title: Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling.
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.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Yu
authors.forename: Sang-Oh
authors.initials: SO
authors.lastname: Yoon
authors.forename: George
authors.initials: G
authors.lastname: Poulogiannis
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
authors.forename: Xiaoju Max
authors.initials: XM
authors.lastname: Ma
authors.forename: Judit
authors.initials: J
authors.lastname: Villén
authors.forename: Neil
authors.initials: N
authors.lastname: Kubica
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Hoffman
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: John
authors.initials: J
authors.lastname: Blenis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002460:Cell Line; D051383:GRB10 Adaptor Protein / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
chemical_list: D000903:Antibiotics, Antineoplastic; D051383:GRB10 Adaptor Protein; D007328:Insulin; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011506:Proteins; D020543:Proteome; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C495959:Grb10 protein, mouse