TI - dFOXO is a critical target of dPKB but mediates only part of its function . AB - Genetic studies in C.elegans and Drosophila have led to two models regarding the output of the insulin pathway . First , the complete epistasis of daf-16 over the insulin pathway mutants daf-2 , age-1 , akt-1 and akt-2 suggests that the primary function of PKB is to inactivate FOXO transcription factors [60] . Second , it has been proposed that the TSC tumor suppressor complex is the major target of PKB [61,62] in the regulation of cell growth in Drosophila . Our analysis of Drosophila FOXO indicates that it is indeed a critical PKB target , but that it mediates only one aspect of PKB function . Several lines of evidence support this model . Firstly , the effects of ectopic overexpression of dFOXO and hFOXO3a in the developing Drosophila eye are altered by Dp110 and dPKB signaling as well as by nutrient levels . Under conditions of lowered insulin signaling , the phenotypes resulting from expression of dFOXO and hFOXO3a were dramatically enhanced . This situation was mimicked by expressing a dPKB-insensitive PHOSphorylation mutant , suggesting that endogenous dPKB signaling is required to mitigate the effects of ectopically expressed dFOXO and hFOXO3a . Secondly , the physiological relevance of dFOXO in dPKB signaling is most vividly demonstrated by our observation that the larval lethality associated with the complete loss of dPKB is rescued by dFOXO mutations to the extent that some flies develop to pharate adults . The lethality associated with loss of dPKB function is therefore to a large extent due to the hyperactivation of dFOXO . Thirdly , loss of dFOXO function suppresses the effects of insulin-signaling mutations only partially ; dFOXO mediated a reduction in cell number but not in cell size in response to reduced insulin signaling .