TY - JOUR
T1 - Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling
AU - Yu, Yonghao
AU - Yoon, Sang Oh
AU - Poulogiannis, George
AU - Yang, Qian
AU - Ma, Xiaoju Max
AU - Villén, Judit
AU - Kubica, Neil
AU - Hoffman, Gregory R.
AU - Cantley, Lewis C.
AU - Gygi, Steven P.
AU - Blenis, John
PY - 2011/6/10
Y1 - 2011/6/10
N2 - 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.
AB - 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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U2 - 10.1126/science.1199484
DO - 10.1126/science.1199484
M3 - Article
C2 - 21659605
AN - SCOPUS:79958696336
SN - 0036-8075
VL - 332
SP - 1322
EP - 1326
JO - Science
JF - Science
IS - 6035
ER -