Fig. 2
From: Eukaryotic translation initiation factors as promising targets in cancer therapy
The major substrates of mTORC1 and their signaling to the translational machinery. 4E-BPs and S6Ks are the two major mediators of the effects of mTORC1 on mRNA translation. In non-phosphorylated states, 4E-BPs block the assembly of the eIF4F complex by competing with eIF4G for binding to eIF4E. When phosphorylated by mTORC1, the hyper-phosphorylation of 4E-BPs facilitates their dissociation from eIF4E, allowing the interaction of eIF4E and eIF4G and the assembly of eIF4F complex. In addition to 4E-BPs, S6Ks also mediate the effects of mTORC1 on mRNA translation. The major S6Ks substrates involved in the regulation of translation are rpS6, eIF4B, eEF2K and PDCD4, which are also phosphorylated by other AGC kinases including RSK and AKT. rpS6 is a component of the 40S ribosomal subunit, and eIF4B is an auxiliary factor that enhances the RNA-unwinding activity of eEF4A. The phosphorylation of rpS6 and eIF4B by AGC kinases significantly promote the translation of mRNA. PDCD4 is reported as pro-apoptotic factor and has been suggested to possess tumor suppressor properties. eEF2K functions as a negative regulator of protein synthesis via phosphorylation and inhibition of eEF2. The phosphorylation of PDCD4 and eEF2K by AGC kinases leads to PDCD4 degradation and the inhibition of eEF2K kinase activity, respectively. Black arrows and red T-bars represent stimulatory and inhibitory signals, respectively