Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase

Nature. 1992 Jul 2;358(6381):70-3. doi: 10.1038/358070a0.


The macrolide rapamycin induces cell cycle G1 arrest in yeast and in mammalian cells, which suggests that an evolutionarily conserved, rapamycin-sensitive pathway may regulate entry into S phase. In mammals, rapamycin inhibits interleukin-2 receptor-induced S phase entry and subsequent T-cell proliferation, resulting in immunosuppression. Here we show that interleukin-2 selectively stimulates the phosphorylation and activation of p70 S6 kinase but not the erk-encoded MAP kinases and rsk-encoded S6 kinases. Rapamycin completely and rapidly inhibits interleukin-2-induced phosphorylation and activation of p70 S6 kinase at concentrations comparable to those blocking S phase entry of T cells (0.05-0.2 nM). The structurally related macrolide FK506 competitively antagonizes the actions of rapamycin, indicating that these effects are mediated by FKBP, which binds the transition-state mimic structure common to both rapamycin and FK506 (refs 4, 6, 9-11). The selective blockade of the p70 S6 kinase activation cascade by the rapamycin-FKBP complex implicates this signalling pathway in the regulation of T cell entry into S phase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Carrier Proteins / metabolism
  • Cell Line
  • Enzyme Activation / drug effects
  • Humans
  • In Vitro Techniques
  • Interleukin-2 / antagonists & inhibitors*
  • Lymphocyte Activation / drug effects
  • Polyenes / pharmacology*
  • Protein Kinases / metabolism*
  • Receptors, Interleukin-2 / physiology*
  • Ribosomal Protein S6 Kinases
  • Signal Transduction / drug effects
  • Sirolimus
  • T-Lymphocytes / metabolism*
  • Tacrolimus Binding Proteins


  • Carrier Proteins
  • Interleukin-2
  • Polyenes
  • Receptors, Interleukin-2
  • Protein Kinases
  • Ribosomal Protein S6 Kinases
  • Tacrolimus Binding Proteins
  • Sirolimus