Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin

Area of Science:

• Cell biology
• Molecular biology
• Pharmacology

Background:

• Rapamycin is an immunosuppressant that halts cell cycle progression.
• The mammalian target of rapamycin (mTOR) is a key signaling protein involved in cell growth and proliferation.
• mTOR acts as a terminal kinase in a pathway linking cell stimulation to protein synthesis regulation.

Purpose of the Study:

• To elucidate the role of mTOR in regulating cell cycle progression.
• To investigate the mechanism by which rapamycin inhibits G1-phase progression.
• To define mTOR's function in translational control.

Main Methods:

• Investigated the effect of rapamycin on G1-phase progression in lymphoid and other cell types.
• Determined mTOR's position in the signaling pathway regulating PHAS-I phosphorylation.
• Examined the requirement of rapamycin-sensitive mTOR kinase activity for PHAS-I phosphorylation in insulin-stimulated cells.
• Performed in vitro phosphorylation assays of PHAS-I by mTOR.

Main Results:

• Rapamycin inhibits G1-phase progression by inhibiting mTOR function.
• mTOR is a terminal kinase coupling mitogenic stimulation to PHAS-I phosphorylation.
• mTOR kinase activity is essential for PHAS-I phosphorylation in response to insulin.
• mTOR phosphorylates PHAS-I on serine and threonine residues.
• PHAS-I phosphorylation by mTOR inhibits its binding to eukaryotic initiation factor (eIF)-4E.

Conclusions:

• mTOR plays a critical role in translational control.
• Rapamycin's inhibition of G1-phase progression is mediated by its effect on mTOR and subsequent translational regulation.
• These findings provide insight into the molecular mechanisms of rapamycin's action on cell cycle progression.