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Molecular and Cellular Biology, March 2002, p. 1674-1683, Vol. 22, No. 6
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.6.1674-1683.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Caspase Cleavage of Initiation Factor 4E-Binding Protein 1 Yields a Dominant Inhibitor of Cap-Dependent Translation and Reveals a Novel Regulatory Motif

Andrew R. Tee and Christopher G. Proud*

Division of Molecular Physiology, School of Life Sciences, Medical Sciences Institute, University of Dundee, Dundee DD1 5EH, United Kingdom

Received 27 September 2001/ Returned for modification 15 November 2001/ Accepted 10 December 2001

Eukaryotic initiation factor 4E (eIF4E) binding proteins (4E-BPs) regulate the assembly of initiation complexes required for cap-dependent mRNA translation. 4E-BP1 undergoes insulin-stimulated phosphorylation, resulting in its release from eIF4E, allowing initiation complex assembly. 4E-BP1 undergoes caspase-dependent cleavage in cells undergoing apoptosis. Here we show that cleavage occurs after Asp24, giving rise to the N-terminally truncated polypeptide {Delta}4E-BP1, which possesses the eIF4E-binding site and all the known phosphorylation sites. {Delta}4E-BP1 binds to eIF4E and fails to become sufficiently phosphorylated upon insulin stimulation to bring about its release from eIF4E. Therefore, {Delta}4E-BP1 acts as a potent inhibitor of cap-dependent translation. Using a mutagenesis approach, we identify a novel regulatory motif of four amino acids (RAIP) which lies within the first 24 residues of 4E-BP1 and which is necessary for efficient phosphorylation of 4E-BP1. This motif is conserved among sequences of 4E-BP1 and 4E-BP2 but is absent from 4E-BP3. Insulin increased the phosphorylation of 4E-BP3 but not sufficiently to cause its release from eIF4E. However, a chimeric protein that was generated by replacing the N terminus of 4E-BP3 with the N-terminal sequence of 4E-BP1 (containing this RAIP motif) underwent a higher degree of phosphorylation and was released from eIF4E. This suggests that the N-terminal sequence of 4E-BP1 is required for optimal regulation of 4E-BPs by insulin.

* Corresponding author. Mailing address: Division of Molecular Physiology, School of Life Sciences, Medical Sciences Institute/Wellcome Trust Building Complex, University of Dundee, Dow St., Dundee DD1 5EH, United Kingdom. Phone: 44 (0)1382 344919. Fax: 44 (0)1382 322424. E-mail: c.g.proud{at}dundee.ac.uk.

Molecular and Cellular Biology, March 2002, p. 1674-1683, Vol. 22, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.6.1674-1683.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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