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Vol. 15, No. 21, pp. 2852-2864, November 1, 2001
1 Department of Biochemistry and McGill Cancer Centre,
McGill University, Montréal, Québec H3G 1Y6, Canada;
2 Department of Molecular Biotechnology, University of
Washington, Seattle, Washington 98195-7730, USA;
3 Department of Biophysics, Institute of Experimental
Physics, Warsaw University, Warsaw PL 02-089, Poland;
4 Laboratories of Molecular Biophysics, Howard Hughes Medical
Institute, The Rockefeller University, New York, New York 10021, USA;
5 Cell Signaling Technology, Beverly, Massachusetts 01915, USA; 6 Institute of Biochemistry and Biophysics, Polish
Academy of Sciences, PL 02-106 Warsaw, Poland
In most instances, translation is regulated at the initiation phase,
when a ribosome is recruited to the 5' end of an mRNA. The
eIF4E-binding proteins (4E-BPs) interdict translation initiation by
binding to the translation factor eIF4E, and preventing recruitment of
the translation machinery to mRNA. The 4E-BPs inhibit translation in a
reversible manner. Hypophosphorylated 4E-BPs interact avidly with
eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of
cells with hormones, cytokines, or growth factors, results in an
abrogation of eIF4E-binding activity. We reported previously that
phosphorylation of 4E-BP1 on Thr 37 and Thr 46 is relatively insensitive to serum deprivation and rapamycin treatment, and that
phosphorylation of these residues is required for the subsequent phosphorylation of a set of unidentified serum-responsive sites. Here,
using mass spectrometry, we identify the serum-responsive, rapamycin-sensitive sites as Ser 65 and Thr 70. Utilizing a novel combination of two-dimensional isoelectric focusing/SDS-PAGE and Western blotting with phosphospecific antibodies, we also establish the
order of 4E-BP1 phosphorylation in vivo; phosphorylation of Thr 37/Thr
46 is followed by Thr 70 phosphorylation, and Ser 65 is phosphorylated
last. Finally, we show that phosphorylation of Ser 65 and Thr 70 alone
is insufficient to block binding to eIF4E, indicating that a
combination of phosphorylation events is necessary to dissociate 4E-BP1
from eIF4E.
[Key Words: 4E-BP1; translation initiation; eIF4E; phosphorylation; phosphospecific antibody; phosphopeptide mapping]
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