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Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle
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S6 Kinase- and β-TrCP2-Dependent Degradation of p19Arf Is Required for Cell Proliferation

Tadashi Nakagawa1, Takaaki Araki2, Makiko Nakagawa1

  • 1Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Japan.

Molecular and Cellular Biology
|August 5, 2015
PubMed

Insights

The mammalian target of rapamycin (mTOR) pathway promotes cell proliferation by enabling the degradation of p19Arf, a cell cycle inhibitor. This process involves S6K phosphorylation of p19Arf, targeting it for degradation via β-TrCP2.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The mammalian target of rapamycin (mTOR) kinase regulates cell survival and proliferation, particularly under nutrient-rich conditions.
  • While mTOR's role in translation is understood, its mechanism in promoting cell proliferation remained unclear.

Purpose of the Study:

  • To elucidate the mechanism by which mTOR signaling facilitates cell proliferation.
  • To identify novel substrates of S6K involved in cell cycle regulation.

Main Methods:

  • Investigated the interaction between mTOR, S6K, and p19Arf.
  • Utilized phosphorylation site mapping (Ser75) and proteasome degradation assays.
  • Employed gene ablation of β-TrCP2 in cell cultures and mouse models.

Main Results:

  • Identified p19Arf as a novel S6K substrate phosphorylated at Ser75, promoting cell proliferation.
  • Demonstrated that phosphorylated p19Arf is specifically recognized and degraded by the F-box protein β-TrCP2.
  • Showed that ablation of β-TrCP2 leads to p19Arf accumulation and cell cycle arrest.
  • Observed embryonic lethality in β-TrCP2-deficient mice due to p19Arf accumulation.

Conclusions:

  • The mTOR pathway promotes cell proliferation by facilitating β-TrCP2-dependent degradation of the cell cycle inhibitor p19Arf.
  • This finding reveals a critical link between nutrient sensing, cell cycle control, and organismal development.

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