Find EIF4E Products Interaction Network for EIF4E EIF4E Details

Related Pathways PI3K/AKT Signaling ERK/MAPK Signaling Axonal Guidance Signaling View All Pathways

Synonyms: CAP-BINDING PROTEIN, CBP, EG668879, EIF4E, Eif4e-ps, EIF4E1, EIF4EL1, EIF4F, IF4E, MGC103177, MGC111573, MGC134278, MGC93265

eIF4 and p70S6K

Initiation of protein synthesis (translation) in eukaryotes requires the formation of an 80S complex in which initiator Met-tRNA (Meti-tRNA) is based paired with an mRNA AUG start codon in the P-site of the ribosome. The assembly of an active translation complex requires the pre-assembly of a 43S preinitiation complex and an initiation-factor complex. The 43S preinitiation complex is assembled by the association of the 40S ribosomal subunit with a ternary complex (TC) composed of Meti-tRNA and GTP-charged eIF2. The assembled preinitiation complex interacts with and scans mRNA to pair Meti-tRNA with the AUG start codon. This process is facilitated by the initiation-factor complex, eIF4F, composed of (eIF4A-eIF4E-eIF4G); poly(A)-binding protein, mRNA and eIF3. Eucaryote IF4F is a protein complex that regulates the efficiency of translation of capped mRNAs with secondary structure in their untranslated regions (UTR). Binding of the eIF4F protein complex to capped (m7GpppX, X any nucleotide) mRNA is mediated by eIF4E, which together with eIF4A and B unwinds the 5’-secondary structure of mRNA. The assembly and disassembly of the eIF4F complex depends upon binding of the scaffold protein eIF4G. The eIF4F complex assembles when eIF4G, which can simultaneously bind eIF4A and the eIF4E-kinase, Mnk1, binds to eIF4E.

The activity of mammalian eIF4F is regulated by two mechanisms. First, the phosphorylation of eIF4E is required to form a stable initiation complex. Mitogens and stresses induce the phosphorylation of eIF4E increasing its affinity for capped mRNA and for an associated scaffolding protein, eIF4G which organizes the eIF4F complex. A major pathway leading to the phosphorylation of eIF4E by Mnk is induced by the Ras-activated MAP-kinase pathway: Ras/Raf/MEK/ERK. The S6 kinase, p70S6K, also phosphorylates eIF4E. P70S6K is activated by hierarchical phosphorylation of multiple Ser/Thr sites, primarily by the rapamycin-sensitive pathway involving PI3-K, PDK1, Akt/PKB; mTOR/FRAP and by classical and novel PKCs. Second, eIF4E is sequestered by binding proteins, such as eIF4E-BP1, in quiescent cells. Mitogens induce the release of eIF4E by stimulating the phosphorylation of eIF4E-BP1. The mitogen and cytokine activated PI3-kinase/PDK/Akt/mTOR/FRAP pathway regulates the translation repressor, eIF4E-binding protein 1 (4E-BP1).