Wei Zhang1,2, Barry J. Thompson3, Ville Hietakangas4#, Stephen M. Cohen1,2#
1 - Institute of Molecular and Cell Biology, Singapore, Singapore
2 - Department of Biological Sciences, National University of Singapore, Singapore
3 - London Research Institute, Cancer Research UK, London, United Kingdom
4 - Institute of Biotechnology, University of Helsinki, Helsinki, Finland
# These authors contributed equally to this work
Published in PLoS Genetics December 29, 2011
The insulin/IGF-activated AKT signaling pathway plays a crucial role in regulating tissue growth and metabolism in multicellular animals. Although core components of the pathway are well defined, less is known about mechanisms that adjust the sensitivity of the pathway to extracellular stimuli. In humans, disturbance in insulin sensitivity leads to impaired clearance of glucose from the blood stream, which is a hallmark of diabetes. Here we present the results of a genetic screen in Drosophila designed to identify regulators of insulin sensitivity in vivo. Components of the MAPK/ERK pathway were identified as modifiers of cellular insulin responsiveness. Insulin resistance was due to downregulation of insulin-like receptor gene expression following persistent MAPK/ERK inhibition. The MAPK/ERK pathway acts via the ETS-1 transcription factor Pointed. This mechanism permits physiological adjustment of insulin sensitivity and subsequent maintenance of circulating glucose at appropriate levels.
Author Summary: Insulin signaling is an important and conserved physiological regulator of growth, metabolism, and longevity in multicellular animals. Disturbance in insulin signaling is common in human metabolic disorders. For example insulin resistance is a hallmark of diabetes and metabolic syndrome. While the core components of the insulin signaling pathway have been well established, the mechanisms that adjust the insulin responsiveness are only known to a limited extent. Here we present results from a genetic screen in Drosophila that was designed to identify regulators of cellular insulin sensitivity in an in vivo context. Surprisingly, we discovered cross-talk between the epidermal growth factor receptor (EGFR)–activated MAPK/ERK and insulin signaling pathways. This regulatory mechanism, which involves transcriptional control of insulin-like receptor gene, is utilized in vivo to maintain circulating glucose at appropriate levels. We provide evidence for a regulatory feed-forward mechanism that allows for dynamic transient responsiveness as well as more stable, long-lasting modulation of insulin responsiveness by growth factor receptor signaling. The combination of these mechanisms may contribute to robustness, allowing metabolism to be appropriately responsive to physiological inputs while mitigating the effects of biological noise.