Regulation of ras-Interacting Proteins in Saccharomyces cerevisiae

  • K. Tanaka
  • A. Toh-e
  • K. Matsumoto
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 108 / 1)


The environment surrounding cells of multicellular organisms is rich in nutrients; cells can easily take up nutrients available in special spaces such as blood vessels. However, these cells require growth factor(s) to start the cell division cycle. In contrast, in unicellular microorganisms such as yeast, nutrients themselves regulate cell growth. Yeast cells continue to divide as long as there is a sufficient supply of extracellular nutrients. In poor nutrient conditions, cells stop growing and arrest at the G1 phase of the cell cycle. The physiology of the G1 phase in nutrient-deprived conditions is apparently different from that of the G1 phase of growing cells. G1-arrested cells acquire resistance to environmental stress such as starvation or heat shock and become competent for the meiotic process.


Saccharomyces Cerevisiae Adenylyl Cyclase GTPase Activate Protein CDC25 Gene Intrinsic GTPase Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adari H, Lowy D-R, Willumsen B-M, Der C-J, McCormick F (1988) Guanosine triphosphatase activating protein (GAP) interacts with the p21 ras effector binding domain. Science 240:518–521PubMedCrossRefGoogle Scholar
  2. Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, Collins F (1990) The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63:851–859PubMedCrossRefGoogle Scholar
  3. Barbacid M (1987) ras Genes. Annu Rev Biochem 56:779–827PubMedCrossRefGoogle Scholar
  4. Basu T-N, Gutmann D-H, Fletcher J-A, Glover T-W, Collins F-S, Downward J (1992) Aberrant regulation of ras proteins in malignant tumor cells from type 1 neurofibromatosis patients. Nature 356:713–715PubMedCrossRefGoogle Scholar
  5. Beckner S-K, Hattori S, Shih T-Y (1985) The ras oncogene product p21 is not a regulatory component of adenylate cyclase. Nature 317:71–72PubMedCrossRefGoogle Scholar
  6. 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 77:21–30PubMedCrossRefGoogle Scholar
  7. Bourne H-R, Sanders D-A, McCormick F (1991) The GTPase superfamily: conserved structure and molecular mechanism. Nature 349:117–127PubMedCrossRefGoogle Scholar
  8. Broek D, Samily N, Fasano O, Fujiyama A, Tamanoi F, Northup J, Wigler M (1985) Differential activation of yeast adenylate cyclase by wild-type and mutant ras proteins. Cell 41:763–770PubMedCrossRefGoogle Scholar
  9. Broek D, Toda T, Michaeli T, Levin L, Birchmeier C, Zoller M, Powers S, Wigler M (1987) The Saccharomyces cerevisiae CDC25 gene product regulates the RAS-adenylate cyclase pathway. Cell 48:789–800PubMedCrossRefGoogle Scholar
  10. Cales C, Hancock J-F, Marshall C, Hall A (1988) The cytoplasmic protein GAP is implicated as the targer for regulation by the ras gene product. Nature 332:548–551PubMedCrossRefGoogle Scholar
  11. Camonis J-H, Kalekine M, Gondre B, Garreau H, Boy-Marcotte E, Jacquet M (1986) Characterization, cloning and sequence analysis of the CDC25 gene which controls the cyclic AMP level of Saccharomyces cerevisiae. EMBO J 5:375–380PubMedGoogle Scholar
  12. Chant J, Corrado K, Pringle J-R, Herskowitz I (1991) Yeast BUD5, encoding a putative GDP-GTP exchange factor, is necessary for bud site selection and interacts with bud formation gene BEM1. Cell 65:1213–1224PubMedCrossRefGoogle Scholar
