Endocrine Abstracts (2006) 11 S32

Giant flies and more: probing the functions and genetics of insulin signalling in Drosophila

C Wilson, D Meredith, CAR Boyd & DCI Goberdhan

University of Oxford, Oxford, United Kingdom.

Defective signalling by insulin-like molecules is not only a fundamental characteristic of diabetes, but is also associated with the majority of human tumours, where signalling is typically hyperactivated. Although both these diseases have a significant genetic component, we are still some distance from identifying all the genes and cellular mechanisms affected.

We and other groups use the powerful genetics of the fruit fly, Drosophila melanogaster, to dissect the insulin signalling pathway, which is highly conserved in all higher eukaryotes. We showed that PTEN, a major human tumour suppressor, functions by restricting cell growth through acting as an antagonist of PI3-kinase signalling in flies. Other groups have shown an important link between the insulin signalling cascade and the local nutrient sensor TOR and demonstrated that this signalling pathway has a range of physiological roles beyond metabolism and growth, including developmental timing and longevity. All these novel functions appear to be conserved in mammals.

Here we discuss our recent identification of several new conserved components in the insulin signalling pathway. We show that surprisingly the proton-assisted amino acid transporters (PATs) play an essential role in regulating TOR-dependent cellular nutrient sensing, potentially via a novel ‘transceptor’ mechanism that sets the sensitivity of cells to insulin-like molecules. We also demonstrate that subcellularly localised phosphatase activity plays a critical role in modulating the intracellular insulin signalling in different parts of the cell, allowing a single pathway to differentially regulate processes including cellular morphology, growth and metabolism. Our work suggests that many of the diverse cellular effects of insulin-like molecules are regulated by overlapping signalling mechanisms that can to some extent be independently controlled at the subcellular level. This model may have important implications for our understanding of events involved in establishment of cellular defects linked with diabetes and cancer, such as insulin resistance and metastasis.

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