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Guanine Nucleotide Dissociation Stimulators

  • Chapter
GTPases in Biology I

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 108 / 1))

  • 169 Accesses

Abstract

Small Ras-like GTPases function as bipolar molecular switches to control a variety of cellular processes (Bourne et al. 1991a,b). The switches cycle between GTP- and GDP-bound states. Evidence from oncogenic mutants of Ras identified the GTP-bound form as the active state, a conclusion that has been substantiated by the effects of dominant negative mutants and from observations that the Ras GTP to GDP ratio is increased following growth factor or cytokine stimulation of cells (e. g., Stacey et al. 1991; Satoh et al. 1991). Ras and other similar proteins possess slow intrinsic GTPase activities that can be catalytically augmented by GTPase activating proteins (GAPs) (Trahey and McCormick 1987). The existence of a second catalytic factor which would convert Ras to the GTP-bound form was expected because of the very low k off for GDP from the p21 Ras protein (<0.01min−1) in the presence of physiologically relevant concentrations of Mg2+ (Hall and Self 1986; Neal et al. 1988). This slow off-rate would lead to the irreversible accumulation of inactive Ras-GDP if no mechanism existed to catalyze conversion to the Ras-GTP state. Mutations which confer abnormally high nucleotide release rates can, however, abrogate the necessity for such a mechanism and activate the transforming potential of the Ras proteins (Lacal and Aaronson 1986; Feig and Cooper 1988b).

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References

  • Araki S, Kikuchi A, Hata Y, Isomura M, Takai Y (1990) Regulation of reversible binding of smg p25A, a ras p21-like GTP-binding protein, to synaptic plasma membranes and vesicles by its specific regulatory protein, GDP dissociation inhibitor. J Biol Chem 265:13007–13015

    PubMed  CAS  Google Scholar 

  • Araki S, Kaibuchi K, Sasaki T, Hata Y, Takai Y (1991) Role of the C-terminal region of smg p25A in its interaction with membranes and the GDP/GTP exchange protein. Mol Cell Biol 11:1438–1447

    PubMed  CAS  Google Scholar 

  • Barbacid M (1987) Ras genes. Annu Rev Biochem 56:779–827

    Article  PubMed  CAS  Google Scholar 

  • Biggs J, Hersperger E, Steeg PS, Liotta LA, Shearn A (1990) A Drosophila gene that is homologous to a mammalian gene associated with tumor metastasis codes for a nucleoside diphosphate kinase. Cell 63:933–940

    Article  PubMed  CAS  Google Scholar 

  • Bischoff FR, Ponstingl H (1991a) Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1. Nature 354:80–82

    Article  PubMed  CAS  Google Scholar 

  • Bischoff FR, Ponstingl H (1991b) Mitotic regulator protein RCC1 is complexed with a nuclear ras-related polypeptide. Proc Natl Acad Sci USA 88:10830–10834

    Article  PubMed  CAS  Google Scholar 

  • Bischoff FR, Maier G, Tilz G, Ponstingl H (1990) A 47-kDa human nuclear protein recognized by antikinetochore autoimmune sera is homologous with the protein encoded by RCC1, a gene implicated in onset of chromosome condensation. Proc Natl Acad Sci USA 87:8617–8621

    Article  PubMed  CAS  Google Scholar 

  • Bonfini L, Karlovich CA, Dasgupta C, Banerjee U (1992) The Son of sevenless gene product: a putative activator of Ras. Science 255:603–605

    Article  PubMed  CAS  Google Scholar 

  • Bourne HR, Sanders DA, McCormick F (1991a) The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348:125–132

    Article  Google Scholar 

  • Bourne HR, Sanders DA, McCormick F (1991b) The GTPase superfamily: conserved structure and molecular mechanism. Nature 349:117–127

    Article  PubMed  CAS  Google Scholar 

  • Boy-Marcotte E, Damak F, Camonis J, Garreau H, Jacquet M (1989) The C-terminal part of a gene partially homologous to CDC25 gene suppresses the cdc25-5 mutation in Saccharomyces cerevisiae. Gene 77:21–30

    Article  PubMed  CAS  Google Scholar 

  • Broek D, Toda T, Michaeli T, Levin L, Birchmeier C, Zoller M, Powers S, Wigler M (1987) The S. cerevisiae CDC25 gene product regulates the RAS/adenylate cyclase pathway. Cell 48:789–799

    Article  PubMed  CAS  Google Scholar 

  • Burstein ES, Macara IG (1989) The ras-like protein p25rab3A is partially cytosolic and is expressed only in nueral tissue. Mol Cell Biol 9:4807–4811