  13. Crechet J-B, Poullet P, Mistou M-Y, Parmeggiani A, Camonis J, Boy-Marcotte E, Damak F, Jacquet M (1990) Enhancement of the GTP-GDP exchange of RAS proteins by the carboxyl-terminal domain of SCD25. Science 248:866–868PubMedCrossRefGoogle Scholar
  14. Damak F, Boy-Marcotte E, Le-Roscouet D, Guilbaud R, Jacquet M (1991) SDC25, a CDC25-like gene which contains a RAS-activating domain and is a dispensable gene of Saccharomyces cerevisiae. Mol Cell Biol 11:202–212PubMedGoogle Scholar
  15. Declue J-E, Papageorge A-G, Fletcher J-A, Diehl S-R, Ratner N, Vass W-C, Lowy D-R (1992) Abnormal regulation of mammalian p21 ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 69:265–273PubMedCrossRefGoogle Scholar
  16. DeFeo-Jones D, Scolnick E, Koller R, Dhar R (1983) ras-Related gene sequences identified and isolated from Saccharomyces cerevisiae. Nature 306:707–709PubMedCrossRefGoogle Scholar
  17. DeFeo-Jones D, Tatchell K, Robinson L-C, Sigal I-S, Vass W-C, Lowy D-R, Scolnick E-M (1985) Mammalian and yeast ras gene products: biological function in their heterologous systems. Science 228:179–184PubMedCrossRefGoogle Scholar
  18. Deschenes R-J, Broach J-R (1989) The function of RAS genes in Saccharomyces cerevisiae. Adv Cancer Res 54:79–138Google Scholar
  19. Eraso P, Gancedo J-M (1985) Use of glucose analogues to study the mechanism of glucose-mediated cAMP increase in yeast. FEBS Lett 191:51–54CrossRefGoogle Scholar
  20. Fedor-Chaiken M, Deschenes R-J, Broach J-R (1990) SRV2, a gene required for RAS activation of adenylyl cyclase in yeast. Cell 61:329–340PubMedCrossRefGoogle Scholar
  21. Field J, Nikawa J, Broek D, MacDonald B, Rodgeers L, Wilson I-A, Lerner R-A, Wigler M (1988) Purification of a RAS-responsive adenylyl cyclase complex from Saccharomyces cerevisiae by use of an epitope addition method. Mol Cell Biol 8:2159–2165PubMedGoogle Scholar
  22. Field J, Vojtek A, Ballester R, Bolger G, Colicelli J, Ferguson K, Gerst J, Kataoka T, Michaeli T, Powers S, Riggs M, Rodgers L, Wieland I, Wheland B, Wigler M (1990) Cloning and characterization of CAP, the S. cerevisiae gene encoding the 70 kd adenylyl cyclase-associated protein. Cell 61:319–327PubMedCrossRefGoogle Scholar
  23. Fukui Y, Kozasa T, Kaziro Y, Takeda T, Yamamoto M (1986) Role of a ras homolog in the life cycle of Schizosaccharomyces pombe. Cell 44:329–336PubMedCrossRefGoogle Scholar
  24. Gaul U, Mardon G, Rubin G-M (1992) A putative Ras GTPase activating protein acts as a negative regulator of signaling by the Sevenless receptor tyrosine kinase. Cell 68:1007–1019PubMedCrossRefGoogle Scholar
  25. Gerst J, Ferguson K, Vojtek A, Wigler M, Field J (1991) CAP is a bifunctional component of the S. cerevisiae adenylyl cyclase complex. Mol Cell Biol 11:1248–1257PubMedGoogle Scholar
  26. Gibbs J-B (1991) Ras C-terminal processing enzymes — new drug targets? Cell 65:1–4PubMedCrossRefGoogle Scholar
  27. Gibbs J-B, Marshall M-S (1989) The ras oncogene-an important regulatory element in lower eukaryotic organisms. Microbiol Rev 53:171–185PubMedGoogle Scholar
  28. Hughes D-A, Fukui Y, Yamamoto M (1990) Homologous activators of ras in fission and budding yeast. Nature 344:355–357PubMedCrossRefGoogle Scholar
  29. Imai Y, Miyake S, Hughes D-A, Yamamoto M (1991) Identification of a GTPase-activating-protein homolog in Schizosaccharomyces pombe. Mol Cell Biol 11:3088–3094PubMedGoogle Scholar
  30. Jones S, Vignais M-L, Broach J-R (1991) The CDC25 protein of Saccharomyces cerevisiae promotes exchange of guanine nucleotides bound to Ras. Mol Cell Biol 11:2641–2646PubMedGoogle Scholar
