The mTORC1 and MEK-ERK signaling pathways regulate eIF4F activity and assembly. 4E-BP is phosphorylated and inactivated by mTORC1, which frees eIF4E and allows it to bind to eIF4G and incorporate into the complex. eIF4E also is phosphorylated by Mnk1, which activates it, and is bound by CYFIP1, which sequesters it from the eIF4F complex. PDCD4 and eIF4B are both phosphorylated by S6K1 and RSK, which are downstream from mTORC1 and MEK-ERK, respectively. The phosphorylation of eIF4B results in its activation and the phosphorylation of PDCD4 results in its inactivation via ubiquitination and degradation by the proteasome pathway, resulting in decreased repression of eIF4A.
