The initiation step of protein translation requires a number of eukaryotic translation initiation factors (eIFs).
Initially, the 40S ribosomal subunit associates with Met-tRNAi and a group of initiation factors, including eIF1, eIF1A, eIF2, eIF3, and eIF5 to form the 43S pre-initiation complex.
This complex is then recruited to the 5'-end of capped mRNA by another complex of factors (known as eIF4F) consisting of eIF4E, eIF4G, and eIF4A.
eIF4E is an indispensable element for cap-dependent translation initiation and plays a major role in recognition of the mRNA cap structure.
It binds to eIF4G, which serves as a scaffolding protein to gather eIF4A (ATP-dependent RNA helicase), eIF4B, eIF3, and poly-A-binding protein to form the 48S complex.
This complex then scans the mRNA for an initiation codon and, once this is located, the 60S ribosomal subunit joins to form the elongation-competent fully functional 80S.
eIF4E is the least abundant of the cellular translation initiation components and it represents the rate-limiting element for the initiation process.
Under resting conditions, eIF4E is kept in an inactive form bound to 4E-binding proteins (4E-BPs); once the latter have been phosphorylated through the PI3K-AKT-mTOR signaling pathway, eIF4E is released and binds eIF4G to launch translation.
eIF4E is upregulated in various human tumors, and it contributes to transformation, tumorigenesis, and cancer progression.
eIF4E overexpression facilitates translation of weak and highly structured mRNAs that typically encode proteins involved in cancer biology, such as proto-oncoproteins (e.g.
