Abstract
THE macrolide rapamycin induces cell cycle Gl arrest in yeast and in mammalian cells1–3, 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 proliferation4–6, resulting in immunosuppression. Here we show that interleukin-2 selectively stimulates the phosphor) lation and activation of p70 S6 kinase but not the erk-encoded MAP kinases and rsk-encoded S6 kinases7,8. 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Heitman, J., Movva, N. R. & Hall, M. N. Science 253, 905–909 (1991).
Morris, R. E. Immun. Today 5, 137–140 (1991).
Dumont F. J. et al. J. Immun. 144, 1418–1424 (1990).
Bierer, B. E. et al. Proc. natn. Acad. Sci. U.S.A. 87, 9231–9235 (1990).
Dumont, F. J., Staruch, M. J., Koprak, S. L., Melino, M. R. & Sigal, N. H. J. Immun 144, 251–258 (1990).
Schreiber, S. L. Science 251, 283–287 (1991).
Erikson, R. L. J. biol. Chem. 266, 6007–6010 (1992).
Blenis, J. Cancer Cells 3, 1–4 (1991).
Siekierka, J. J., Hung, S. H. Y., Poe, M., Lin, C. S. & Sigal, N. H. Nature 341, 755–757 (1989).
Harding, M. W., Galat, A., Uehling, D. E. & Schreiber, S. L. Nature 341, 758–760 (1989).
Standaert, R. F., Galat, A., Verdine, G. L. & Schreiber, S. L. Nature 346, 671–674 (1990).
Miyazaki, T., Maruyama, M., Yamada, G., Hatakeyama, M. & Taniguchi, T. EMBO J. 10, 3191–3197 (1991).
Chung, J. Chen, R.-H. & Blenis, J. Molec. cell Biol. 11, 1868–1874 (1991).
Chen, R.-H., Chung, J. & Blenis, J. Molec. cell. Biol. 11, 1861–1867 (1991).
Cantrell, D. A. & Smith, K. A. Science 224, 1312–1316 (1984).
Pelech, S. L., Olwin, B. B. & Krebs, E. G. Proc. natn. Acad. Sci. U.S.A. 83, 5968–5972 (1986).
Price, D. J., Gunsalus, J. R. & Avruch, J. Proc. natn. Acad. Sci. U.S.A. 87, 7944–7948 (1990).
Schreiber, S. L. & Crabtree, G. R. Immun. Today 13, 136–142 (1992).
Liu, J. et al. Cell 66, 807–815 (1991).
Friedman, J. & Weissman, I. Cell 66, 799–806 (1991).
Banerjee, P. et al. Proc. natn. Acad. Sci. U.S.A. 87, 8550–8554 (1990).
Kozma, S. C. et al. Proc. natn. Acad. Sci. U.S.A. 87, 7365–7369 (1990).
Chung, J., Kuo, C. J., Crabtree, G. R. & Blenis, J. Cell (in the press).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kuo, C., Chung, J., Fiorentino, D. et al. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature 358, 70–73 (1992). https://doi.org/10.1038/358070a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/358070a0
This article is cited by
-
Hypoxia-inducible factor-1 alpha expression is induced by IL-2 via the PI3K/mTOR pathway in hypoxic NK cells and supports effector functions in NKL cells and ex vivo expanded NK cells
Cancer Immunology, Immunotherapy (2022)
-
mTOR as a central hub of nutrient signalling and cell growth
Nature Cell Biology (2019)
-
Sirolimus and mTOR Inhibitors: A Review of Side Effects and Specific Management in Solid Organ Transplantation
Drug Safety (2019)
-
TAK1 mediates convergence of cellular signals for death and survival
Apoptosis (2019)
-
Biosynthesis, regulation, and engineering of a linear polyketide tautomycetin: a novel immunosuppressant in Streptomyces sp. CK4412
Journal of Industrial Microbiology and Biotechnology (2017)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.