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J. Biol. Chem., Vol. 282, Issue 8, 5468-5477, February 23, 2007

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Inhibition of B56-containing Protein Phosphatase 2As by the Early Response Gene IEX-1 Leads to Control of Akt Activity^*

Géraldine Rocher^¶||, Claire Letourneux^¶||, Philippe Lenormand^**, and Françoise Porteu^¶||1

From the Institut Cochin, Department of Hematology, Paris F-75014, France, the INSERM U567, F-75014 Paris, the ^¶CNRS, UMR 8104, Paris F-75014, the ^||Université Paris Descartes, Faculté de Médecine René Descartes, UMR-S 8104, F-75014 Paris, and the ^**Institute of Signaling Developmental Biology and Cancer, Centre A. Lacassagne, CNRS UMR 6543, 06189 Nice, France

The importance of PP2A in the regulation of Akt/PKB activity has long been recognized but the nature of the holoenzyme involved and the mechanisms controlling dephosphorylation are not yet known. We identified IEX-1, an early gene product with proliferative and survival activities, as a specific inhibitor of B56 regulatory subunit-containing PP2A. IEX-1 inhibits B56-PP2A activity by allowing the phosphorylation of B56 by ERK. This leads to sustained ERK activation. IEX-1 has no effect on PP2A containing other B family subunits. Thus, studying IEX-1 contribution to signaling should help the discovery of new pathways controlled by B56-PP2A. By using overexpression and RNA interference, we show here that IEX-1 increases Akt/PKB activity in response to various growth factors by preventing Akt dephosphorylation on both Thr³⁰⁸ and Ser⁴⁷³ residues. PP2A-B56 and subunits have the opposite effect and reverse IEX-1-mediated Akt activation. The effect of IEX-1 on Akt is ERK-dependent. Indeed: (i) a IEX-1 mutant deficient in ERK binding had no effect on Akt; (ii) ERK dominant-negative mutants reduced IEX-1-mediated increase in pAkt; (iii) a B56 mutant that cannot be phosphorylated in the ERK·IEX-1 complex showed an enhanced ability to compete with IEX-1. These results identify B56-containing PP2A holoenzymes as Akt phosphatases. They suggest that IEX-1 behaves as a general inhibitor of B56 activity, enabling the control of both ERK and Akt signaling downstream of ERK.

Received for publication, October 16, 2006 , and in revised form, December 22, 2006.

^* This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, and grants from the Ligue Contre le Cancer Comité de Paris, Association pour la Recherche contre le Cancer, Association for International Cancer Research, and Fondation de France. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Hôpital Cochin, Bat. G. Roussy, 27 Rue du Fg St. Jacques, 75014 Paris, France. Tel.: 33-1-40-51-65-15; Fax: 33-1-40-51-65-10; E-mail: Porteu{at}cochin.inserm.fr.

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