A number of Drosophila genes within the PI3K-AKT signaling pathway have been used in models of cancer, including Pi3K92E (orthologous to human PIK3C kinase catalytic subunit genes) and Pten (ortholog of human PTEN phosphatase, a negative regulator of the PI3K/AKT pathway). Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both Pten and Pi3K92E. Other Drosophila genes in this pathway include Pdk1 (ortholog of human PDPK1 kinase) and Akt1 (orthologous to human AKT kinase genes).
The human PTEN gene has been identified as a tumor suppressor that is mutated in a large number of cancers, especially in advanced stages (see OMIM:601728). UAS constructs of the human Hsap\PTEN gene have been introduced into flies; heterologous rescue has not been tested.
Animals homozygous for loss-of-function alleles of Dmel\Pten die during the larval stage. When induced in larvae, clones of cells carrying an amorphic mutation of Pten exhibit mild hypertrophic growth, with increased cell size but no (or little) increase in cell number. However, under conditions of nutrient restriction, cells in clones lacking Pten switch from hypertrophic growth to hyperplastic growth. This hyperproliferation occurs at the expense of neighboring wild-type cells. Under the nutrient restriction conditions, induction of insulin signaling in the surrounding cells suppresses the overgrowth of Pten mutant clones. Thus, this works may reflect an integration of PTEN roles as a tumor suppressor and as a negative regulator of insulin-PI3K signaling.
Many physical and genetic interactions of Dmel\Pten have been described; see below and in the Pten gene report. See also Vinayagam et al., 2016 (FBrf0233454), which describes a comprehensive analysis of the InR/PI3K/AKT network in Drosophila.
[updated Dec. 2018 by FlyBase; FBrf0222196]