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Molecular and Cellular Biology, December 2003, p. 9117-9126, Vol. 23, No. 24
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.24.9117-9126.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Signaling from Akt to FRAP/TOR Targets both 4E-BP and S6K in Drosophila melanogaster

Mathieu Miron,1,{dagger} Paul Lasko,2 and Nahum Sonenberg1*

Department of Biochemistry and McGill Cancer Center, McGill University, Montréal, Québec H3G 1Y6,1 Department of Biology, McGill University, Montréal, Québec H3A 1B1, Canada2

Received 18 June 2003/ Returned for modification 5 August 2003/ Accepted 16 September 2003

The eIF4E-binding proteins (4E-BPs) interact with translation initiation factor 4E to inhibit translation. Their binding to eIF4E is reversed by phosphorylation of several key Ser/Thr residues. In Drosophila, S6 kinase (dS6K) and a single 4E-BP (d4E-BP) are phosphorylated via the insulin and target of rapamycin (TOR) signaling pathways. Although S6K phosphorylation is independent of phosphoinositide 3-OH kinase (PI3K) and serine/threonine protein kinase Akt, that of 4E-BP is dependent on PI3K and Akt. This difference prompted us to examine the regulation of d4E-BP in greater detail. Analysis of d4E-BP phosphorylation using site-directed mutagenesis and isoelectric focusing-sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that the regulatory interplay between Thr37 and Thr46 of d4E-BP is conserved in flies and that phosphorylation of Thr46 is the major phosphorylation event that regulates d4E-BP activity. We used RNA interference (RNAi) to target components of the PI3K, Akt, and TOR pathways. RNAi experiments directed at components of the insulin and TOR signaling cascades show that d4E-BP is phosphorylated in a PI3K- and Akt-dependent manner. Surprisingly, RNAi of dAkt also affected insulin-stimulated phosphorylation of dS6K, indicating that dAkt may also play a role in dS6K phosphorylation.

* Corresponding author. Mailing address: Department of Biochemistry and McGill Cancer Center, McGill University, 3655 Promenade Sir-William-Osler, Montréal, Québec H3G 1Y6, Canada. Phone: (514) 398-7274. Fax: (514) 398-1287. E-mail: nahum.sonenberg{at}mcgill.ca.

{dagger} Present address: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada H3A 1A4.

Molecular and Cellular Biology, December 2003, p. 9117-9126, Vol. 23, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.24.9117-9126.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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