Cell cycle-dependent phosphorylation of the translational repressor eIF-4E binding protein-1 (4E-BP1).
A fundamental control point in the regulation of the initiation of protein synthesis is the formation of the eukaryotic initiation factor 4F (eIF-4F) complex. The formation of this complex depends upon the availability of the mRNA cap binding protein, eIF-4E, which is sequestered away from the translational machinery by the tight association of eIF-4E binding proteins (4E-BPs). Phosphorylation of 4E-BP1 is critical in causing its dissociation from eIF-4E, leaving 4E available to form translationally active eIF-4F complexes, switching on mRNA translation. In this report, we provide the first evidence that the phosphorylation of 4E-BP1 increases during mitosis and identify Ser-65 and Thr-70 as phosphorylated sites. Phosphorylation of Thr-70 has been implicated in the regulation of 4E-BP1 function, but the kinase phosphorylating this site was unknown. We show that the cyclin-dependent kinase, cdc2, phosphorylates 4E-BP1 at Thr-70 and that phosphorylation of this site is permissive for Ser-65 phosphorylation. Crucially, the increased phosphorylation of 4E-BP1 during mitosis results in its complete dissociation from eIF-4E.
Heesom
K J
KJ
University of Bristol, Department of Biochemistry, School of Medical Sciences, University Walk, BS8 1TD, Bristol, United Kingdom. k.heesom@bristol.ac.uk
Gampel
A
A
Mellor
H
H
Denton
R M
RM
D048868:Adaptor Proteins, Signal Transducing; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D039561:Eukaryotic Initiation Factor-4E; D006367:HeLa Cells; D006801:Humans; D010448:Peptide Initiation Factors / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012097:Repressor Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D039561:Eukaryotic Initiation Factor-4E; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D012097:Repressor Proteins; D016203:CDC2 Protein Kinase