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Papers In Press, published online ahead of print January 19, 2005
Department of Cell Biology, Harvard Medical School, Boston, MA 02115
Corresponding Author: jblenis{at}hms.harvard.edu
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 characterize 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 show that the RSPRR motif significantly suppresses S6K1 phosphorylation at two phosphorylation sites (Thr389 and Thr229) that are crucial for S6K1 activation. Importantly, introducing both the Thr389 phospho-mimetic and RSPRR motif mutations into the catalytically inactive S6K1-F5A S6K1 mutant completely rescues its activity and renders it fully rapamycin resistant. This data shows 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.
J. Biol. Chem, 10.1074/jbc.M413995200
Submitted on December 13, 2004
Revised on January 18, 2005
Accepted on January 19, 2005
Characterization of a conserved C-terminal (RSPRR) motif in S6K1 required for its mTOR-dependent regulation
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