mTOR complex 1 and 2 regulate S6 kinase 1 activation in tandem.
Eukaryotic translation initiation factor 4E was recently shown to be a substrate of mTORC1, suggesting it may be a mediator of mTORC1 signaling. Here, we present evidence that eIF4E phosphorylated at S209 interacts with TOS motif of S6 Kinase1 (S6K1). We also show that this interaction is sufficient to overcome rapamycin sensitivity and mTORC1 dependence of S6K1. Furthermore, we show that eIF4E-TOS interaction relieves S6K1 from auto-inhibition due to carboxy terminal domain (CTD) and primes it for hydrophobic motif (HM) phosphorylation and activation in mTORC1 independent manner. We conclude that the role of mTORC1 is restricted to engaging eIF4E with S6K1-TOS motif to influence its state of HM phosphorylation and inducing its activation. HighlightsO_LIPhosphorylated eIF4E interacts with TOS motif of S6 Kinase1 C_LIO_LIeIF4E-TOS interaction relieves S6 Kinase 1 from carboxy terminal domain auto-inhibition and primes it for activation. C_LI