  31. Kataoka T, Powers S, McGill C, Fasano O, Strathern J, Broach J, Wigler M (1984) Genetic analysis of yeast Saccharomyces cerevisiae RAS1 and RAS2 genes. Cell 37:437–445PubMedCrossRefGoogle Scholar
  32. Kataoka T, Powers S, Cameron S, Fasano O, Goldfarb M, Broach J, Wigler M (1985a) Functional homology of mammalian and yeast ras genes. Cell 40:19–26PubMedCrossRefGoogle Scholar
  33. Kataoka T, Broek D, Wigler M (1985b) DNA sequence and characterization of the Saccharomyces cerevisiae gene encoding adenylate cyclase. Cell 43:493–505PubMedCrossRefGoogle Scholar
  34. Kim J-H, Powers S (1991) Overexpression of RPI1, a novel inhibitor of the yeast Ras-cyclic AMP pathway, down-regulates normal but not mutationally activated Ras function. Mol Cell Biol 11:3894–3904PubMedGoogle Scholar
  35. Martin G-A, Viskochil D, Bollag G, McCabe P-C, Crosier W-J, Haubruck H, Conroy L, Clark R, O’Connell P, Cawthon R-M, Innis M-A, McCormick F (1990) The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63:843–849PubMedCrossRefGoogle Scholar
  36. Marshall M-S, Gibbs J-B, Scolnick E-M, Sigal I-S (1988) An adenylate cyclase from Saccharomyces cerevisiae that is stimulated by ras proteins with effector mutations. Mol Cell Biol 8:52–61PubMedGoogle Scholar
  37. Matsumoto K, Uno I, Kato K, Ishikawa T (1985) Genetic analysis of the role of cAMP in yeast. Yeast 1:15–24PubMedCrossRefGoogle Scholar
  38. Mbonyi K, Beullens M, Detremerie K, Geerts L, Thevelein J-M (1988) Requirement of one functional RAS gene and inability of an oncogenic RAS variant to mediate the glucose-induced cyclic AMP signal in the yeast Saccharomyces cerevisiae. Mol Cell Biol 8:3051–3057PubMedGoogle Scholar
  39. Milburn M-V, Tong L, deVos A-M, Brunger A, Yamaizumi Z, Nishimura S, Kim S-H (1990) Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science 247:939–945PubMedCrossRefGoogle Scholar
  40. Mitts M-R, Bradshaw-Rouse J, Heideman W (1991) Interactions between adenylate cyclase and the yeast GAP protein, IRA1. Mol Cell Biol 11:4591–4598PubMedGoogle Scholar
  41. Munder T, Kuntzel H (1989) Glucose-induced cAMP signalling in Saccharomyces cerevisiae is mediated by the CDC25 protein. FEBS Lett 242:341–345PubMedCrossRefGoogle Scholar
  42. Powers S, Kataoka T, Fasano O, Goldfarb M, Strathern J, Broach J, Wigler M (1984) Genes in Saccharomces cerevisiae encoding proteins with domains homologous to the mammalian ras proteins. Cell 36:607–612PubMedCrossRefGoogle Scholar
  43. 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 65:1225–1231PubMedCrossRefGoogle Scholar
  44. Robinson L-C, Gibbs J-B, Marshall M-S, Sigal I-S, Tatchell K (1987) CDC25: a compoent of the RAS-adenylate cyclase pathway in Saccharomyces cerevisiae. Science 235:1218–1221PubMedCrossRefGoogle Scholar
  45. Schlichting I, Almo S-C, Rapp G, Wilson K, Petratos K, Lentfer A, Wittinghofer A, Kabsch W, Pai E-F, Petsko G-A, Goody R-S (1990) Time-resolved X-ray crystallographic study of the conformational change in Ha-Ras p21 protein on GTP hydrolysis. Nature 345:309–315PubMedCrossRefGoogle Scholar
  46. Sigal I-S, Gibbs J-B, D’Alonzo J-S, Scolnick E-M (1986) Identification of effector residues and a neutralizing epitope of Ha-ras-encoded p21. Proc Natl Acad Sci USA 83:4725–4729PubMedCrossRefGoogle Scholar
  47. Simon M-A, Bowtell D-D-L, Dodson G-S, Laverty T-R, Rubin G-M (1991) Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signalling by the Sevenless protein tyrosine kinase. Cell 67:701–716PubMedCrossRefGoogle Scholar
