mTOR directly phosphorylates 4E-BP1 (PHAS-I), releasing eIF4E and establishing mTOR's role in translational control.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | HEK293; in vitro |
| Journal | Science |
| Year | 1997 |
| Peer reviewed | Yes |
| Source | DOI 10.1126/science.277.5322.99 · PMID 9204908 |
The immunosuppressant rapamycin interferes with G1-phase progression in lymphoid and other cell types by inhibiting the function of the mammalian target of rapamycin (mTOR). mTOR was determined to be a terminal kinase in a signaling pathway that couples mitogenic stimulation to the phosphorylation of the eukaryotic initiation factor (eIF)-4E-binding protein, PHAS-I. The rapamycin-sensitive protein kinase activity of mTOR was required for phosphorylation of PHAS-I in insulin-stimulated human embryonic kidney cells. mTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. These studies define a role for mTOR in translational control and offer further insights into the mechanism whereby rapamycin inhibits G1-phase progression in mammalian cells.
| Intervention | Biochemical (mTOR/PHAS-I) |
| Target | mTOR / PHAS-I (4E-BP1) / eIF4E |
| Model | HEK293; in vitro |
| Effect | mTOR is a terminal kinase phosphorylating the translational repressor PHAS-I (4E-BP1) |