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

Eric J. Brown, Peter A. Beal, Curtis T. Keith, Jie Chen, Tae Bum Shin, Stuart L. Schreiber

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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.

Original languageEnglish (US)
Pages (from-to)441-446
Number of pages6
JournalNature
Volume377
Issue number6548
StatePublished - 1995
Externally publishedYes

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Cite this

Brown, E. J., Beal, P. A., Keith, C. T., Chen, J., Bum Shin, T., & Schreiber, S. L. (1995). Control of p70 S6 kinase by kinase activity of FRAP in vivo. Nature, 377(6548), 441-446.