    PubMed  CAS  Google Scholar 

  • Burstein ES, Macara IG (1992a) Characterization of a guanine nucleotide-releasing factor and a GTPase-activating protein that are specific for the ras-related protein p25rab3A. Proc Natl Acad Sci USA 89:1154–1158

    Article  PubMed  CAS  Google Scholar 

  • Burstein ES, Macara IG (1992b) Interactions of the ras-like protein, p25rab3A, with Mg2+ and Guanine Nucleotides. Biochem J 282:387–392

    PubMed  CAS  Google Scholar 

  • Burstein ES, Linko-Stentz K, Lu Z, Macara IG (1991) Regulation of the GTPase Activity of the ras-like Protein p25rab3A: Evidence for a rab3A-specific GAP. J Biol Chem 266:2689–2692

    PubMed  CAS  Google Scholar 

  • Chant J, Corrado K, Pringle JR, Herskowitz I (1991) Yeast BUD5, encoding a putative GDP-GTP exchange factor, is necessary for bud site selection and interacts with bud formation gene BGM1. Cell 65:1213–1224

    Article  PubMed  CAS  Google Scholar 

  • Colicelli J, Nicoletter C, Birchmeier C, Rodgers L, Riggs M, Wigler M (1991) Expression of three mammalian cDNAs that interfere with RAS function in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 88:2913–2917

    Article  PubMed  CAS  Google Scholar 

  • Crechet J-B, Poullet P, Mistou M-Y, Parmeggiani A, Camonis J, Boy-Marcotte E, Damak F, Jacquet M (1990) Enhancement of the GDP-GTP exchange of RAS proteins by the carboxyl-terminal domain of SCD25. Science 248:866–868

    Article  PubMed  CAS  Google Scholar 

  • Darchen F, Zahraoui A, Hammel F, Monteils M-P, Tavitian A, Scherman D (1990) Association of the GTP-binding protein Rab3A with bovine adrenal chromaffin granules. Proc Natl Acad Sci USA 87:5692–5696

    Article  PubMed  CAS  Google Scholar 

  • Downward J, Graves JD, Warne PH, Rayter S, Cantrell DA (1990a) Stimulation of p21ras upon T-cell activation. Nature 346:719–723

    Article  PubMed  CAS  Google Scholar 

  • Downward J, Riehl R, Wu L, Weinberg RA (1990b) Identification of a nucleotide exchange-promoting activity for p21ras. Proc Natl Acad Sci USA 87:5998–6002

    Article  PubMed  CAS  Google Scholar 

  • Drivas GT, Shih A, Coutavas E, Rush MG, D’Eustachio P (1990) Characterization of four novel ras-like genes expressed in a human teratocarcinoma cell line. Mol Cell Biol 10:1793–1798

    PubMed  CAS  Google Scholar 

  • Eva A, Vecchio G, Rao CD, Tronick SR, Aaronson SA (1988) The predicted DBL oncogene product defines a distinct class of transforming proteins. Proc Natl Acad Sci USA 85:2061–2065

    Article  PubMed  CAS  Google Scholar 

  • Farnsworth CC, Kawata M, Yoshida Y, Takai Y, Gelb MH, Glomset JA (1991) C terminus of the small GTP-binding protein smg p25A contains two geranylgeranylated cysteine residues and a methyl ester. Proc Natl Acad Sci USA 88:6196–6200

    Article  PubMed  CAS  Google Scholar 

  • Feig LA, Cooper GM (1988a) Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP. Mol Cell Biol 8:3235–3243

    PubMed  CAS  Google Scholar 

  • Feig LA, Cooper GM (1988b) Relationship among guanine nucleotide exchange, GTP hydrolysis, and transforming potential of mutated ras proteins. Mol Cell Biol 8:2472–2478

    PubMed  CAS  Google Scholar 

  • Gilman A (1987) G-proteins: transducers of receptor-generated signals. Annu Rev Biochem 56:615–649

    Article  PubMed  CAS  Google Scholar 

  • Hall A, Self AJ (1986) The effect of Mg2+ on the guanine nucleotide exchange rate of p21N-ras. J Biol Chem 261:10963–10965

    PubMed  CAS  Google Scholar 

  • Hart MJ, Eva A, Evans T, Aaronson SA, Cerione RA (1991) Catalysis of guanine nucleotide exchange on the CDC42Hs protein by the dbl oncogene product. Nature 354:311–314

    Article  PubMed  CAS  Google Scholar 

  • Hori Y, Kikuchi A, Isomura M, Katayama M, Miura Y, Fujioka H, Kaibuchi K, Takai Y (1991) Post-translational modifications of the C-terminal region of the rho protein are important for its interaction with membranes and the stimulatory and inhibitory GDP/GTP exchange proteins. Oncogene 6:515–522

