Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase.
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.
Kuo
C J
CJ
Howard Hughes Medical Institute, Unit in Molecular and Genetic Medicine, Beckman Center, Stanford University School of Medicine, California 94305-5425.
Chung
J
J
Fiorentino
D F
DF
Flanagan
W M
WM
Blenis
J
J
Crabtree
G R
GR
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
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