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Gene Review

IRA2  -  Ira2p

Saccharomyces cerevisiae S288c

Synonyms: CCS1, GLC4, Inhibitory regulator protein IRA2, O0985, YOL081W
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Disease relevance of IRA2

  • Three proteins, GTPase activating protein (GAP), neurofibromatosis 1 (NF1) and the yeast inhibitory regulator of the RAS-cAMP pathway (IRA2), have the ability to stimulate the GTPase activity of Ras proteins from higher animals or yeast [1].

High impact information on IRA2


Biological context of IRA2


Associations of IRA2 with chemical compounds

  • Deletion of the Ras-GAPs IRA2 (alone or with IRA1) or the presence of RAS2Val19 allele causes constitutively high Ras GTP loading that no longer increases upon glucose addition [9].
  • Deletion of IRA2 uniquely led to high sensitivity to cumene hydroperoxide, suggesting that IRA2 may have a distinct role for the response to this stress [10].
  • Rather, this mutation, RAS2-P41S (proline 41 to serine), which lies in the effector region of RAS, is shown to abolish the ability of the IRA2 protein to stimulate the GTPase activity of the mutant RAS protein [11].
  • Deletion of PDE2, similar to ira2 deletion, rendered cells sensitive to freeze-thawing, peroxides, paraquat, cycloheximide, heavy metals, NaCl, heat, or cold shock [10].
  • The stimulatory activity of Ira2p on Ha-Ras increased by substituting segments of the finger loop region with p120-GAP residues, especially with the six residues forming the tip of the arginine loop [12].

Physical interactions of IRA2

  • In this work, the results of (i) a two-hybrid screen of a yeast genomic library, (ii) glutathione S-transferase pulldown experiments, (iii) multicopy suppressor tests of cdc25-1 mutants, and (iv) stress resistance tests to evaluate the activation level of Ras demonstrate that Tfs1p interacts with and inhibits Ira2p [13].

Regulatory relationships of IRA2

  • The region homologous between the IRA1 protein and ras GTPase-activating protein is also conserved in IRA2 [4].
  • A mutant allele of RAS1 that dominantly interferes with the wild-type Ras function in the yeast Saccharomyces cerevisiae was discovered during screening of mutants that suppress an ira2 disruption mutation [14].
  • (i) Extracts of yeast cells overexpressing IRA2 stimulated the GTPase activity of the yeast RAS2 protein [15].

Other interactions of IRA2

  • We identified IRA2, encoding a protein of 3,079 amino acids, that is 45% identical to the IRA1 protein [4].
  • Disruption of the IRA2 gene resulted in (i) increased sensitivity to heat shock and nitrogen starvation, (ii) sporulation defects, and (iii) suppression of the lethality of the cdc25 mutant [4].
  • We present evidence that the down-regulatory effect of RPI1 requires the presence of one of the two Ras GTPase activators, IRA1 and IRA2 [16].
  • Increases in cAMP levels were detected in the rom2 deletion mutants, and these were comparable with the effects of an ira2 mutation [17].
  • This subcellular localization was conserved in a ras1 ras2 double disruption mutant and in a ira2 disruption mutant [18].


