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Final Activity Report Summary - INSULIN SIGNALING (Analysis of TOR complex 2 in Drosophila)

The objective of the project was to characterise the role of TOR complex 2 (TORC2) in fruit fly Drosophila melanogaster. TORC2 is a newly identified and long-sought member of the signalling network that responds to insulin and growth factors. Therefore understanding the function of TORC2 has great potential to lead to further understanding of mechanisms underlying human diseases, such as cancer and diabetes. Our findings were surprising and intriguing. Unlike other members of the insulin signalling network, TORC2 was not essential for the viability of the fly as mutants lacking essential components of the complex were viable and fertile, having normal appearance. Careful examination revealed, however, a very modest reduction of body size, a feature earlier shown to be regulated by insulin signalling.

We were able to pinpoint the molecular mechanism behind the growth regulation, showing increased activity of FOXO transcription factor, a downstream effector of insulin signalling. Most interestingly, growth regulation by TOR complex 2 depends on the activity of the signalling network. While physiological functions are usually mediated by modest changes in signalling levels, disease states, such as cancer, often depend on hyperactive signalling.

Mimicking cancer-like conditions in the fly, by hyper-activating insulin signalling using a mutant of tumour suppressor gene PTEN, revealed that TORC2 had a crucial role in tissue that is growing in an uncontrolled way. As the insulin signalling network is overactive in more than 50% of human cancers, our findings suggest that TORC2 would be an optimal target for anti-cancer treatment. This finding led us to expand our study to human cancer cells that are dependent on high levels of insulin signalling. In agreement with our results from the fly, growth of human cancer cells was strongly dependent on TORC2. These findings have now led to new research in the host laboratory that is aimed in finding new ways to inhibit TORC2 activity, which could optimally be used in therapeutic purposes.

Reported by

European Molecular Biology Laboratory (EMBL)
Meyerhofstraße 1
69012 Heidelberg
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