Abstract
WHEN complexed with the intracellular protein FKBP12, rapamy-cin is a potent immunosuppressant1,2 and an inhibitor of a mitogen-stimulated signalling pathway that leads to activation of p70 S6 kinase3-6 (p70S6k) and cyclin-dependent kinases7-10 (CDKs). A recently cloned FKBP12-rapamycin-associated protein (FRAP/ RAFT) is the likely mediator of these effects11,12. Using FRAP variants that do not bind FKBP12-rapamycin, we demonstrate here that FRAP is a rapamycin-sensitive regulator of p70S6k in vivo and that the kinase activity of FRAP is required for this regulation. In addition, we show that FRAP autophosphorylates in vitro. Consistent with an essential role for FRAP kinase activity in vivo, autophosphorylation of FRAP is inhibited by FKBP12-rapamycin. Deletion studies indicate that the kinase activity of FRAP alone is not sufficient for control of p70S6k and that an amino-terminal domain in FRAP is also required.
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References
- 1
Bierer, B. E. et al. Proc. natn. Acad. Sci. U.S.A. 87, 9231–9235 (1990).
- 2
Dumont, F. J., Staruch, M. J., Koprak, S. L., Melino, M. R. & Sigal, N. H. J. Immun. 144, 251–258 (1990).
- 3
Kuo, C. J. et al. Nature 358, 70–73 (1992).
- 4
Chung, J., Kuo, C. J., Crabtree, G. R. & Blenis, J. Cell 69, 1227–1236 (1992).
- 5
Price, D. J., Grove, J. R., Calvo, V., Avruch, J. & Bierer, B. E. Science 257, 973–977 (1992).
- 6
Calvo, V., Crews, C. M., Vik, T. A. & Bierer, B. Proc. natn. Acad. Sci. U.S.A. 89, 7571–7575 (1992).
- 7
Morice, W. G., Brunn, G. J., Wiederrecht, G., Siekierka, J. J. & Abraham, R. T. J. biol. Chem. 268, 3734–3738 (1993).
- 8
Morice, W. G., Wiederrecht, G., Brunn, G. J., Siekierka, J. J. & Abraham, R. T. J. biol. Chem. 268, 22737–22745 (1993).
- 9
Albers, M. W. et al. J. biol. Chem. 268, 22825–22829 (1993).
- 10
Nourse, J. et al. Nature 372, 570–573 (1994).
- 11
Brown, E. J. et al. Nature 369, 756–758 (1994).
- 12
Sabatini, D. M., Erdjument, B. H., Lui, M., Tempst, P. & Snyder, S. H. Cell 78, 35–43 (1994).
- 13
Schu, P. V. et al. Science 260, 88–91 (1993).
- 14
Dhand, R. et al. EMBO J. 13, 522–533 (1994).
- 15
Taylor, S. S. et al. Trends biochem. Sci. 18, 84–89 (1993).
- 16
Clipstone, N. A. & Crabtree, G. R. Nature 357, 695–697 (1992).
- 17
Chen, J., Zheng, X.-F., Brown, E. J. & Schreiber, S. L. Proc. natn. Acad. Sci. U.S.A. 92, 4947–4951 (1995).
- 18
Ballou, L. M., Siegmann, M. & Thomas, G. Proc. natn. Acad. Sci. U.S.A. 85, 7154–7158 (1988).
- 19
Chung, J., Grammer, T. C., Lemon, K. P., Kazlauskas, A. & Blenis, J. Nature 370, 71–75 (1994).
- 20
Zheng, X.-F., Fiorentino, D., Chen, J., Crabtree, G. R. & Schreiber, S. L. Cell 82, 121–130 (1995).
- 21
Herman, P. K. & Emr, S. D. Molec. cell. Biol. 10, 6742–6754 (1990).
- 22
Boyle, W. J., Van Der Geer, P. & Hunter, T. Meth. Enzym. 201, 110–148 (1991).
- 23
Kolodziej, P. A. & Young, R. A. Meth. Enzym. 194, 508–519 (1991).
- 24
Kozma, S. C. et al. Proc. natn. Acad. Sci. U.S.A. 87, 7365–7369 (1990).
- 25
Jeno, P., Ballou, L. M., Novak-Hofer, I. & Thomas, G. Proc. natn. Acad. Sci U.S.A. 85, 406–410 (1988).
- 26
Flotow, H. & Thomas, G. J. biol. Chem. 267, 3074–3078 (1992).
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Brown, E., Beal, P., Keith, C. et al. Control of p70 S6 kinase by kinase activity of FRAP in vivo. Nature 377, 441–446 (1995). https://doi.org/10.1038/377441a0
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