The Adaptor Protein p66Shc Inhibits mTOR-Dependent Anabolic Metabolism
Name
Sabatini_The adaptor.pdf
Size
527.54 KB
Format
Adobe PDF
Checksum (MD5)
4862dec3253c5c2d2adaf8320f4936da
Author(s)
Lamming, Dudley W.
Soliman, Mohamed A.
Abdel Rahman, Anas M.
Birsoy, Kivanc
Pawling, Judy
Frigolet, Maria E.
Lu, Huogen
Fantus, I. George
Pasculescu, Adrian
Zheng, Yong
Date Issued
February 2014
Journal
Science Signaling
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Soliman, M. A., A. M. Abdel Rahman, D. W. Lamming, K. Birsoy, J. Pawling, M. E. Frigolet, H. Lu, et al. “The Adaptor Protein p66Shc Inhibits mTOR-Dependent Anabolic Metabolism.” Science Signaling 7, no. 313 (February 18, 2014): ra17–ra17.
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1126/scisignal.2004785
