PHOSPHORYLATION OF THE TRANSLATIONAL REPRESSOR PHAS-I BY THE MAMMALIAN TARGET OF RAPAMYCIN

The immunosuppressant rapamycin interferes with G(1)-phase progression in lymphoid and other cell types by inhibiting the function; of the m ammalian target of rapamycin (mTOR), mTOR was determined to be a termi nal kinase in a signaling pathway that couples mitogenic stimulation t o the phosphorylation of the eukaryotic initiation factor (eIF)-4E-bin ding protein, PHAS-I. The rapamycin-sensitive protein kinase activity of mTOR was required for phosphorylation of PHAS-I in insulin-stimulat ed 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 wh ereby rapamycin inhibits G(1)-phase progression in mammalian cells.