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, Françoise Porteu

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

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    Résumé

    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-B56α and γ 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 B56β 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.

    langue originaleAnglais
    Pages (de - à)5468-5477
    Nombre de pages10
    journalJournal of Biological Chemistry
    Volume282
    Numéro de publication8
    Les DOIs
    étatPublié - 23 févr. 2007

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