The multisubunit eukaryotic translation initiation factor (eIF) 4F recruits 40S
ribosomal subunits to the 5' end of mRNA. The eIF4F subunit eIF4E interacts
directly with the mRNA 5' cap structure. Assembly of the eIF4F complex is
inhibited by a family of repressor polypeptides, the eIF4E-binding proteins
(4E-BPs). 4E-BP1 (also known as PHAS-1) normally binds eIF4E, inhibiting
cap-dependent translation. Hyper-phosphorylation of 4E-BP1 disrupts this
binding, activating cap-dependent translation. The PI3-kinase/Akt pathway
and the FRAP/mTOR kinase regulate 4E-BP1. 4E-BP1 is phosphorylated in
vivo on multiple residues and phosphorylation by FRAP/mTOR on Threonine
37 and Threonine 46 of human 4E-BP1 may prime it for subsequent phosphorylation
at sites including Serine 65 and Threonine 70. The corresponding rat
residues include Threonine 36, Threonine 45, Serine 64 and Threonine 69. In
vitro, 4E-BP1 is also phosphorylated by ataxia telangiectasia (ATM) at human
Serine 112 (rat Serine 111) in response to an increase in insulin levels.