Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling

Yonghao Yu, Sang Oh Yoon, George Poulogiannis, Qian Yang, Xiaoju Max Ma, Judit Villén, Neil Kubica, Gregory R. Hoffman, Lewis C. Cantley, Steven P. Gygi, John Blenis

Research output: Contribution to journalArticle

541 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1322-1326
Number of pages5
JournalScience
Volume332
Issue number6035
DOIs
StatePublished - Jun 10 2011

ASJC Scopus subject areas

  • General

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    Yu, Y., Yoon, S. O., Poulogiannis, G., Yang, Q., Ma, X. M., Villén, J., Kubica, N., Hoffman, G. R., Cantley, L. C., Gygi, S. P., & Blenis, J. (2011). Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science, 332(6035), 1322-1326. https://doi.org/10.1126/science.1199484