  48. Tamanoi F, Walsh M, Kataoka T, Wigler M (1984) A product of yeast RAS2 gene is a guanine nucleotide binding protein. Proc Natl Acad Sci USA 81:6924–6928PubMedCrossRefGoogle Scholar
  49. Tanaka K, Matsumoto K, Tohe A (1989) IRA1, an inhibitory regulator of the RAS-cyclic AMP pathway in Saccharomyces cerevisiae. Mol Cell Biol 9:757–768PubMedGoogle Scholar
  50. Tanaka K, Nakafuku M, Satoh T, Marshall M-S, Gibbs J-B, Matsumoto K, Kaziro Y, Tohe A (1990a) Saccharomyces cerevisiae genes, IRA1 and IRA2 encode proteins that may be functionally equivalent to mammalian ras GTPase activating protein (GAP). Cell 60:803–807PubMedCrossRefGoogle Scholar
  51. Tanaka K, Nakafuku M, Tamanoi F, Kaziro Y, Matsumoto K, Tohe A (1990b) IRA2, a second gene of Saccharomycess cerevisiae that encodes a protein with a domain homologous to mammalian ras GTPase-activating protein. Mol Cell Biol 10:4303–4313PubMedGoogle Scholar
  52. Tanaka K, Lin B-K, Wood D-R, Tamanoi F (1991) IRA2, an upstream negative regulator of RAS in yeast, is a RAS GTPase activating protein (GAP). Proc Natl Acad Sci USA 88:468–472PubMedCrossRefGoogle Scholar
  53. Tanaka K, Wood D-R, Lin B-K, Khalil M, Tamanoi F, Cannon J-F (1992) A dominant activating mutation in the effector region of RAS abolishes IRA2 sensitivity. Mol Cell Biol 12:631–637PubMedGoogle Scholar
  54. Temeles G-L, Gibbs J-B, D’Alonzo J-S, Sigal I-S, Scolnick E-M (1985) Yeast and mammalian ras proteins have conserved biochemical properties. Nature 313:700–703PubMedCrossRefGoogle Scholar
  55. Toda T, Uno I, Ishikawa T, Powers S, Kataoka T, Broek D, Cameron S, Broach J, Matsumoto K, Wigler M (1985) In yeast, RAS proteins are controlling elements of adenylate cyclase. Cell 40:27–36PubMedCrossRefGoogle Scholar
  56. Toda T, Cameron S, Saas P, Zoller M, Wigler M (1987) Three different genes in S. cerevisiae encode the catalytic subunits of the cAMP-dependent protein kinase. Cell 50:277–287PubMedCrossRefGoogle Scholar
  57. Trahey M, McCormick F (1987) A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238:542–545PubMedCrossRefGoogle Scholar
  58. Vojtek A, Haarer B, Field J, Gerst J, Pollard T-D, Brown S, Wigler M (1991) Evidence for a functional link between profilin and CAP in the yeast S. cerevisiae. Cell 66:497–505PubMedCrossRefGoogle Scholar
  59. Wickner R-B, Koh T-J, Crowley J-C, O’neil J, Kaback D-B (1987) Molecular cloning of chromosome I DNA from Saccharomyces cerevisiae: isolation of the MAK16 gene and analysis of an adjacent gene essential for growth at low temperatures. Yeast 3:51–57PubMedCrossRefGoogle Scholar
  60. Xu G, O’Connell P, Viskochil D, Cawthon R, Robertson M, Culver M, Dunn D, Stevens J, Gesteland R, White R, Weiss R (1990a) The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62:599–608PubMedCrossRefGoogle Scholar
  61. Xu G, Lin B, Tanaka K, Dunn D, Wood D, Gesteland R, White R, Weiss R, Tamanoi F (1990b) The catalytic domain of the neurofibromatosis type-1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 63:835–841PubMedCrossRefGoogle Scholar
  62. Yatani A, Okabe K, Polakis P, Halenbeck R, McCormick F, Brown A-M (1990) RAS p21 and GAP inhibit coupling of muscarinic receptors to atrial K+ channels. Cell 61:769–776PubMedCrossRefGoogle Scholar
  63. Zhang K, DeClue J-E, Vass W-C, Papageorge A-G, McCormick F, Lowy D-R (1990) Suppression of c-ras transformation by GTPase activating protein. Nature 346:754–756PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • K. Tanaka
  • A. Toh-e
  • K. Matsumoto

There are no affiliations available

Personalised recommendations