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Vol. 17, Issue 9, 3940-3951, September 2006

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Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

Marianne Gervais^*,,, Céline Dugourd^*,,, Laurent Muller^*, Corinne Ardidie^*, Brigitte Canton^||, Laetitia Loviconi^*, Pierre Corvol^*, Hervé Chneiweiss^||, and Catherine Monnot^*

*Institut National de la Santé et de la Recherche Médicale U36 and ^||Institut National de la Santé et de la Recherche Médicale U114, Collège de France, 75231 Paris, France

Submitted June 6, 2006; Accepted June 22, 2006
Monitoring Editor: John York

Angiotensin II (AngII) type 1 receptors (AT1) regulate cell growth through the extracellular signal-regulated kinase (ERK)1/2 and phosphatidylinositol 3-kinase (PI3K) pathways. ERK1/2 and Akt/protein kinase B, downstream of PI3K, are independently activated but both required for mediating AngII-induced proliferation when expressed at endogenous levels. We investigate the effect of an increase in the expression of wild-type Akt1 by using Chinese hamster ovary (CHO)-AT1 cells. Unexpectedly, Akt overexpression inhibits the AT1-mediated proliferation. This effect could be generated by a cross-talk between the PI3K and ERK1/2 pathways. A functional partner is the phosphoprotein enriched in astrocytes of 15 kDa (PEA-15), an Akt substrate known to bind ERK1/2 and to regulate their nuclear translocation. We report that Akt binds to PEA-15 and that Akt activation leads to PEA-15 stabilization, independently of PEA-15 interaction with ERK1/2. Akt cross-talk with PEA-15 does not affect ERK1/2 activation but decreases their nuclear activity as a result of the blockade of ERK1/2 nuclear accumulation. In response to AngII, PEA-15 overexpression displays the same functional consequences on ERK1/2 signaling as Akt overactivation. Thus, Akt overactivation prevents the nuclear translocation of ERK1/2 and the AngII-induced proliferation through interaction with and stabilization of endogenous PEA-15.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-06-0501) on July 5, 2006.

These authors contributed equally to this work.

Present addresses: Unité Mixte de Recherche, Centre National de la Recherche Scientifique 7054, Centre de Recherches Chirurgicales, Hôpital Henri-Mondor, Créteil, France;

Département de la Recherche Clinique et de la Valorisation, Hôpital Cimiez CHU de Nice, Nice, France.

Address correspondence to: Catherine Monnot (catherine.monnot{at}college-de-france.fr)

Abbreviations used: AngII, angiotensin II; CHO, Chinese hamster ovary cells; ERK, extracellular signal-regulated kinases; GSK, glycogen synthase kinase; PEA-15, phosphoprotein enriched in astrocytes of 15 kDa; PI3K, phosphatidylinositol 3-kinase.

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