Description: Phosphorylation of S65 flanking the eIF4E-binding motif of Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) by Serine/threonine-protein kinase mTOR (MTOR) inhibits binding to Eukaryotic translation initiation factor 4E (EIF4E) in response to growth factors and nutrients. This results in release of Eukaryotic translation initiation factor 4E (EIF4E), which associates with other initiation factors to form the eIF-4F complex that mediates initiation of translation. However, disruption of the interaction between Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) and Eukaryotic translation initiation factor 4E (EIF4E) has been shown to be dependent on hyperphosphorylation of Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) by FRAP/mTOR, PI3K and ERK pathways. According to the current model, Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) is phosphorylated on multiple residues in a well-defined order. Basal phosphorylation of T37 and T46 serves as a priming event for subsequent serum-induced phosphorylation of T70, which primes for subsequent phosphorylation of S65.
Participants: (1) Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) (2) Eukaryotic translation initiation factor 4E (EIF4E)
(1) PHAS-I as a link between mitogen-activated protein kinase and translation initiation.Lin et al. Science (1994) (2) Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism.Gingras et al. Genes Dev. (1999) (3) Multiple mechanisms control phosphorylation of PHAS-I in five (S/T)P sites that govern translational repression.Mothe-Satney et al. Mol. Cell. Biol. (2000) (4) Mammalian target of rapamycin-dependent phosphorylation of PHAS-I in four (S/T)P sites detected by phospho-specific antibodies.Mothe-Satney et al. J. Biol. Chem. (2000) (5) Regulation of translation initiation by FRAP/mTOR.Gingras et al. Genes Dev. (2001) (6) Hierarchical phosphorylation of the translation inhibitor 4E-BP1.Gingras et al. Genes Dev. (2001) (7) The extracellular signal-regulated kinase pathway regulates the phosphorylation of 4E-BP1 at multiple sites.Herbert et al. J. Biol. Chem. (2002) (8) Coordinate regulation of translation by the PI 3-kinase and mTOR pathways.Martin et al. Adv. Cancer Res. (2002) (9) TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function.Schalm et al. Curr. Biol. (2003)
