Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling |
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Authors: | Yu Yonghao Yoon Sang-Oh Poulogiannis George Yang Qian Ma Xiaoju Max Villén Judit Kubica Neil Hoffman Gregory R Cantley Lewis C Gygi Steven P Blenis John |
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Affiliation: | Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. |
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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. |
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