The adaptor protein p66Shc inhibits mTOR-dependent anabolic metabolism.

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.
Authors	Mohamed A Soliman, Anas M Abdel Rahman, Dudley W Lamming, Dudley A Lamming, Kivanç Birsoy, Judy Pawling, Maria E Frigolet, Huogen Lu, I George Fantus, Adrian Pasculescu, Yong Zheng, David M Sabatini, James W Dennis, Tony Pawson
Journal	Science signaling (Sci Signal) Vol. 7 Issue 313 Pg. ra17 (Feb 18 2014) ISSN: 1937-9145 [Electronic] United States
PMID	24550542 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Antibiotics, Antineoplastic SHC1 protein, human Shc Signaling Adaptor Proteins Shc1 protein, mouse Src Homology 2 Domain-Containing, Transforming Protein 1 MTOR protein, human mTOR protein, mouse TOR Serine-Threonine Kinases Glucose Sirolimus
Topics	Animals Antibiotics, Antineoplastic (pharmacology) Glucose (genetics, metabolism) Glycolysis (drug effects, physiology) HeLa Cells Humans Mice Mice, Knockout Shc Signaling Adaptor Proteins (genetics, metabolism) Signal Transduction (drug effects, physiology) Sirolimus (pharmacology) Src Homology 2 Domain-Containing, Transforming Protein 1 TOR Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)

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