Control of p70 S6 kinase by kinase activity of FRAP in vivo

An Erratum to this article was published on 07 December 1995

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. 1

    Bierer, B. E. et al. Proc. natn. Acad. Sci. U.S.A. 87, 9231–9235 (1990).

    ADS  CAS  Article  Google Scholar 

  2. 2

    Dumont, F. J., Staruch, M. J., Koprak, S. L., Melino, M. R. & Sigal, N. H. J. Immun. 144, 251–258 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Kuo, C. J. et al. Nature 358, 70–73 (1992).

    ADS  CAS  Article  Google Scholar 

  4. 4

    Chung, J., Kuo, C. J., Crabtree, G. R. & Blenis, J. Cell 69, 1227–1236 (1992).

    CAS  Article  Google Scholar 

  5. 5

    Price, D. J., Grove, J. R., Calvo, V., Avruch, J. & Bierer, B. E. Science 257, 973–977 (1992).

    ADS  CAS  Article  Google Scholar 

  6. 6

    Calvo, V., Crews, C. M., Vik, T. A. & Bierer, B. Proc. natn. Acad. Sci. U.S.A. 89, 7571–7575 (1992).

    ADS  CAS  Article  Google Scholar 

  7. 7

    Morice, W. G., Brunn, G. J., Wiederrecht, G., Siekierka, J. J. & Abraham, R. T. J. biol. Chem. 268, 3734–3738 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Morice, W. G., Wiederrecht, G., Brunn, G. J., Siekierka, J. J. & Abraham, R. T. J. biol. Chem. 268, 22737–22745 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Albers, M. W. et al. J. biol. Chem. 268, 22825–22829 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Nourse, J. et al. Nature 372, 570–573 (1994).

    ADS  CAS  Article  Google Scholar 

  11. 11

    Brown, E. J. et al. Nature 369, 756–758 (1994).

    ADS  CAS  Article  Google Scholar 

  12. 12

    Sabatini, D. M., Erdjument, B. H., Lui, M., Tempst, P. & Snyder, S. H. Cell 78, 35–43 (1994).

    CAS  Article  Google Scholar 

  13. 13

    Schu, P. V. et al. Science 260, 88–91 (1993).

    ADS  CAS  Article  Google Scholar 

  14. 14

    Dhand, R. et al. EMBO J. 13, 522–533 (1994).

    CAS  Article  Google Scholar 

  15. 15

    Taylor, S. S. et al. Trends biochem. Sci. 18, 84–89 (1993).

    CAS  Article  Google Scholar 

  16. 16

    Clipstone, N. A. & Crabtree, G. R. Nature 357, 695–697 (1992).

    ADS  CAS  Article  Google Scholar 

  17. 17

    Chen, J., Zheng, X.-F., Brown, E. J. & Schreiber, S. L. Proc. natn. Acad. Sci. U.S.A. 92, 4947–4951 (1995).

    ADS  CAS  Article  Google Scholar 

  18. 18

    Ballou, L. M., Siegmann, M. & Thomas, G. Proc. natn. Acad. Sci. U.S.A. 85, 7154–7158 (1988).

    ADS  CAS  Article  Google Scholar 

  19. 19

    Chung, J., Grammer, T. C., Lemon, K. P., Kazlauskas, A. & Blenis, J. Nature 370, 71–75 (1994).

    ADS  CAS  Article  Google Scholar 

  20. 20

    Zheng, X.-F., Fiorentino, D., Chen, J., Crabtree, G. R. & Schreiber, S. L. Cell 82, 121–130 (1995).

    CAS  Article  Google Scholar 

  21. 21

    Herman, P. K. & Emr, S. D. Molec. cell. Biol. 10, 6742–6754 (1990).

    CAS  Article  Google Scholar 

  22. 22

    Boyle, W. J., Van Der Geer, P. & Hunter, T. Meth. Enzym. 201, 110–148 (1991).

    CAS  Article  Google Scholar 

  23. 23

    Kolodziej, P. A. & Young, R. A. Meth. Enzym. 194, 508–519 (1991).

    CAS  Article  Google Scholar 

  24. 24

    Kozma, S. C. et al. Proc. natn. Acad. Sci. U.S.A. 87, 7365–7369 (1990).

    ADS  CAS  Article  Google Scholar 

  25. 25

    Jeno, P., Ballou, L. M., Novak-Hofer, I. & Thomas, G. Proc. natn. Acad. Sci U.S.A. 85, 406–410 (1988).

    ADS  CAS  Article  Google Scholar 

  26. 26

    Flotow, H. & Thomas, G. J. biol. Chem. 267, 3074–3078 (1992).

    CAS  Google Scholar 

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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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