Gene interactions and pathways from curated databases and text-mining
Curr Biol 2003, PMID: 12747827

TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function.

Schalm, Stefanie S; Fingar, Diane C; Sabatini, David M; Blenis, John


The mammalian target of rapamycin, mTOR, is a serine/threonine kinase that controls cell growth and proliferation via the translation regulators eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). We recently identified a TOR signaling (TOS) motif in the N terminus of S6K1 and the C terminus of 4E-BP1 and demonstrated that in S6K1, the TOS motif is necessary to facilitate mTOR signaling to phosphorylate and activate S6K1. However, it is unclear how the TOS motif in S6K1 and 4E-BP1 mediates mTOR signaling.


Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by the mTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor-regulated phosphorylation is necessary for 4E-BP's efficient release from the translational initiation factor eIF4E. Consistently, overexpression of a mutant of 4E-BP1 containing a single amino acid change in the TOS motif (F114A) reduces cell size, demonstrating that mTOR-dependent regulation of cell growth by 4E-BP1 is dependent on a functional TOS motif.


Our data demonstrate that the TOS motif functions as a docking site for the mTOR/raptor complex, which is required for multisite phosphorylation of 4E-BP1, eIF4E release from 4E-BP1, and cell growth.

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Text Mining Data

4E-BP1 → raptor: " TOS motif mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function "

Manually curated Databases

  • IRef Biogrid Interaction: RPTOR — MTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: EIF4EBP1 — MTOR (direct interaction, pull down)
  • IRef Biogrid Interaction: EIF4EBP1 — RPTOR (physical association, affinity chromatography technology)
  • IRef Hprd Interaction: RPTOR — EIF4EBP1 (in vitro)
  • IRef Hprd Interaction: RPTOR — EIF4EBP1 (in vivo)
  • IRef Innatedb Interaction: EIF4E — EIF4EBP1 (unknown, -)
  • IRef Innatedb Interaction: EIF4EBP1 — MTOR (unknown, -)
  • NCI Pathway Database mTOR signaling pathway: mTORC1 complex (MTOR-MLST8-RPTOR) → 4E-BP1/eIF4E complex (EIF4EBP1-EIF4E) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
In total, 10 gene pairs are associated to this article in curated databases