title: Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, Unit in Molecular and Genetic Medicine, Beckman Center, Stanford University School of Medicine, California 94305-5425.
authors.forename: C J
authors.initials: CJ
authors.lastname: Kuo
authors.forename: J
authors.initials: J
authors.lastname: Chung
authors.forename: D F
authors.initials: DF
authors.lastname: Fiorentino
authors.forename: W M
authors.initials: WM
authors.lastname: Flanagan
authors.forename: J
authors.initials: J
authors.lastname: Blenis
authors.forename: G R
authors.initials: GR
authors.lastname: Crabtree
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation / Q000187:drug effects; D011090:Polyenes / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus; D013601:T-Lymphocytes / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins
chemical_list: D002352:Carrier Proteins; D007376:Interleukin-2; D011090:Polyenes; D015375:Receptors, Interleukin-2; D011494:Protein Kinases; D019893:Ribosomal Protein S6 Kinases; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus