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Sci. Signal., 18 February 2014
Vol. 7, Issue 313, p. ra17
[DOI: 10.1126/scisignal.2004785]

RESEARCH ARTICLES

The Adaptor Protein p66Shc Inhibits mTOR-Dependent Anabolic Metabolism

Mohamed A. Soliman1,2,3*, Anas M. Abdel Rahman1{dagger}, Dudley W. Lamming4, Kivanç Birsoy4, Judy Pawling1, Maria E. Frigolet1,5, Huogen Lu1,5, I. George Fantus1,5, Adrian Pasculescu1, Yong Zheng1, David M. Sabatini4,6,7,8,9, James W. Dennis1,2*, and Tony Pawson1,2{ddagger}

1 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
2 Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
3 Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
4 Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
5 Banting and Best Diabetes Centre, Toronto General Research Institute, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L6, Canada.
6 Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
7 David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
8 Broad Institute, Seven Cambridge Center, Cambridge, MA 02142, USA.
9 Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA.

{dagger} Present address: School of Pharmacy, Yarmouk University, Irbid 21163, Jordan.

{ddagger} Deceased.

Abstract: Adaptor proteins link surface receptors to intracellular signaling pathways and potentially control the way cells respond to nutrient availability. Mice deficient in p66Shc, the most recently evolved isoform of the Shc1 adaptor proteins and a mediator of receptor tyrosine kinase signaling, display resistance to diabetes and obesity. Using quantitative mass spectrometry, we found that p66Shc inhibited glucose metabolism. Depletion of p66Shc enhanced glycolysis and increased the allocation of glucose-derived carbon into anabolic metabolism, characteristics of a metabolic shift called the Warburg effect. This change in metabolism was mediated by the mammalian target of rapamycin (mTOR) because inhibition of mTOR with rapamycin reversed the glycolytic phenotype caused by p66Shc deficiency. Thus, unlike the other isoforms of Shc1, p66Shc appears to antagonize insulin and mTOR signaling, which limits glucose uptake and metabolism. Our results identify a critical inhibitory role for p66Shc in anabolic metabolism.

* Corresponding author. E-mail: ma.soliman{at}utoronto.ca (M.A.S.); dennis{at}lunenfeld.ca (J.W.D.)

Citation: M. A. Soliman, A. M. Abdel Rahman, D. W. Lamming, K. Birsoy, J. Pawling, M. E. Frigolet, H. Lu, I. G. Fantus, A. Pasculescu, Y. Zheng, D. M. Sabatini, J. W. Dennis, T. Pawson, The Adaptor Protein p66Shc Inhibits mTOR-Dependent Anabolic Metabolism. Sci. Signal. 7, ra17 (2014).

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Science Signaling Podcast: 18 February 2014.
J. W. Dennis, M. A. Soliman, and A. M. VanHook (2014)
Science Signaling 7, pc6
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