Phosphorylation of the Translational Repressor PHAS-I by the Mammalian Target of Rapamycin

TLDR

Rapamycin blocks G1‑phase progression by inhibiting mTOR, a terminal kinase that phosphorylates the eIF‑4E‑binding protein PHAS‑I in response to mitogenic signals. mTOR phosphorylates PHAS‑I on serine/threonine residues, blocking its binding to eIF‑4E, and this rapamycin‑sensitive activity is required for insulin‑stimulated PHAS‑I phosphorylation, linking mTOR to translational control and G1‑phase arrest.

Abstract

The immunosuppressant rapamycin interferes with G 1 -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 G 1 -phase progression in mammalian cells.