Figure 1. Eukaryotic Cap-Dependent Translation Initiation and Its Regulation by eIF2α Kinases and Other Signaling Pathways.

eIFs 1, 1A, and 3 promote dissociation of 80S ribosomes and, together with eIF5 and ternary complex (eIF2-GTP-Met-tRNA_i), assemble the 43S preinitiation complex (PIC). In yeast, these eIFs form a multifactor complex (MFC), which could bind to the 40S ribosomal subunit. mRNA is activated by binding of eIF4F (eIF4E·eIF4G·eIF4A) to the cap and PABP to the poly(A) tail, circularizing the mRNA. The 43S PIC binds near the cap, facilitated by eIF3/eIF5 interactions with eIF4G/eIF4B, and scans the leader for the AUG codon in an ATP-dependent reaction, with partial hydrolysis of the eIF2-bound GTP in the ternary complex to eIF2-GDP-Pi. AUG recognition triggers eIF1 dissociation from the 40S platform (not depicted), allowing release of Pi and eIF2-GDP. Joining of the 60S subunit, with release of other eIFs, is catalyzed by eIF5B-GTP, and GTP hydrolysis triggers release of eIF5B-GDP and eIF1A to yield the final 80S initiation complex. Under stress or starvation conditions, ternary complex formation is reduced by eIF2α phosphorylation, and eIF4F assembly is blocked by 4E-BP binding to eIF4E. Phosphorylation by mTOR dissociates 4E-BP from eIF4E. mTOR also promotes eIF4G and eIF4B phosphorylation either directly or via S6Ks. Mitogens and growth factors promote all of these phosphorylation events by activating mTOR via PI3K/Akt signaling or RAS/MAPK signaling. (Not shown is that MAPK signaling also engenders phosphorylation of eIF4E by kinases Mnk1/Mnk2.) (Figure adapted from Sonenberg and Hinnebusch, 2007.)