Studies on molecular mechanism of mTOR signaling that controls various cellular functions in response to amino acid sufficiency.

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The mammalian target of rapamycin (mTOR) is a protein kinase that controls multiple cellular functions, including cell growth, in response to amino acids and growth factors, in part by regulating the phosphorylation of p70 S6 kinase (p70S6k) and eukaryotic initiation fector 4E-binding protein 1 (4E-BP1). The mechanisms by which mTOR regulates p70S6k and 4E-BP1 in vivo remain incompletely understood. We identified a novel mTOR-binding partner, raptor (regulatory associated protein of mTOR) that also binds p70S6k and 4E-BP1 and is essential for TOR signaling in vivo. We also demonstrated that raptor binds to p70S6k and 4E-BP1 through their respective TOS (conserved TOR signaling) motifs, a short conserved segment previously shown to be required for amino acid- and mTOR-dependent regulation of these mTOR substrates in vivo. A point mutation within the TOS motif of p70S6k or 4E-BP1 known to abolish both amino acid- and mTOR-regulation, selectively abolishes their binding to raptor. This mutation of the TOS motif also eliminates all in vitro mTOR-catalyzed 4E-BP1 phosphorylation and abolishes the raptor-dependent component of mTOR-catalyzed p70S6k phosphorylation in vitro. Raptor does not alter mTOR's intrinsic catalytic activity, but appears to serve as an mTOR scaffold protein whose binding to the TOS motif of mTOR substrates is necessary for effective mTOR-catalyzed phosphorylation in vivo and perhaps for conferring their sensitivity to rapamycin and amino acid sufficiency.