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Sci. Signal., 27 March 2012
Vol. 5, Issue 217, p. ra25
[DOI: 10.1126/scisignal.2002469]

RESEARCH ARTICLES

A Dynamic Network Model of mTOR Signaling Reveals TSC-Independent mTORC2 Regulation

Piero Dalle Pezze1,2*, Annika G. Sonntag3*, Antje Thien4, Mirja T. Prentzell3, Markus Gödel4, Sven Fischer3, Elke Neumann-Haefelin4, Tobias B. Huber4,5, Ralf Baumeister3,5,6,7, Daryl P. Shanley1,2{dagger}, and Kathrin Thedieck3,5,6{dagger}

1 Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK.
2 Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.
3 Bioinformatics and Molecular Genetics (Faculty of Biology), Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany.
4 Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany.
5 BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany.
6 Center for Systems Biology (ZBSA), Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany.
7 ZBMZ (Faculty of Medicine) and Freiburg Institute for Advanced Studies (FRIAS), Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany.

* These authors contributed equally to this work.

Abstract: The kinase mammalian target of rapamycin (mTOR) exists in two multiprotein complexes (mTORC1 and mTORC2) and is a central regulator of growth and metabolism. Insulin activation of mTORC1, mediated by phosphoinositide 3-kinase (PI3K), Akt, and the inhibitory tuberous sclerosis complex 1/2 (TSC1-TSC2), initiates a negative feedback loop that ultimately inhibits PI3K. We present a data-driven dynamic insulin-mTOR network model that integrates the entire core network and used this model to investigate the less well understood mechanisms by which insulin regulates mTORC2. By analyzing the effects of perturbations targeting several levels within the network in silico and experimentally, we found that, in contrast to current hypotheses, the TSC1-TSC2 complex was not a direct or indirect (acting through the negative feedback loop) regulator of mTORC2. Although mTORC2 activation required active PI3K, this was not affected by the negative feedback loop. Therefore, we propose an mTORC2 activation pathway through a PI3K variant that is insensitive to the negative feedback loop that regulates mTORC1. This putative pathway predicts that mTORC2 would be refractory to Akt, which inhibits TSC1-TSC2, and, indeed, we found that mTORC2 was insensitive to constitutive Akt activation in several cell types. Our results suggest that a previously unknown network structure connects mTORC2 to its upstream cues and clarifies which molecular connectors contribute to mTORC2 activation.

{dagger} To whom correspondence should be addressed. E-mail: kathrin.thedieck{at}biologie.uni-freiburg.de (K.T.); daryl.shanley{at}newcastle.ac.uk (D.P.S.)

Citation: P. Dalle Pezze, A. G. Sonntag, A. Thien, M. T. Prentzell, M. Gödel, S. Fischer, E. Neumann-Haefelin, T. B. Huber, R. Baumeister, D. P. Shanley, K. Thedieck, A Dynamic Network Model of mTOR Signaling Reveals TSC-Independent mTORC2 Regulation. Sci. Signal. 5, ra25 (2012).

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