Control of growth and differentiation by Drosophila RasGAP, a homolog of p120 Ras-GTPase-activating protein

Mammalian Ras GTPase-activating protein (GAP), p120 Ras-GAP, has been impli cated as both a down-regulator and effector of Ras proteins, but its precis e role in Ras-mediated signal transduction pathways is unclear. To begin a genetic analysis of the role of p120 Ras-GAP we identified a homolog from t he fruit fly Drosophila melanogaster through its ability to complement the sterility of a Schizosaccharomyces pombe (fission yeast) gap1 mutant strain . Like its mammalian homolog, Drosophila RasGAP stimulated the intrinsic GT Pase activity of normal mammalian H-Ras but not that of the oncogenic Val12 mutant. RasGAP was tyrosine phosphorylated in embryos and its Src homology 2 (SH2) domains could bind in vitro to a small number of tyrosine-phosphor ylated proteins expressed at various developmental stages. Ectopic expressi on of RasGAP in the wing imaginal disc reduced the size of the adult wing b y up to 45% and suppressed ectopic wing vein formation caused by expression of activated forms of Breathless and Heartless, two Drosophila receptor ty rosine kinases of the fibroblast growth factor receptor family. The in vivo effects of RasGAP overexpression required intact SH2 domains, indicating t hat intracellular localization of RasGAP through SH2-phosphatyrosine intera ctions is important for its activity. These results show that RasGAP can fu nction as an inhibitor of signaling pathways mediated by Ras and receptor t yrosine kinases in vivo. Genetic interactions, however, suggested a Ras-ind ependent role for RasGAP in the regulation of growth. The system described here should enable genetic screens to be performed to identify regulators a nd effecters of p120 Ras-GAP.