title: Rapamycin-insensitive mTORC1 activity controls eIF4E:4E-BP1 binding.
abstract: The recent development of mammalian target of rapamycin (mTOR) kinase domain inhibitors and genetic dissection of rapamycin-sensitive and -insensitive mTOR protein complexes (mTORC1 and mTORC2) have revealed that phosphorylation of the mTOR substrate 4E-BP1 on amino acids Thr37 and/or Thr46 represents a rapamycin-insensitive activity of mTORC1. Despite numerous previous reports utilizing serine (Ser)-to-alanine (Ala) and threonine (Thr)-to-Ala phosphorylation site mutants of 4E-BP1 to assess which post-translational modification(s) directly regulate binding to eIF4E, an ambiguous understanding persists. This manuscript demonstrates that the initial, rapamycin-insensitive phosphorylation event at Thr46 is sufficient to prevent eIF4E:4E-BP1 binding. This finding is relevant, particularly as mTOR kinase domain inhibitors continue to be assessed for clinical efficacy, since it clarifies a difference between the action of these second-generation mTOR inhibitors and those of rapamycin analogues.
authors.affiliation: Biochemistry and McGill Cancer Centre, McGill University, Montreal, Canada ; Cytokine Signalling Unit, Institut Pasteur, Paris, France.
authors.forename: Mark
authors.initials: M
authors.lastname: Livingstone
authors.affiliation: Biochemistry and McGill Cancer Centre, McGill University, Montreal, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Bidinosti