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

      Science (New York, N.Y.)

      TOR Serine-Threonine Kinases, pharmacology, Sirolimus, drug effects, Signal Transduction, metabolism, Proteome, Proteins, Phosphorylation, Phosphoproteins, Phosphatidylinositol 3-Kinases, Multiprotein Complexes, Molecular Sequence Data, Mice, Insulin, Humans, GRB10 Adaptor Protein, Cell Line, Antibiotics, Antineoplastic, Animals, Amino Acid Sequence

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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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          Author and article information

          Journal
          10.1126/science.1199484
          3195509
          21659605

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