S6 Kinase- and β-TrCP2-Dependent Degradation of p19^Arf Is Required for Cell Proliferation

The kinase mTOR (mammalian target of rapamycin) promotes translation as well as cell survival and proliferation under nutrient- rich conditions. Whereas mTOR activates translation through ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein (4E-BP), how it facilitates cell proliferation has remained unclear. We have now identified p19^Arf, an inhibitor of cell cycle progression, as a novel substrate of S6K that is targeted to promote cell proliferation. Serum stimulation induced activation of the mTOR-S6K axis and consequent phosphorylation of p19^Arf at Ser⁷⁵. Phosphorylated p19^Arf was then recognized by the F-box protein β-TrCP2 and degraded by the proteasome. Ablation of β-TrCP2 thus led to the arrest of cell proliferation as a result of the stabilization and accumulation of p19^Arf. The β-TrCP2 paralog β-TrCP1 had no effect on p19^Arf stability, suggesting that phosphorylated p19^Arf is a specific substrate of β-TrCP2. Mice deficient in β-TrCP2 manifested accumulation of p19^Arf in the yolk sac and died in utero. Our results suggest that the mTOR pathway promotes cell proliferation via β-TrCP2-dependent p19^Arf degradation under nutrient-rich conditions.