Regulation of eIF4 and p70S6K Signaling

Eukaryotic translation initiation factor 4 (eIF4) and p70S6K play critical roles in translational regulation. The signaling pathway that regulates p70S6k also regulates the phosphorylation of 4E-binding protein (4EBP1), although there appears to be a bifurcation in the pathway upstream of p70S6K and 4EBP1. Recruitment of mRNAs to ribosomes to initiate translation is mediated by initiation factors of the eIF4 group and PABP. The eIF4 group includes: 1) eIF4A - an RNA helicase, 2) eIF4B - an RNA binding protein that stimulates eIF4A, 3) eIF4E - a cap binding protein, and 4) eIF4γ - the central organizing protein that colocalizes eIF4E, eIF4A, eIF3, PABP, MNK1 and RNA in the 48S initiation complex.Several stimuli including growth factors and cytokines regulate the eIF4 complex and p70S6K by initiating a phosphorylation cascade involving the sequential activation of PI3K, PDK1, AKT and mTOR. In conjunction with an unidentified kinase, mTOR phosphorylates eIF4EBP leading to its dissociation from and activation of eIF4E. MNK, activated by ERK1/2 and p38 MAPK, phosphorylates and activates eIF4E. Both processes contribute to the association of eIF4E and eIF4γ to form the active eIF4F complex, a necessary component of the 48S initiation complex. eIF4F is a complex which consists of three subunits: eIF4E, eIF4A and eIF4γ. Through the action of eIF4F, mRNA is bound to the 43S preinitiation complex resulting in formation of the 48S preinitiation complex. The 48S complex finally initiates translation. Since the association of eIF4E with 4EBP1 blocks the phosphorylation of eIF4E by MNK, it is likely that the fall in eIF4E phosphorylation is due to its increased binding to eIF4E in response to amino acid depletion resulting in inhibition of its phosphorylation and consequent net dephosphorylation. Consistent with this, the ability of amino acid restoration to increase eIF4E phosphorylation is blocked either by rapamycin or by inhibitors of PI3K, all of which also block the ability of amino acids to induce dissociation of 4EBP1 from eIF4E.p70S6K is a ser/thr kinase that participates in the control of protein synthesis. It phosphorylates the 40S ribosomal protein S6 which is involved in the translation of certain mRNAs, the so called 5'-TOP mRNAs encoding ribosomal proteins and elongation factors. This enzyme has a complex regulation: phosphorylation by PDK1 at the activation loop is required for activation. Activity is also modulated by phosphorylation by ERK1/2 kinases and by dephosphorylation by phosphatases. A role for AKT in the insulin-stimulated activation process of p70S6K has also been proposed. mTOR is also required for full activation of p70S6K. It phosphorylates p70S6K on Thr389 and is inhibited by the immunosuppressant rapamycin. The inhibition of S6K by rapamycin is mediated by the protein phosphatase PP2A. The major target for rapamycin in cells is the FKPB12 and rapamycin-associated protein FRAP. Activation of FRAP leads to increased p70S6K activity, which in turn leads to phosphorylation of p70S6K and increased translation of a set of proteins, including ribosomal proteins and translation factors. Disruption of p70S6K leads to growth defects.