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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase

C J Kuo1, J Chung, D F Fiorentino

  • 1Howard Hughes Medical Institute, Unit in Molecular and Genetic Medicine, Beckman Center, Stanford University School of Medicine, California 94305-5425.

Nature
|July 2, 1992
PubMed

Insights

The macrolide rapamycin halts cell cycle progression by inhibiting p70 S6 kinase activation. This discovery reveals a conserved pathway regulating T-cell proliferation and immunosuppression.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Rapamycin, a macrolide, arrests the cell cycle in yeast and mammalian cells, suggesting a conserved regulatory pathway for S phase entry.
  • In mammals, rapamycin inhibits T-cell proliferation by blocking interleukin-2 receptor-induced S phase entry, leading to immunosuppression.

Purpose of the Study:

  • To investigate the mechanism by which rapamycin inhibits interleukin-2-induced T-cell proliferation.
  • To identify the specific signaling pathway targeted by rapamycin in T cells.

Main Methods:

  • Investigated the effect of interleukin-2 on the phosphorylation and activation of p70 S6 kinase, MAP kinases (ERK), and S6 kinases (RSK).
  • Assessed the impact of rapamycin on interleukin-2-induced p70 S6 kinase activation.
  • Examined the interaction between rapamycin, FK506, and FKBP.

Main Results:

  • Interleukin-2 selectively stimulates p70 S6 kinase phosphorylation and activation, but not ERK or RSK.
  • Rapamycin rapidly and completely inhibits interleukin-2-induced p70 S6 kinase activation at low concentrations (0.05-0.2 nM).
  • FK506 competitively antagonizes rapamycin's effects, indicating mediation through FKBP.

Conclusions:

  • The rapamycin-FKBP complex selectively blocks the p70 S6 kinase activation cascade.
  • This signaling pathway is implicated in the regulation of T-cell entry into S phase.
  • Rapamycin's immunosuppressive effects are linked to the inhibition of p70 S6 kinase signaling.

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