HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 12, 11101-11106, March 25, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/12/11101    most recent M413995200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schalm, S. S. Articles by Blenis, J. Search for Related Content PubMed PubMed Citation Articles by Schalm, S. S. Articles by Blenis, J. Social Bookmarking                      What's this?

Characterization of a Conserved C-terminal Motif (RSPRR) in Ribosomal Protein S6 Kinase 1 Required for Its Mammalian Target of Rapamycin-dependent Regulation^*

Stefanie S. Schalm, Andrew R. Tee¶, and John Blenis||

From the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

The mammalian target of rapamycin, mTOR, is a Ser/Thr kinase that promotes cell growth and proliferation by activating ribosomal protein S6 kinase 1 (S6K1). We previously identified a conserved TOR signaling (TOS) motif in the N terminus of S6K1 that is required for its mTOR-dependent activation. Furthermore, our data suggested that the TOS motif suppresses an inhibitory function associated with the C terminus of S6K1. Here, we have characterized the mTOR-regulated inhibitory region within the C terminus. We have identified a conserved C-terminal "RSPRR" sequence that is responsible for an mTOR-dependent suppression of S6K1 activation. Deletion or mutations within this RSPRR motif partially rescue the kinase activity of the S6K1 TOS motif mutant (S6K1-F5A), and this rescued activity is rapamycin resistant. Furthermore, we have shown that the RSPRR motif significantly suppresses S6K1 phosphorylation at two phosphorylation sites (Thr-389 and Thr-229) that are crucial for S6K1 activation. Importantly, introducing both the Thr-389 phosphomimetic and RSPRR motif mutations into the catalytically inactive S6K1 mutant S6K1-F5A completely rescues its activity and renders it fully rapamycin resistant. These data show that the N-terminal TOS motif suppresses an inhibitory function mediated by the C-terminal RSPRR motif. We propose that the RSPRR motif interacts with a negative regulator of S6K1 that is normally suppressed by mTOR.

Received for publication, December 13, 2004 , and in revised form, January 18, 2005.

^* This work was supported in part by National Institutes of Health Grant GM51405 to (J. B.), the Tuberous Sclerosis Alliance, and The Rothberg Courage Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

Supported by the Boehringer Ingelheim Fonds, Germany. Present address: Dept. of Molecular and Cellular Biology, Harvard University, 7 Divinity Ave., Cambridge, MA 02138.

^¶ Supported by the European Molecular Biology Organization and the British Heart Foundation through BHF Intermediate Research Fellowship FS/04/002. Present address: University of Dundee, Medical Sciences Inst./Wellcome Bldg. Complex, Dow St., Dundee DD1 5EH, UK.

^|| To whom correspondence should be addressed. Tel.: 617-432-4848; Fax: 617-432-1144; E-mail: john_blenis{at}hms.harvard.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				U. Narayanan, V. Nalavadi, M. Nakamoto, G. Thomas, S. Ceman, G. J. Bassell, and S. T. Warren S6K1 Phosphorylates and Regulates Fragile X Mental Retardation Protein (FMRP) with the Neuronal Protein Synthesis-dependent Mammalian Target of Rapamycin (mTOR) Signaling Cascade J. Biol. Chem., July 4, 2008; 283(27): 18478 - 18482. [Abstract] [Full Text] [PDF]

				Z. Hou, L. He, and R. Z. Qi Regulation of S6 Kinase 1 Activation by Phosphorylation at Ser-411 J. Biol. Chem., March 9, 2007; 282(10): 6922 - 6928. [Abstract] [Full Text] [PDF]

				D. L. Williamson, D. R. Bolster, S. R. Kimball, and L. S. Jefferson Time course changes in signaling pathways and protein synthesis in C2C12 myotubes following AMPK activation by AICAR. Am J Physiol Endocrinol Metab, July 1, 2006; 291(1): E80 - E89. [Abstract] [Full Text] [PDF]

				W. W. Chen, D. C. Chan, C. Donald, M. B. Lilly, and A. S. Kraft Pim Family Kinases Enhance Tumor Growth of Prostate Cancer Cells Mol. Cancer Res., August 1, 2005; 3(8): 443 - 451. [Abstract] [Full Text] [PDF]

				M. K. Holz and J. Blenis Identification of S6 Kinase 1 as a Novel Mammalian Target of Rapamycin (mTOR)-phosphorylating Kinase J. Biol. Chem., July 15, 2005; 280(28): 26089 - 26093. [Abstract] [Full Text] [PDF]