title: Input from Ras is required for maximal PI(3)K signalling in Drosophila.
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 signalling. They contain Ras-binding domains (RBDs) and can also be activated through direct association with active GTP-bound Ras. 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 metabolism. To investigate the importance of Ras-mediated PI(3)K activation for normal PI(3)K function, we replaced Dp110 with Dp110(RBD), 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 Dp110(RBD) flies. Furthermore, insulin cannot maximally activate PI(3)K signalling in Dp110(RBD) imaginal discs and Dp110(RBD) 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.
authors.affiliation: Growth Regulation Laboratory, Cancer Research UK London Research Institute, PO Box 123, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Mariam H
authors.initials: MH
authors.lastname: Orme
authors.forename: Saif
authors.initials: S
authors.lastname: Alrubaie
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Bradley
authors.forename: Cherryl D
authors.initials: CD
authors.lastname: Walker
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Leevers
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D002470:Cell Survival; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015151:Immunoblotting; D007328:Insulin / Q000494:pharmacology; D008297:Male; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D015398:Signal Transduction; D014921:Wings, Animal / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins