Beyond molecular tumor heterogeneity: protein synthesis takes control

Ramon y Cajal, Santiago; Castellvi, Josep; Hümmer, Stefan; Peg, Vicente; Pelletier, Jerry; Sonenberg, Nahum

The eIF4F complex, consisting of eIF4E (the cap-binding protein), eIF4A (a DEAD-box RNA helicase), and eIF4G (a large scaffolding protein), regulates ribosome recruitment to mRNA templates [35] . This step in translation initiation is thought to be rate-limiting for protein synthesis. The assembly of eIF4F is regulated by mTOR via phosphorylation of 4E-BPs (of which there are three, with 4E-BP1 being the best studied), as well as of PDCD4 [36] [37] [38] [39] . Binding of 4E-BP1 to eIF4E prevents eIF4F complex formation [40] . mTOR activation (as occurs in a broad range of human cancers) causes direct phosphorylation of 4E-BP1 and its dissociation from eIF4E to consequently stimulate eIF4F formation [41] [42] [43] . eIF4F discriminates between different mRNAs and therefore an increase in eIF4F levels or activity causes a selective change in the translatome. Although the features responsible for mRNA discrimination by eIF4F are not completely understood, cap accessibility and 5′ leader secondary structure are important contributors [44] [45] [46] . PDCD4 forms an inhibitory complex with eIF4A and phosphorylation of the former by S6K1/2 leads to its degradation and allows eIF4A to enter the eIF4F complex [38, 39] . In addition, eIF4E can be directly phosphorylated upon activation of the RAS-RAF-ERK1/2-MNK pathway or through p38 and this is also associated with a selective increase in translation, the mechanistic basis of which remains to be elucidated [47] [48] [49] [50] [51] .