Ira1p and Ira2p are Ras GTPase activating proteins (GAP) that act as negative regulators of the Ras-cAMP signaling pathway by increasing the rate Ras proteins (encoded by RAS1 and RAS2) hydrolyze GTP to GDP (reviewed in 6, 7, 8, 2, 5). In addition to regulating the Ras-cAMP pathway via the GTPase activity of Ras2p, Ira1p may regulate the localization of Cyr1p, the catalytic subunit of adenylate cyclase (9).

Consistent with their role as negative regulators of the Ras-cAMP pathway, disruption of IRA1 or IRA2 results in the increase of intracellular cAMP levels (5). In addition, ira1 or ira2 mutants have phenotypes consistent with phenotypes of a constitutively active Ras2p mutant, which has reduced GTPase activity. These phenotypes include sensitivity to heat shock or nitrogen starvation, aberrant response to glucose, sporulation defects, pseudohyphal growth defects, filamentous growth defects, and aberrant colony morphology (2, 5, 10, 11, 12, 13). Although both Ira1p and Ira2p regulate Ras2p, biochemical and genetic evidence suggest Ira1p and Ira2p are not functionally redundant and may be involved in responding to different environmental stresses (2, 14, 15).

The C-terminal regions of Ira1p and Ira2p are important for their activity as well as regulation by the kelch proteins Gpb1p and Gpb2p, which are involved in Gpr1p-coupled receptor signaling (10, 12). In addition, Ira2p activity can be inhibited by arachidonic acid (8). Expression of IRA1 and IRA2 increases under conditions when cAMP levels decrease (16).

Ira1p and Ira2p belong to a large family of GAPs which include the S. pombe gap1 gene and the human disease gene NF1, which causes neurofibromatosis type 1 (OMIM) (17, 18, 19, 20). Mutations in Ira1p based on mutations identified in patients with neurofibromatosis effect the Ira1p GAP activity, confirming that yeast is an effective model system for studying the function of NF1 (3).

Last updated: 2007-02-01