Input from Ras is required for maximal PI(3)K signalling in Drosophila

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Abstract
Class I phosphoinositide 3-kinases (PI(3)Ks) are activated through associated adaptor molecules in response to G protein-coupled and tyrosine kinase receptor signalling1. They contain Ras-binding domains (RBDs) and can also be activated through direct association with active GTP-bound Ras2,3,4,5,6,7,8,9,10. The ability of Ras to activate PI(3)K has been established in vitro and by overexpression analysis, but its relevance for normal PI(3)K function in vivo is unknown. The Drosophila class I PI(3)K, Dp110, is activated by nutrient-responsive insulin signalling and modulates growth, oogenesis and metabolism11,12,13,14,15. To investigate the importance of Ras-mediated PI(3)K activation for normal PI(3)K function, we replaced Dp110 with Dp110RBD, which is unable to bind to Ras but otherwise biochemically normal. We found that Ras-mediated Dp110 regulation is dispensable for viability. However, egg production, which requires large amounts of growth, is dramatically lowered in Dp110RBD flies. Furthermore, insulin cannot maximally activate PI(3)K signalling in Dp110RBD imaginal discs and Dp110RBD flies are small. Thus, Dp110 integrates inputs from its phosphotyrosine-binding adaptor and Ras to achieve maximal PI(3)K signalling in specific biological situations.