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

Lookup NU author(s): Piero Dalle Pezze, Dr Daryl Shanley

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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.


Publication metadata

Author(s): Dalle Pezze P, Sonntag AG, Thien A, Prentzell MT, Godel M, Fischer S, Neumann-Haefelin E, Huber TB, Baumeister R, Shanley DP, Thedieck K

Publication type: Article

Publication status: Published

Journal: Science Signaling

Year: 2012

Volume: 5

Issue: 217

Print publication date: 27/03/2012

ISSN (print): 1945-0877

ISSN (electronic): 1937-9145

Publisher: American Association for the Advancement of Science

URL: http://dx.doi.org/10.1126/scisignal.2002469

DOI: 10.1126/scisignal.2002469

Notes: Article no. ra25 is 18 pp.


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