4EBP

4E-binding proteins, or 4E-BPs, are a small family of eukaryotic translation initiation factor 4E-binding proteins that regulate cap-dependent translation by binding to eIF4E. In their hypo-phosphorylated state, 4E-BPs bind eIF4E and prevent the assembly of the eIF4F complex (which includes eIF4G and eIF4A), thereby repressing initiation of translation. Phosphorylation by mTOR complex 1 (mTORC1) reduces the affinity of 4E-BPs for eIF4E, releasing eIF4E to form the active eIF4F complex and promote translation. This regulatory mechanism links nutrient availability and growth signals to protein synthesis.

In humans, three genes encode 4E-BPs: EIF4EBP1 (4E-BP1), EIF4EBP2 (4E-BP2), and EIF4EBP3 (4E-BP3). 4E-BP1 is ubiquitously expressed, 4E-BP2 is enriched in the brain, and 4E-BP3 has a more limited characterization. The proteins share a conserved eIF4E-binding motif that enables competition with eIF4G for eIF4E binding. Their activity is modulated by cellular energy status and signaling through the PI3K–AKT–mTOR pathway; under stress or growth factor deprivation, hypophosphorylated 4E-BPs accumulate and broadly repress cap-dependent translation, while some transcripts may be selectively translated.

Clinical relevance arises from the involvement of the mTOR–4E-BP axis in cancer, metabolic disorders, and neurological diseases. Pharmacological mTOR inhibitors, such as rapamycin and its analogs, influence 4E-BP phosphorylation and can alter cellular protein synthesis and growth. Overall, 4E-BPs act as key translational repressors that integrate extracellular cues to regulate protein production.