Neurofibromin Homologs IRA1 and IRA2 Impinge Upon Phospholipid Metabolism in Saccharomyces cerevisiae

Neurofibromatosis 1, a metastatic disease affecting 1 in 3,500 individuals, is caused by mutations in the NF1 gene. In Saccharomyces cerevisiae, two homologs of this gene have been identified, IRA1 and IRA2 . NF1, Ira1, and Ira2 have known RAS‐GAP functions and therefore, negatively regulate Ras1 and Ras2. Interestingly, NF1, Ira1, and Ira2 are large proteins of approximately 3,000 amino acids while their RAS‐GAP domains occupy only 300 amino acids, prompting studies exploring non RAS‐GAP related functions for the proteins. We have identified phospholipid metabolism related phenotypes associated with loss of IRA1/2 that do not appear to be completely attributable to upregulation of RAS signaling. The phenotypes include misregulation of the gene encoding the rate‐limiting step in inositol biosynthesis, INO1 , and the production and subsequent utilization of the phospholipid metabolite, glycerophosphoinositol (GPI). We are in the process of employing site‐directed mutagenesis of Ira1/2 to determine RAS‐GAP versus non RAS‐GAP related functions for the proteins in phospholipid metabolism.