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J. Biol. Chem., Vol. 281, Issue 20, 14307-14313, May 19, 2006

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The Valosin-containing Protein (VCP) Is a Target of Akt Signaling Required for Cell Survival^*

Franck Vandermoere¹, Ikram El Yazidi-Belkoura, Christian Slomianny, Yohann Demont, Gabriel Bidaux, Eric Adriaenssens, Jérôme Lemoine^¶, and Hubert Hondermarck²

From the ERI-8 INSERM, "Growth factor signaling in breast cancer. Functional proteomics," EMI-0228 INSERM, and ^¶UMR-8576 CNRS IFR-118, University of Sciences and Technologies Lille, 59655 Villeneuve d'Ascq, France

The serine/threonine kinase Akt is a key mediator of cell survival and growth, but its precise mechanism of action, and more specifically, the nature of its signaling partners largely remain to be elucidated. We show, using a proteomics-based approach, that the valosin-containing protein (VCP), a member of the AAA (ATPases associated with a variety of cellular activities) family, is a target of Akt signaling. SDS-PAGE of Akt co-immunoprecipitated proteins obtained from MCF-7 breast cancer cells revealed the increase of a 97-kDa band under Akt activation. Mass spectrometry analysis allowed the identification of VCP, and we have shown a serine/threonine phosphorylation on an Akt consensus site upon activation by growth factors. Site-directed mutagenesis identified Ser-351, Ser-745, and Ser-747 as Akt phosphorylation sites on VCP. Confocal microscopy indicated a co-localization between Akt and VCP upon Akt stimulation. Interestingly, small interfering RNA against VCP induced an inhibition of the growth factor-induced activation of NF-B and a potent pro-apoptotic effect. Together, these data identify VCP as an essential target of Akt signaling.

Received for publication, September 12, 2005 , and in revised form, March 15, 2006.

^* This work was supported by grants from the Ligue Nationale Contre le Cancer (Equipe labellisée 2006), the Fondation pour la Recherche Médicale (FRM comité du Nord), the Institut Universitaire de France, and the Region Nord-pas-de-Calais and the Genopole of Lille. 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 A recipient of a fellowship from the French Ministry for Research and Education and the Ligue National Contre le Cancer.

² To whom correspondence should be addressed: ERI-8 INSERM, batiment SN3, Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq, France. Tel.: 33-3-20-43-40-97; Fax: 33-3-20-47-40-38; E-mail: hubert.hondermarck{at}univ-lille1.fr.

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