A number of eukaryotic initiation factors participate in both mRNA binding and scanning of the 5 UTR of the mRNA by the small ribosomal subunit. The cap-binding protein eIF4E, together with the DEAD-box helicase eIF4A and the translation initiation factor eIF4G, forms the protein complex eIF4F. The heterotrimeric complex eIF4F is required for recruiting the 43S preinitiation complex onto the cap structure located at the 5 end of the mRNA [83] . In this sense, eIF4G, the larger polypeptide of eIF4F, functions as an adaptor molecule that bridges the mRNAs to ribosomes via interactions with factors eIF4E (which binds the 5 cap structure), PABP (which binds the poly(A) tail), and eIF3, which interacts with the 40S ribosome subunit ( Figure 3 ) [81, [84] [85] [86] . In addition, eIF4G also contains binding sites for other polypeptides involved in translation, such as the RNA helicase eIF4A ( Figure 3 ) [87] , which is required to unwind the secondary structure within the mRNA 5 leader sequence that would otherwise inhibit ribosome scanning. The simultaneous interaction of eIF4G with eIF4E and PABP promotes circularization of the mRNA in a closed loop that facilitates the initiation of new rounds of translation by the proximity of the 5 and 3 ends [88, 89] . Furthermore, eIF4G also interacts with the mitogen-activated protein kinase 1 (Mnk1) (Figure 3 ), which phosphorylates eIF4E, although the role of this phosphorylation in the initiation of translation in still unclear [90] [91] [92] [93] [94] . Two forms of eIF4G, known as eIF4GI and eIF4GII, have been identified in mammalian cells. Both forms show only 46% amino acid sequence identity but they are thought to be functionally interchangeable due to the high homology in key domains that interact with other factors [88] . Evidence obtained by specific depletion of each eIF4G form or differential cleavage of each of them by specific proteases (see below) points to the idea that both factors should be lacking for complete abolition of protein synthesis [95, 96] . eIF4GI is the dominant form in HeLa cells, in which the ratio between eIFGI and eIF4GII is 9 : 1 [97] . However, the specific role of each form of eIF4G in the initiation of translation remains unknown. It was proposed that both eIF4G forms are differentially regulated by different kinases, supporting the hypothesis that eIF4GI and eIF4GII could drive differentially translation initiation [98] . eIF4GI is phosphorylated in response to serum and in a rapamycin-dependent manner at Ser 1148, 1188, and 1232, although the role of these posttranslational modifications is still under investigation [99] . In addition, eIF4GI is phosphorylated by p21-activated protein kinase (Pak-2) that is induced under stress conditions. This phosphorylation takes place in the eIF4E-binding site of eIF4G and avoids the interaction between these two factors, inhibiting cap-dependent initiation of translation [100] . On the other hand, eIF4GII is phosphorylated during mitosis [101] by calmodulin-dependent kinase I at Ser 1156 [102] . Therefore, activity of eIF4GI and eIF4GII might be tightly and reversibly regulated by phosphorylation under different physiological conditions. Nevertheless, this factor is also subjected to irreversible modifications such as caspasemediated proteolysis, which is triggered during apoptosis and leads to shutoff of protein synthesis. Caspase-3 cleaves directly eIF4GI in positions 532 and 1175 removing PABP, Mnk1, and one eIF4A-binding domain from the eIF4GI core ( Figure 3 ) [103, 104] . In contrast, eIF4GII is degraded during apoptosis with a delayed kinetics in relation to eIF4GI proteolysis, correlating with the shutoff of the protein synthesis [104] .