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Molecular and Cellular Biology, June 2004, p. 4909-4919, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.4909-4919.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Functional Studies of Shaggy/Glycogen Synthase Kinase 3 Phosphorylation Sites in Drosophila melanogaster

Deppie Papadopoulou,1,{dagger} Michele Wolfe Bianchi,1,{ddagger} and Marc Bourouis1,2*

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch C.U. de Strasbourg,1 Institut de Recherche, Signalisation Biologie du Développement et Cancer, CNRS-UMR 6543 Centre de Biochimie, Université de Nice, Nice, France2

Received 9 July 2003/ Returned for modification 22 September 2003/ Accepted 12 March 2004

Early studies of glycogen synthase kinase 3 (GSK-3) in mammalian systems focused on its pivotal role in glycogen metabolism and insulin-mediated signaling. It is now recognized that GSK-3 is central to a number of diverse signaling systems. Here, we show that the major form of the kinase Shaggy (Sgg), the GSK-3 fly ortholog, is negatively regulated during insulin-like/phosphatidylinositol 3-kinase (PI3K) signaling in vivo. Since genetic studies of Drosophila melanogaster had previously shown that Wingless (Wg) signaling also acts to antagonize Sgg, we investigate how the kinase might integrate, or else discriminate, signaling inputs by Wg and insulin. Using Drosophila cell line assays, we found, in contrast to previous reports, that Wg induces accumulation of its transducer Armadillo (Arm)/ß-catenin without significant alteration of global Sgg-specific activity. In agreement with a previous study using human GSK-3ß, Wg did not cause phosphorylation changes of the Ser9 or Tyr214 regulatory phosphorylated sites of Sgg. Conversely, as shown in mammalian systems, insulin-induced inhibition of Sgg-specific activity by phosphorylation at the N-terminal pseudosubstrate site (Ser9) did not induce Arm/ß-catenin accumulation, showing selectivity in response to the different signaling pathways. Interestingly, a minigene bearing a Ser9-to-Ala change rescued mutant sgg without causing abnormal development, suggesting that the regulation of Sgg via the inhibitory pseudosubstrate domain is dispensable for many aspects of its function. Our studies of Drosophila show that Wg and insulin or PI3K pathways do not converge on Sgg but that they exhibit cross-regulatory interactions.

* Corresponding author. Mailing address: ISBDC, CNRS-UMR 6543 Centre de Biochimie, Université de Nice, 06108 Nice Cedex 2, France. Phone: 33 4 92 07 64 43. Fax: 33 4 92 07 64 05. E-mail: bourouis{at}unice.fr.

{dagger} Present address: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032.

{ddagger} Present address: Institut des Sciences du Végétal, CNRS, 91198 Gif sur Yvette-Cedex, France.

Molecular and Cellular Biology, June 2004, p. 4909-4919, Vol. 24, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.11.4909-4919.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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