Abstract
Multi-cellular organisms need to successfully link cell growth and metabolism to environmental cues during development. Insulin receptor–target of rapamycin (InR–TOR) signalling is a highly conserved pathway that mediates this link. Herein, we describe poly, an essential gene in Drosophila that mediates InR–TOR signalling. Loss of poly results in lethality at the third instar larval stage, but only after a stage of extreme larval longevity. Analysis in Drosophila demonstrates that Poly and InR interact and that poly mutants show an overall decrease in InR–TOR signalling, as evidenced by decreased phosphorylation of Akt, S6K and 4E-BP. Metabolism is altered in poly mutants, as revealed by microarray expression analysis and a decreased triglyceride : protein ratio in mutant animals. Intriguingly, the cellular distribution of Poly is dependent on insulin stimulation in both Drosophila and human cells, moving to the nucleus with insulin treatment, consistent with a role in InR–TOR signalling. Together, these data reveal that Poly is a novel, conserved (from flies to humans) mediator of InR signalling that promotes an increase in cell growth and metabolism. Furthermore, homology to small subunits of Elongator demonstrates a novel, unexpected role for this complex in insulin signalling.
Highlights
Multi-cellular organisms have evolved mechanisms to link cellular metabolism and growth to external environmental cues, such as nutrient and growth factor levels, in order to survive and adapt to fluctuations in the availability of these factors
insulin receptor substrate (IRS) acts as a recruitment site for phosphatidylinositol 3-kinase (PI3K), which catalyses the conversion of phosphatidylinositol (4,5)-bisphosphate (PIP2) into phosphatidylinositol & 2012 The Authors
The poly05137 insertion led to an absence of poly mRNA as assessed by Northern blotting, reverse transcriptase – polymerase chain reaction (RT-PCR; figure 1b) and Poly protein as revealed by immunoblotting
Summary
Multi-cellular organisms have evolved mechanisms to link cellular metabolism and growth to external environmental cues, such as nutrient and growth factor levels, in order to survive and adapt to fluctuations in the availability of these factors. The InR–TOR pathway is one of the key regulators of cellular energy homeostasis and growth [1], and this signalling pathway is evolutionarily conserved among metazoa [1,2]. Studies carried out using Drosophila as a model system have played a major role in expanding our understanding of the mechanisms, as well as downstream consequences, of signalling via this pathway [3,4,5]. Aberrations of InR–TOR signalling lead to various metabolic syndromes, including diabetes and obesity, as well as to the development of various types of cancers [6]. A cascade of phosphorylation events mediates signalling through the InR– TOR pathway. The binding of insulin to the InR leads to the phosphorylation of insulin receptor substrate (IRS) by the InR. IRS acts as a recruitment site for phosphatidylinositol 3-kinase (PI3K), which catalyses the conversion of phosphatidylinositol (4,5)-bisphosphate (PIP2) into phosphatidylinositol
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