The Mammalian Target of Rapamycin (mTOR) Partner, Raptor, Binds the mTOR Substrates p70 S6 Kinase and 4E-BP1 through Their TOR Signaling (TOS) Motif*

By H. Nojima, C. Tokunaga, S. Eguchi, N. Oshiro, Sujuti Hidayat, K. Yoshino, K. Hara, Noriaki Tanaka, J. Avruch, K. Yonezawa. Journal of Biological Chemistry, 2003

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The mammalian target of rapamycin (mTOR) controls multiple cellular functions in response to amino acids and growth factors, in part by regulating the phosphorylation of p70 S6 kinase (p70S6k) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). Raptor (regulatory associated protein of mTOR) is a recently identified mTOR binding partner that also binds p70S6k and 4E-BP1 and is essential for TOR signaling in vivo. Herein we demonstrate that raptor binds to p70S6k and 4E-BP1 through their respective TOS (conserved TOR signaling) motifs to be required for amino acid- and mTOR-dependent regulation of these mTOR substrates in vivo. A point 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 appears to serve as an mTOR scaffold protein, the binding of which 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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/37ac51b6f6c02c3658cf54fde0d75f3e82fb60ff

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Citations in the corpus

mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “Raptor facilitates substrate recruitment to mTORC1 through binding to the TOR signaling (TOS) motif found on several canonical mTORC1 substrates (Nojima et al., 2003; Schalm et al., 2003) and, as described later, is required for the correct subcellular localization of mTORC1. mLST8 by contrast…”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “Raptor facilitates substrate recruitment to mTORC1 through binding to the TOR signaling (TOS) motif found on several canonical mTORC1 substrates (Nojima et al., 2003; Schalm et al., 2003), and, as described later, is required for the correct subcellular localization of mTORC1.”
TOR signaling in growth and metabolism. (2006, background): “…during Early Development Deletion of CeTOR in the nematode worm Caenorhabditis elegans or of dTOR in the fruit fly Drosophila melanogaster causes developmental arrests that share some features with the arrests observed in starved larvae (Long et al., 2002; Oldham et al., 2000; Zhang et al., 2000).”
Oncogenic PI3K deregulates transcription and translation (2005, background): “The function of Raptor in this process depends on a specific motif in the target proteins, named the TOS (TOR signalling) moti”
Upstream and downstream of mTOR. (2004, background): “Mutations in the TOS motif markedly inhibit mTOR-mediated phosphorylation of 4E-BP1 (Beugnet et al. 2003; Choi et al. 2003; Nojima et al. 2003; Schalm et al. 2003).”
Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression (2004, background): “The TOS motif is required for raptor to interact Oncogene with 4E-BP1 (either directly or indirectly), thus functioning to assemble an mTOR/raptor/4E-BP1 complex (Choi et al., 2003; Nojima et al., 2003; Schalm et al., 2003).”
mTOR Controls Cell Cycle Progression through Its Cell Growth Effectors S6K1 and 4E-BP1/Eukaryotic Translation Initiation Factor 4E (2004, background): “F114A-4E-BP1 contains a mutation in the TOS motif and does not associate with the mTOR/ raptor complex; consequently, F114A-4E-BP1 cannot be phosphorylated (8, 33, 45, 59).”
mTOR Is Essential for Growth and Proliferation in Early Mouse Embryos and Embryonic Stem Cells (2004, background): “that raptor functions as a scaffolding protein for mTOR-catalyzed phosphorylation of p70 and 4E-BP1 (7, 14, 39).”
mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. (2005, positive): “S6K1 activation is initiated by mTOR/raptor-mediated phosphorylation of T389 (Kim et al., 2002), which requires the TOS motif located at the N terminus of S6K1 (Nojima et al., 2003; Schalm and Blenis, 2002).”