  1. The GTPase stimulatory activities of the neurofibromatosis type 1 and the yeast IRA2 proteins are inhibited by arachidonic acid. Golubić, M., Tanaka, K., Dobrowolski, S., Wood, D., Tsai, M.H., Marshall, M., Tamanoi, F., Stacey, D.W. EMBO J. (1991) [Pubmed]
  2. S. cerevisiae genes IRA1 and IRA2 encode proteins that may be functionally equivalent to mammalian ras GTPase activating protein. Tanaka, K., Nakafuku, M., Satoh, T., Marshall, M.S., Gibbs, J.B., Matsumoto, K., Kaziro, Y., Toh-e, A. Cell (1990) [Pubmed]
  3. The kelch proteins Gpb1 and Gpb2 inhibit Ras activity via association with the yeast RasGAP neurofibromin homologs Ira1 and Ira2. Harashima, T., Anderson, S., Yates, J.R., Heitman, J. Mol. Cell (2006) [Pubmed]
  4. IRA2, a second gene of Saccharomyces cerevisiae that encodes a protein with a domain homologous to mammalian ras GTPase-activating protein. Tanaka, K., Nakafuku, M., Tamanoi, F., Kaziro, Y., Matsumoto, K., Toh-e, A. Mol. Cell. Biol. (1990) [Pubmed]
  5. The CCS1 gene from Saccharomyces cerevisiae which is involved in mitochondrial functions is identified as IRA2 an attenuator of RAS1 and RAS2 gene products. Bussereau, F., Dupont, C.H., Boy-Marcotte, E., Mallet, L., Jacquet, M. Curr. Genet. (1992) [Pubmed]
  6. Sequence of a 10.27 kb segment on the left arm of chromosome XV from Saccharomyces cerevisiae includes part of the IRA2 gene and a putative new gene. Zumstein, E., Griffin, H., Schweizer, M. Yeast (1994) [Pubmed]
  7. Activation of the Ras-cAMP signal transduction pathway inhibits the proteasome-independent degradation of misfolded protein aggregates in the endoplasmic reticulum lumen. Umebayashi, K., Fukuda, R., Hirata, A., Horiuchi, H., Nakano, A., Ohta, A., Takagi, M. J. Biol. Chem. (2001) [Pubmed]
  8. Properties and regulation of the catalytic domain of Ira2p, a Saccharomyces cerevisiae GTPase-activating protein of Ras2p. Parrini, M.C., Jacquet, E., Bernardi, A., Jacquet, M., Parmeggiani, A. Biochemistry (1995) [Pubmed]
  9. Activation state of the Ras2 protein and glucose-induced signaling in Saccharomyces cerevisiae. Colombo, S., Ronchetti, D., Thevelein, J.M., Winderickx, J., Martegani, E. J. Biol. Chem. (2004) [Pubmed]
  10. The high-affinity cAMP phosphodiesterase of Saccharomyces cerevisiae is the major determinant of cAMP levels in stationary phase: involvement of different branches of the Ras-cyclic AMP pathway in stress responses. Park, J.I., Grant, C.M., Dawes, I.W. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  11. A dominant activating mutation in the effector region of RAS abolishes IRA2 sensitivity. Tanaka, K., Wood, D.R., Lin, B.K., Khalil, M., Tamanoi, F., Cannon, J.F. Mol. Cell. Biol. (1992) [Pubmed]
  12. The arginine finger loop of yeast and human GAP is a determinant for the specificity toward Ras GTPase. te Biesebeke, R., Krab, I.M., Parmeggiani, A. Biochemistry (2001) [Pubmed]
  13. Tfs1p, a member of the PEBP family, inhibits the Ira2p but not the Ira1p Ras GTPase-activating protein in Saccharomyces cerevisiae. Chautard, H., Jacquet, M., Schoentgen, F., Bureaud, N., Bénédetti, H. Eukaryotic Cell (2004) [Pubmed]
  14. A dominant interfering mutation in RAS1 of Saccharomyces cerevisiae. Fujimura, K., Tanaka, K., Toh-e, A. Mol. Gen. Genet. (1993) [Pubmed]
  15. IRA2, an upstream negative regulator of RAS in yeast, is a RAS GTPase-activating protein. Tanaka, K., Lin, B.K., Wood, D.R., Tamanoi, F. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  16. Overexpression of RPI1, a novel inhibitor of the yeast Ras-cyclic AMP pathway, down-regulates normal but not mutationally activated ras function. Kim, J.H., Powers, S. Mol. Cell. Biol. (1991) [Pubmed]
  17. Rom2p, the Rho1 GTP/GDP exchange factor of Saccharomyces cerevisiae, can mediate stress responses via the Ras-cAMP pathway. Park, J.I., Collinson, E.J., Grant, C.M., Dawes, I.W. J. Biol. Chem. (2005) [Pubmed]
  18. Membrane-anchoring domains of Cdc25p, a Saccharomyces cerevisiae ras exchange factor. Garreau, H., Geymonat, M., Renault, G., Jacquet, M. Biol. Cell (1996) [Pubmed]
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