Comment on "A Dynamic Network Model of mTOR Signaling Reveals TSC-Independent mTORC2 Regulation": Building a Model of the mTOR Signaling Network with a Potentially Faulty Tool

Brendan D. Manning^*

Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.

Abstract: In their study published in Science Signaling (Research Article, 27 March 2012, DOI: 10.1126/scisignal.2002469), Dalle Pezze et al. tackle the dynamic and complex wiring of the signaling network involving the protein kinase mTOR, which exists within two distinct protein complexes (mTORC1 and mTORC2) that differ in their regulation and function. The authors use a combination of immunoblotting for specific phosphorylation events and computational modeling. The primary experimental tool employed is to monitor the autophosphorylation of mTOR on Ser²⁴⁸¹ in cell lysates as a surrogate for mTOR activity, which the authors conclude is a specific readout for mTORC2. However, Ser²⁴⁸¹ phosphorylation occurs on both mTORC1 and mTORC2 and will dynamically change as the network through which these two complexes are connected is manipulated. Therefore, models of mTOR network regulation built using this tool are inherently imperfect and open to alternative explanations. Specific issues with the main conclusion made in this study, involving the TSC1-TSC2 (tuberous sclerosis complex 1 and 2) complex and its potential regulation of mTORC2, are discussed here. A broader goal of this Letter is to clarify to other investigators the caveats of using mTOR Ser²⁴⁸¹ phosphorylation in cell lysates as a specific readout for either of the two mTOR complexes.

Corresponding author: E-mail: bmanning{at}hsph.harvard.edu

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In Science Signaling

LETTERS
Cell Biology
Response to Comment on "A Dynamic Network Model of mTOR Signaling Reveals TSC-Independent mTORC2 Regulation": Building a Model of the mTOR Signaling Network with a Potentially Faulty Tool

Piero Dalle Pezze, Annika G. Sonntag, Daryl P. Shanley, and Kathrin Thedieck (10 July 2012)
Sci. Signal. 5 (232), lc4. [DOI: 10.1126/scisignal.2003224]
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RESEARCH ARTICLES
Computational Biology
A Dynamic Network Model of mTOR Signaling Reveals TSC-Independent mTORC2 Regulation

Piero Dalle Pezze, Annika G. Sonntag, Antje Thien, Mirja T. Prentzell, Markus Gödel, Sven Fischer, Elke Neumann-Haefelin, Tobias B. Huber, Ralf Baumeister, Daryl P. Shanley, and Kathrin Thedieck (27 March 2012)
Sci. Signal. 5 (217), ra25. [DOI: 10.1126/scisignal.2002469]
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