    PubMed  CAS  Google Scholar 

  • Huang Y, Kung H, Kamata T (1990) Purification of a factor capable of stimulating the guanine nucleotide exchange reaction of ras proteins and its effect of ras-related small molecular mass G proteins. Proc Natl Acad Sci USA 87:8008–8012

    Article  PubMed  CAS  Google Scholar 

  • Hughes DA, Fukui Y, Yamamoto M (1990) Homologous activators of ras in fission and budding yeast. Nature 344:355–357

    Article  PubMed  CAS  Google Scholar 

  • Johnson DI, Pringle JR (1990) Molecular characterization of CDC42, a Saccharomyces cerevisiae gene involved in the development of cell polarity. J Cell Biol 111:143–152

    Article  PubMed  CAS  Google Scholar 

  • Jones S, Vignais M-L, Broach JR (1991) The CDC25 protein of Saccharomyces cervisiae promotes exchange of guanine nucleotides bound to Ras. Mol Cell Biol 11:2641–2646

    PubMed  CAS  Google Scholar 

  • Kaibuchi K, Mizuno T, Fujioka H, Yamamoto T, Kishi K, Fukumoto Y, Hori Takai Y (1990) Molecular cloning of the cDNA for stimulatory GDP/GTP exchange protein (GDS) for smg p21s, ras p21-like GTP-binding proteins, and characterization of GDS. J Biol Chem 265:16626–16634

    PubMed  Google Scholar 

  • Kikkawa S, Takahoshi K, Shimada N, Ui M, Kimura N, Katada T (1991) Conversion of GDP into GTP by nucleoside diphosphate kinase on the GTP-binding proteins [Erratum]. J Biol Chem 266:12795

    CAS  Google Scholar 

  • Koch CA, Anderson D, Moran MF, Ellis C, Pawson T (1991) SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science 252:668–674

    Article  PubMed  CAS  Google Scholar 

  • Lacal JC, Aaronson SA (1986) Activation of ras p21 transforming properties associated with an increase in the release rate of bound guanine nucleotide. Mol Cell Biol 6:4212–4220

    Google Scholar 

  • Leone A, Flatow U, King CR, Sandeen MA, Margulies IM, Liotta LA, Steeg PS (1991) Reduced tumor incidence, metastatic potential and cytokine responsiveness of nm23-transfected melanoma cells. Cell 65:25–35

    Article  PubMed  CAS  Google Scholar 

  • Matteoli M, Takei K, Cameron R, Hurlbut P, Johnston PA, Sudhof TC, Jahn R, De Camilli P (1991) Association of Rab3A with synaptic vesicles at late stages of the secretory pathway. J Cell Biol 115:625–633

    Article  PubMed  CAS  Google Scholar 

  • Matsui Y, Kikuchi A, Kondo J, Hishida T, Teranishi Y, Takai Y (1988) Nucleotide and deduced amino acid sequences of a GTP-binding protein family with molecular weights of 25000 from bovine brain. J Biol Chem 263:11071–11074

    PubMed  CAS  Google Scholar 

  • Matsui Y, Kikuchi A, Araki S, Hata Y, Kondo J, Teranishi Y, Takai Y (1990) Molecular cloning and characterization of a novel type of regulatory protein (GDI) for smg p25A, a ras p21-like GTP-binding protein. Mol Cell Biol 10:4116–4122

    PubMed  CAS  Google Scholar 

  • Matsumoto T, Beach D (1991) Premature initiation of mitosis in yeast lacking RCC1 or an interacting GTPase. Cell 66:347–360

    Article  PubMed  CAS  Google Scholar 

  • Mizoguchi A, Kim S, Ueda T, Takai Y (1989) Tissue distribution of smg p25A, a ras p21-like GTP-binding protein, studied by use of a specific monoclonal antibody. Biochem Biophys Res Commun 162:1438–1445

    Article  PubMed  CAS  Google Scholar 

  • Mizuno T, Kaibuchi K, Yamamoto T, Kawamura M, Sakoda T, Fujioka H, Matsuura, Takai Y (1991) A stimulatory GDP/GTP exchange protein for smg p21 is active on the post-translationally processed form of c-Ki-ras p21 and rhoA p21. Proc Natl Acad Sci USA 88:6442–6446

    Article  PubMed  CAS  Google Scholar 

  • Neal SE, Eccleston JF, Hall A, Webb MR (1988) Kinetic analysis of the hydrolysis of GTP by p21N-ras: the basal GTPase mechanism. J Biol Chem 263:19718–19722

    PubMed  CAS  Google Scholar 

  • Ohtsubo M, Okazaki H, Nishimoto T (1989) The RCC1 protein, a regulator for the onset of chromosome condensation locates in the nucleus and binds to DNA. J Cell Biol 109:1389–1397

