Phosphoproteomics identify Grb10 as an mTORC1 substrate driving negative feedback on insulin/PI3K.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mammalian cells |
| Journal | Science |
| Year | 2011 |
| Peer reviewed | Yes |
| Source | DOI 10.1126/science.1199484 · PMID 21659605 · Free full text (PMC3195509) |
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.
| Intervention | Phosphoproteomics (mTORC1/Grb10) |
| Target | mTORC1 / Grb10 / insulin signaling |
| Model | Mammalian cells |
| Effect | Grb10 is an mTORC1 substrate that negatively feeds back on insulin/IGF signaling |