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Molecular and Cellular Biology, July 2003, p. 4511-4521, Vol. 23, No. 13
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.13.4511-4521.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Protein Kinase B/Akt Binds and Phosphorylates PED/PEA-15, Stabilizing Its Antiapoptotic Action

Alessandra Trencia, Anna Perfetti, Angela Cassese, Giovanni Vigliotta, Claudia Miele, Francesco Oriente, Stefania Santopietro, Ferdinando Giacco, Gerolama Condorelli, Pietro Formisano, and Francesco Beguinot*

Dipartimento di Biologia e Patologia Cellulare e Molecolare and Istituto di Endocrinologia ed Oncologia Sperimentale del C.N.R., Federico II University of Naples, Naples, Italy

Received 8 November 2002/ Returned for modification 6 January 2003/ Accepted 8 April 2003

The antiapoptotic protein PED/PEA-15 features an Akt phosphorylation motif upstream from Ser116. In vitro, recombinant PED/PEA-15 was phosphorylated by Akt with a stoichiometry close to 1. Based on Western blotting with specific phospho-Ser116 PED/PEA-15 antibodies, Akt phosphorylation of PED/PEA-15 occurred mainly at Ser116. In addition, a mutant of PED/PEA-15 featuring the substitution of Ser116->Gly (PEDS116->G) showed 10-fold-decreased phosphorylation by Akt. In intact 293 cells, Akt also induced phosphorylation of PED/PEA-15 at Ser116. Based on pull-down and coprecipitation assays, PED/PEA-15 specifically bound Akt, independently of Akt activity. Serum activation of Akt as well as BAD phosphorylation by Akt showed no difference in 293 cells transfected with PED/PEA-15 and in untransfected cells (which express no endogenous PED/PEA-15). However, the antiapoptotic action of PED/PEA-15 was almost twofold reduced in PEDS116->G compared to that in PED/PEA-15WT cells. PED/PEA-15 stability closely paralleled Akt activation by serum in 293 cells. In these cells, the nonphosphorylatable PEDS116->G mutant exhibited a degradation rate threefold greater than that observed with wild-type PED/PEA-15. In the U373MG glioma cells, blocking Akt also reduced PED/PEA-15 levels and induced sensitivity to tumor necrosis factor-related apoptosis-inducing ligand apoptosis. Thus, phosphorylation by Akt regulates the antiapoptotic function of PED/PEA-15 at least in part by controlling the stability of PED/PEA-15. In part, Akt survival signaling may be mediated by PED/PEA-15.

* Corresponding author. Mailing address: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Via S. Pansini, 5, 80131 Naples, Italy. Phone: 39 081 7463248. Fax: 39 081 7463235. E-mail: beguino{at}unina.it.

Molecular and Cellular Biology, July 2003, p. 4511-4521, Vol. 23, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.13.4511-4521.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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