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

Abstract

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.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00343-15.

ACKNOWLEDGMENTS

We thank T. Kitamura for pMX-puro and Plat-E cells, K. Yumimoto and K. I. Nakayama for sharing unpublished data, Y. Nagasawa and T. Senga for technical assistance, and other laboratory members for discussion.

This work was supported by grants 25891003 and 15K18365 from the Japan Society for the Promotion of Science.