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Molecular and Cellular Biology, April 2004, p. 2986-2997, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.2986-2997.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A Novel mTOR-Regulated Phosphorylation Site in Elongation Factor 2 Kinase Modulates the Activity of the Kinase and Its Binding to Calmodulin

Gareth J. Browne and Christopher G. Proud*

Division of Molecular Physiology, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom

Received 8 September 2003/ Returned for modification 22 December 2003/ Accepted 23 January 2004

Eukaryotic elongation factor 2 (eEF2) kinase is an unusual calcium- and calmodulin-dependent protein kinase that is regulated by insulin through the rapamycin-sensitive mTOR pathway. Here we show that insulin decreases the ability of eEF2 kinase to bind calmodulin in a rapamycin-sensitive manner. We identify a novel phosphorylation site in eEF2 kinase (Ser78) that is located immediately next to its calmodulin-binding motif. Phosphorylation of this site is increased by insulin in a rapamycin-sensitive fashion. Regulation of the phosphorylation of Ser78 also requires amino acids and the protein kinase phosphoinositide-dependent kinase 1. Mutation of this site to alanine strongly attenuates the effects of insulin and rapamycin both on the binding of calmodulin to eEF2 kinase and on eEF2 kinase activity. Phosphorylation of Ser78 is thus likely to link insulin and mTOR signaling to the control of eEF2 phosphorylation and chain elongation. This site is not a target for known kinases in the mTOR pathway, e.g., the S6 kinases, implying that it is phosphorylated by a novel mTOR-linked protein kinase that serves to couple hormones and amino acids to the control of translation elongation. eEF2 kinase is thus a target for mTOR signaling independently of previously known downstream components of the pathway.

* Corresponding author. Mailing address: Division of Molecular Physiology, Faculty of Life Sciences, University of Dundee, Dundee DD15EH, United Kingdom. Phone: 44 1382 344919. Fax: 44 1382 345507. E-mail: c.g.proud{at}dundee.ac.uk.

Molecular and Cellular Biology, April 2004, p. 2986-2997, Vol. 24, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.7.2986-2997.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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