    Article  PubMed  CAS  Google Scholar 

  • Panniers R, Rowlands AG, Henshaw EC (1988) The effect of Mg2+ and guanine nucleotide exchange factor on the binding of guanine nucleotides to eukaryotic to eukaryotic initiation factor 2. J Biol Chem 263:5518–5525

    Google Scholar 

  • Penningroth SM, Kirschner MW (1977) Nucleotide binding and phosphorylation in microtubule assembly in vitro. J Mol Biol 115:643–673

    Article  PubMed  CAS  Google Scholar 

  • Powers S, Gonzales E, Christensen T, Cubert J, Broek D (1991) Functional cloning of BUD5, a CDC25-related gene from S. cerevisiae that can suppress a dominant-negative RAS2 mutant. Cell 65:1225–1231

    Article  PubMed  CAS  Google Scholar 

  • Randazzo PA, Northup JK, Kahn RA (1991) Activation of a small GTP-binding protein by nucleoside diphosphate kinase. Science 254:850–853

    Article  PubMed  CAS  Google Scholar 

  • Robinson LC, Gibbs JB, Marshall MS, Sigal IS, Tatchell K (1987) CDC25: a component of the RAS-adenylate cyclase pathway in Saccharomyces cerevisiae. Science 235:1218–1221

    Article  PubMed  CAS  Google Scholar 

  • Shirataki H, Kaibuchi K, Hiroyoshi M, Isomura M, Araki S, Sasaki T, Takai Y (1991) Inhibition of the action of the stimulatory GDP/GTP exchange protein for smg p21 by the geranylgeranylated synthetic peptides designed from its c-terminal region. J Biol Chem 266:20672–20677

    PubMed  CAS  Google Scholar 

  • Simon MA, Bowtell DDL, Dodson GS, Laverty TR, Rubin GM (1991) Rasl and a putative guanine nucleotide exchange factor crucial steps in signaling by the sevenless protein tyrosine kinase. Cell 67:701–716

    Article  PubMed  CAS  Google Scholar 

  • Stacey DW, Feig LA, Gibbs JB (1991) Dominant inhibitory Ras mutants selectively inhibit the activity of either cellular or oncogenic Ras. Mol Cell Biol 11:4053–4064

    PubMed  CAS  Google Scholar 

  • Touchot N, Chardin P, Tavitian A (1987) Four additional members of the ras gene superfamily isolated by an oligonucleotide strategy: molecular cloning of ypt-related cDNAs from a rat brain library. Proc Natl Acad Sci USA 84:8210–8214

    Article  PubMed  CAS  Google Scholar 

  • Trahey M, McCormick F (1987) A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238:542–545

    Article  PubMed  CAS  Google Scholar 

  • Valencia A, Chardin P, Wittinghofer A, Sander C (1991) The ras protein family: evolutionary tree and role of conserved amino acids. Biochemistry 30:4637–4648

    Article  PubMed  CAS  Google Scholar 

  • West M, Kung H, Kamata T (1990) A novel membrane factor stimulates guanine nucleotide exchange reaction of ras proteins. FFBS Lett 259:245–248

    Article  CAS  Google Scholar 

  • Wolfman A, Macara IG (1990) A cytosolic protein catalyzes the release of GDP from p21ras. Science 248:67–69

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto T, Kaibuchi K, Mizuno T, Hiroyoshi M, Shirataki H, Takai Y (1990) Purification and characterization from bovine brain cytosol of proteins that regulate the GDP/GTP exchange reaction of smg p21s, ras p21-like GTP-binding roteins. J Biol Chem 265:16626–16634

    PubMed  CAS  Google Scholar 

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Authors
  1. I. G. Macara
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  2. E. S. Burstein
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Editors and Affiliations

  1. Department of Medicine, Cell Biology and Experimental Therapeutics, Room 3C-385, Houston VA Medical Center, Baylor College of Medicine, 2002 Holcombe Boulevard, Houston, TX, 77030, USA

    Burton F. Dickey M.D.

  2. Department of Cell Biology, Molecular Physiology and Biophysics, Medicine and Neurosciences, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Lutz Birnbaumer Ph.D.

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© 1993 Springer-Verlag Berlin Heidelberg

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Macara, I.G., Burstein, E.S. (1993). Guanine Nucleotide Dissociation Stimulators. In: Dickey, B.F., Birnbaumer, L. (eds) GTPases in Biology I. Handbook of Experimental Pharmacology, vol 108 / 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-78267-1_24

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  • DOI: https://doi.org/10.1007/978-3-642-78267-1_24

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-78269-5

  • Online ISBN: 978-3-642-78267-1

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