Disease relevance of IRA1

• These results suggest that there is a family of sequence-related GAP proteins, which to date includes ras GAP and its yeast counterparts IRA1 and IRA2, rho GAP and the Neurofibromatosis gene product NF1 [1].

High impact information on IRA1

• The silent FLO10 gene is activated by high-frequency loss-of-function mutations at either IRA1 or IRA2 [2].
• The IRA1 and IRA2 genes of S. cerevisiae encode closely related proteins that also share homology with mammalian GAP (ras GTPase activating protein) [3].
• A much broader region, centered around this same 360 amino acid sequence, is strikingly similar to the yeast IRA1 product, which has a similar amino acid sequence and functional homology to mammalian GAP [4].
• Other studies indicate that IRA1 controls the level of RAS activity, presumably by regulating GTP hydrolysis [5].
• Because the Gpb1/2 binding domain on Ira1/2 is conserved in the human neurofibromin protein, an analogous signaling network may contribute to the neoplastic development of neurofibromatosis type 1 [6].

Biological context of IRA1

• Diploids homozygous for the disrupted IRA1 gene were deficient in sporulation [7].
• We have identified eight Schizosaccharomyces pombe cDNAs that, when overexpressed, suppress the HS-sensitive phenotype associated with the deletion of IRA1 in S. cerevisiae [8].
• To identify other genes involved in this pathway, we screened yeast genomic DNA libraries for genes that can suppress the heat shock sensitivity of the ira1 mutation on a multicopy vector [9].
• The ira1- cells harboring these plasmids retained their HS-sensitive phenotype [8].
• The sequence of 12.5 kb from the right arm of chromosome II predicts a new N-terminal sequence for the IRA1 protein and reveals two new genes, one of which is a DEAD-box helicase [10].

Associations of IRA1 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 [11].
• Deletion of IRA1 leads to constitutive activation of the Ras/cyclic AMP (cAMP) pathway, which results in several phenotypes including sensitivity to heat-shock (HS) treatment [8].
• Mutation at the GLC1 locus in Saccharomyces cerevisiae resulted in simultaneous deficiencies in glycogen and trehalose accumulation [12].
• Similar studies employing a strain containing the glc1 mutation, which enhances porphyrin accumulation, did not reveal any significant phenotypic change in catabolite regulation of 5-aminolevulinate dehydratase [13].
• Constructed strains containing both glc1 and the constitutive maltose fermentation gene MAL4c can accumulate trehalose but not glycogen during growth on glucose [14].

Regulatory relationships of IRA1

• The region homologous between the IRA1 protein and ras GTPase-activating protein is also conserved in IRA2 [9].
• Interactions between adenylate cyclase and the yeast GTPase-activating protein IRA1 [15].

Other interactions of IRA1

• We identified IRA2, encoding a protein of 3,079 amino acids, that is 45% identical to the IRA1 protein [9].
• Our results suggest that the IRA1 protein inhibits the function of the RAS proteins in a fashion antagonistic to the function of the CDC25 protein in the RAS-cyclic AMP pathway in Saccharomyces cerevisiae [7].
• We have identified MSI2 as a gene of Saccharomyces cerevisiae which, when on a multicopy vector, suppresses the heat shock sensitivity caused by the loss of the IRA1 product, a negative regulator of the RAS protein [16].
• MSI1 is a multicopy suppressor of a mutation in the IRA1 gene involved in the Ras-cAMP pathway that regulates cellular growth [17].
• We have concluded that IRA1 is a strong candidate for a protein involved in anchoring adenylate cyclase to the membrane [15].

References