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Science 320 (5882): 1496-1501

Copyright © 2008 by the American Association for the Advancement of Science

The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1

Yasemin Sancak,1,2 Timothy R. Peterson,1,2 Yoav D. Shaul,1,2 Robert A. Lindquist,1,2 Carson C. Thoreen,1,2 Liron Bar-Peled,1 David M. Sabatini1,2,3*

Abstract: The multiprotein mTORC1 protein kinase complex is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. We find that the Rag proteins—a family of four related small guanosine triphosphatases (GTPases)—interact with mTORC1 in an amino acid–sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. A Rag mutant that is constitutively bound to guanosine triphosphate interacted strongly with mTORC1, and its expression within cells made the mTORC1 pathway resistant to amino acid deprivation. Conversely, expression of a guanosine diphosphate–bound Rag mutant prevented stimulation of mTORC1 by amino acids. The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb.

1 Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology (MIT), Nine Cambridge Center, Cambridge, MA 02142, USA.
2 MIT Center for Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
3 Broad Institute, Seven Cambridge Center, Cambridge, MA 02142, USA.

* To whom correspondence should be addressed. E-mail: sabatini{at}wi.mit.edu


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