Phosphoproteomic Analysis Identifies Grb10 as an mTORC1 Substrate That Negatively Regulates Insulin Signaling
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- 10 June 2011
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 332 (6035), 1322-1326
- https://doi.org/10.1126/science.1199484
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.Keywords
This publication has 16 references indexed in Scilit:
- Glucose Addiction of TSC Null Cells Is Caused by Failed mTORC1-Dependent Balancing of Metabolic Demand with SupplyMolecular Cell, 2010
- Molecular mechanisms of mTOR-mediated translational controlNature Reviews Molecular Cell Biology, 2009
- Not all substrates are treated equally: Implications for mTOR, rapamycin-resistance, and cancer therapyCell Cycle, 2009
- Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translationProceedings of the National Academy of Sciences, 2008
- Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancerJCI Insight, 2008
- Antitumor Activity of Rapamycin in a Phase I Trial for Patients with Recurrent PTEN-Deficient GlioblastomaPLoS Medicine, 2008
- Peripheral Disruption of the Grb10 Gene Enhances Insulin Signaling and Sensitivity In VivoMolecular and Cellular Biology, 2007
- Phosphorylation of Grb10 by Mitogen-Activated Protein Kinase: Identification of Ser150 and Ser476 of Human Grb10ζ as Major Phosphorylation SitesBiochemistry, 2005
- PIK3CA Mutations Correlate with Hormone Receptors, Node Metastasis, and ERBB2, and Are Mutually Exclusive with PTEN Loss in Human Breast CarcinomaCancer Research, 2005
- Grb10: more than a simple adaptor proteinFrontiers in Bioscience-Landmark, 2004