the function of the nervous, endocrine, and hemopoietic systems, or contributes to development of infections and tumors. Biochemical and genetic data as well as observations from human pathology support the notion that GAPs represent vital elements in the spatiotemporal fine tuning of physiological processes.
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GTPase activating Proteins: structural and functional insights 18 years after discovery
Cellular and molecular life sciences : CMLS, 2005Co-Authors: Klaus Scheffzek, Mohammad Reza AhmadianAbstract:The conversion of guanosine triphosphate (GTP) to guanosine diphosphate (GDP) and inorganic phosphate (P(i)) by guanine nucleotide binding Proteins (GNBPs) is a fundamental process in living cells and represents an important timer in intracellular signalling and transport processes. While the rate of GNBP-mediated GTP hydrolysis is intrinsically slow, direct interaction with GTPase activating Proteins (GAPs) accelerates the reaction by up to five orders of magnitude in vitro. Eighteen years after the discovery of the first GAP, biochemical and structural research has been accumulating evidence that GAPs employ a much wider spectrum of chemical mechanisms than had originally been assumed, in order to regulate the chemical players on the catalytic protein-protein interaction stage.
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GTPase-activating Proteins: helping hands to complement an active site
Trends in biochemical sciences, 1998Co-Authors: Klaus Scheffzek, Mohammad Reza Ahmadian, Alfred WittinghoferAbstract:Stimulation of the intrinsic GTPase activity of GTP-binding Proteins by GTPase-activating Proteins (GAPs) is a basic principle of GTP-binding-protein downregulation. Recently, the molecular mechanism behind this reaction has been elucidated by studies on Ras and Rho, and their respective GAPs. The basic features involve stabilizing the existing catalytic machinery and supplementing it by an external arginine residue. This represents a novel mechanism for enzyme active-site formation.
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The interaction of Ras with GTPase-activating Proteins
FEBS letters, 1997Co-Authors: Alfred Wittinghofer, Klaus Scheffzek, Mohammad Reza AhmadianAbstract:Ras plays a major role as a molecular switch in many signal transduction pathways which lead to cell growth and differentiation. The GTPase reaction of Ras is of central importance in the function of the switch since it terminates Ras-effector interactions. GTPase-activating Proteins (GAPs) accelerate the very slow intrinsic hydrolysis reaction of the GTP-bound Ras by several orders of magnitude and thereby act as presumably negative regulators of Ras action. The GTP hydrolysis of oncogenic mutants of Ras remains unaltered. In this review we discuss recent biochemical and structural findings relating to the mechanism of GAP action, which strengthen the hypothesis that GAP accelerates the actual cleavage step by stabilizing the transition state of the phosphoryl transfer reaction.
Mohammad Reza Ahmadian - One of the best experts on this subject based on the ideXlab platform.
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GTPase activating Proteins: structural and functional insights 18 years after discovery
Cellular and molecular life sciences : CMLS, 2005Co-Authors: Klaus Scheffzek, Mohammad Reza AhmadianAbstract:The conversion of guanosine triphosphate (GTP) to guanosine diphosphate (GDP) and inorganic phosphate (P(i)) by guanine nucleotide binding Proteins (GNBPs) is a fundamental process in living cells and represents an important timer in intracellular signalling and transport processes. While the rate of GNBP-mediated GTP hydrolysis is intrinsically slow, direct interaction with GTPase activating Proteins (GAPs) accelerates the reaction by up to five orders of magnitude in vitro. Eighteen years after the discovery of the first GAP, biochemical and structural research has been accumulating evidence that GAPs employ a much wider spectrum of chemical mechanisms than had originally been assumed, in order to regulate the chemical players on the catalytic protein-protein interaction stage.
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GTPase-activating Proteins: helping hands to complement an active site
Trends in biochemical sciences, 1998Co-Authors: Klaus Scheffzek, Mohammad Reza Ahmadian, Alfred WittinghoferAbstract:Stimulation of the intrinsic GTPase activity of GTP-binding Proteins by GTPase-activating Proteins (GAPs) is a basic principle of GTP-binding-protein downregulation. Recently, the molecular mechanism behind this reaction has been elucidated by studies on Ras and Rho, and their respective GAPs. The basic features involve stabilizing the existing catalytic machinery and supplementing it by an external arginine residue. This represents a novel mechanism for enzyme active-site formation.
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The interaction of Ras with GTPase-activating Proteins
FEBS letters, 1997Co-Authors: Alfred Wittinghofer, Klaus Scheffzek, Mohammad Reza AhmadianAbstract:Ras plays a major role as a molecular switch in many signal transduction pathways which lead to cell growth and differentiation. The GTPase reaction of Ras is of central importance in the function of the switch since it terminates Ras-effector interactions. GTPase-activating Proteins (GAPs) accelerate the very slow intrinsic hydrolysis reaction of the GTP-bound Ras by several orders of magnitude and thereby act as presumably negative regulators of Ras action. The GTP hydrolysis of oncogenic mutants of Ras remains unaltered. In this review we discuss recent biochemical and structural findings relating to the mechanism of GAP action, which strengthen the hypothesis that GAP accelerates the actual cleavage step by stabilizing the transition state of the phosphoryl transfer reaction.
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Minireview The interaction of Ras with GTPase-activating Proteins
1997Co-Authors: Alfred Wittinghofer, Klaus Scheffzek, Mohammad Reza AhmadianAbstract:Ras plays a major role as a molecular switch in many signal transduction pathways which lead to cell growth and differentiation. The GTPase reaction of Ras is of central importance in the function of the switch since it terminates Ras-effector interactions. GTPase-activating Proteins (GAPs) accelerate the very slow intrinsic hydrolysis reaction of the GTP- bound Ras by several orders of magnitude and thereby act as presumably negative regulators of Ras action. The GTP hydrolysis of oncogenic mutants of Ras remains unaltered. In this review we discuss recent biochemical and structural findings relating to the mechanism of GAP action, which strengthen the hypothesis that GAP accelerates the actual cleavage step by stabilizing the transition state of the phosphoryl transfer reaction. © 1997 Federation of European Biochemical Societies.
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formation of a transition state analog of the ras gtpase reaction by ras gdp tetrafluoroaluminate and gtpase activating Proteins
Science, 1996Co-Authors: Rohit Mittal, Mohammad Reza Ahmadian, Roger S Goody, Alfred WittinghoferAbstract:Unlike the α subunits of heterotrimeric guanosine triphosphate (GTP)-binding Proteins, Ras-related GTP-binding Proteins have hitherto been considered not to bind or become activated by tetrafluoroaluminate (AlF4−). However, the product of the proto-oncogene ras in its guanosine diphosphate (GDP)-bound form interacted with AlF4− in the presence of stoichiometric amounts of either of the guanosine triphosphatase (GTPase)-activating Proteins (GAPs) p120GAP and neurofibromin. Neither oncogenic Ras nor a GAP mutant without catalytic activity produced such a complex. Together with the finding that the Ras-binding domain of the protein kinase c-Raf, whose binding site on Ras overlaps that of the GAPs, did not induce formation of such a complex, this result suggests that GAP and neurofibromin stabilize the transition state of the GTPase reaction of Ras.
