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

Research output: Contribution to journalArticle

Abstract

WHEN complexed with the intracellular protein FKBP12, rapamycin is a potent immunosuppressant1,2 and an inhibitor of a mitogenstimulated signalling pathway that leads to activation of p70 S6 kinase3-6 (pTOS6k) 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)
JournalNature
Volume377
Issue number6548
StatePublished - Oct 5 1995
Externally publishedYes

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70-kDa Ribosomal Protein S6 Kinases
Tacrolimus Binding Protein 1A
Sirolimus
Phosphotransferases
TOR Serine-Threonine Kinases
S 6
Cyclins
Proteins

ASJC Scopus subject areas

  • General

Cite this

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

Control of p70 S6 kinase by kinase activity of FRAP in vivo. / Brown, Eric J.; Beal, Peter A.; Keith, Curtis T.; Chen, Jie; Shin, Tae Bum; Schreiber, Stuart L.

In: Nature, Vol. 377, No. 6548, 05.10.1995.

Research output: Contribution to journalArticle

Brown, EJ, Beal, PA, Keith, CT, Chen, J, Shin, TB & Schreiber, SL 1995, 'Control of p70 S6 kinase by kinase activity of FRAP in vivo', Nature, vol. 377, no. 6548.
Brown EJ, Beal PA, Keith CT, Chen J, Shin TB, Schreiber SL. Control of p70 S6 kinase by kinase activity of FRAP in vivo. Nature. 1995 Oct 5;377(6548).
Brown, Eric J. ; Beal, Peter A. ; Keith, Curtis T. ; Chen, Jie ; Shin, Tae Bum ; Schreiber, Stuart L. / Control of p70 S6 kinase by kinase activity of FRAP in vivo. In: Nature. 1995 ; Vol. 377, No. 6548.
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AU - Schreiber, Stuart L.

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