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Science 332 (6035): 1322-1326

Copyright © 2011 by the American Association for the Advancement of Science

Phosphoproteomic Analysis Identifies Grb10 as an mTORC1 Substrate That Negatively Regulates Insulin Signaling

Yonghao Yu,1 Sang-Oh Yoon,1,* George Poulogiannis,2 Qian Yang,1,3 Xiaoju Max Ma,1,{dagger} Judit Villén,1,{ddagger} Neil Kubica,1,§ Gregory R. Hoffman,1 Lewis C. Cantley,2 Steven P. Gygi,1,|| John Blenis1,||

Abstract: The evolutionarily conserved serine-threonine kinase mammalian target of rapamycin (mTOR) plays a critical role in regulating many pathophysiological processes. Functional characterization of the mTOR signaling pathways, however, has been hampered by the paucity of known substrates. We used large-scale quantitative phosphoproteomics experiments to define the signaling networks downstream of mTORC1 and mTORC2. Characterization of one mTORC1 substrate, the growth factor receptor–bound protein 10 (Grb10), showed that mTORC1-mediated phosphorylation stabilized Grb10, leading to feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal–regulated, mitogen-activated protein kinase (ERK-MAPK) pathways. Grb10 expression is frequently down-regulated in various cancers, and loss of Grb10 and loss of the well-established tumor suppressor phosphatase PTEN appear to be mutually exclusive events, suggesting that Grb10 might be a tumor suppressor regulated by mTORC1.

1 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
2 Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
3 Harvard School of Dental Medicine, Boston, MA 02115, USA.

* Present address: Department of Cancer and Cell Biology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.

{dagger} Present address: Department of Research Oncology Diagnostics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

{ddagger} Present address: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.

§ Present address: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.

|| To whom correspondence should be addressed. E-mail: steven_gygi{at}hms.harvard.edu (S.P.G); john_blenis{at}hms.harvard.edu (J.B.)

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