Phosphoproteomic Analysis Identifies Grb10 as an mTORC1 Substrate That Negatively Regulates Insulin Signaling

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-sc...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2011-06, Vol.332 (6035), p.1322-1326
Main 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
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino acids
Animals
Antibiotics, Antineoplastic - pharmacology
Antibodies
Birds of prey
Cancer
Cell Line
Control loops
GRB10 Adaptor Protein - metabolism
Growth factors
HEK293 cells
HeLa cells
Humans
Insulin
Insulin - metabolism
Kinases
Literary Devices
Mechanistic Target of Rapamycin Complex 1
Mice
Molecular biology
Molecular Sequence Data
Multiprotein Complexes
Networks
Pathways
Phosphatidylinositol 3-Kinases - metabolism
Phosphoproteins - metabolism
Phosphorylation
Phosphorylation - drug effects
Proteins
Proteins - metabolism
Proteome - metabolism
Proteomics
Signal transduction
Signal Transduction - drug effects
Sirolimus - pharmacology
Suppressors
TOR Serine-Threonine Kinases
Tumors
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1199484