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Freiburg Researchers Unravel Insulin Action on a Metabolic Master Regulator

Systems Biology Opens Up New Possibilities for Targeted Interventions in Insulin Metabolism Signaling Networks

Freiburg, Mar 30, 2012

In collaboration with scientists from Newcastle University in Newcastle upon Tyne, Great Britain, Freiburg researchers have unraveled a novel mechanism by which insulin activates the metabolic regulator mammalian target of rapamycin (mTOR). mTOR plays an important role in the regulation of cellular metabolism and is therefore a central target for treatment of age-related diseases like cancer, type II diabetes, and neurodegenerative diseases.
The metabolic regulator mTOR is a component of the protein complexes mTORC1 and mTORC2, which fulfill various functions in the process of insulin metabolism. The process by which insulin activates mTORC1 is well known. Although it is well established that mTORC2 also responds to insulin, the underlying mechanism is a matter of controversy in the literature. Several feedback mechanisms in the mTOR signaling network make it exceedingly difficult to investigate. In the past, it was necessary to apply complex experimental approaches that interfered with the physiological signal transmission.  Therefore, scientists came to different conclusions on how insulin activates mTORC2.
Dr. Kathrin Thedieck, Department of Bioinformatics and Molecular Genetics, led by Prof. Dr. Ralf Baumeister at the University of Freiburg, is a member of the BIOSS Cluster of Excellence and the Center for Systems Biology. Her junior research group, together with the group of Dr. Daryl Shanley from Newcastle University, Great Britain, opted for a systems biological approach combining experiments and computer-based modeling. This enabled the researchers to study the mTOR network with only minimal intrusion into the cell. The data-driven mathematical model of the mTOR signaling network can be used to simulate the signaling dynamics and predict network responses to perturbations by metabolic regulation or medical intervention.
Piero Dalle Pezze from Newcastle University, Great Britain, and Annika Sonntag from the Institute of Biology III of the University of Freiburg and their colleagues succeeded in identifying a new mTORC2 activation pathway through experimental validation of model-based predications. In addition, they described a mechanism of the insulin response of AMPK, a target molecule for the diabetes drug metformin. A detailed understanding of the structures of the mTOR network is the basis for the development of personalized treatment approaches. It enables scientists to predict the effects of drugs that act in the insulin-mTOR network.
The project is supported by funding from the Federal Ministry of Education and Research and the EU. The results were published in Science Signaling and the FEBS Journal.
P. Dalle Pezze, A. G. Sonntag, et al. (2012). "A Dynamic Network Model of mTOR Signaling Reveals TSC-Independent mTORC2 Regulation." Sci Signal 5(217): ra25.