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A more recent version of this article appeared on September 1, 2006
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Submitted on June 6, 2006
Accepted on June 22, 2006
*INSERM U36 and ||INSERM U114, Collège de France, 75231 Paris Cedex 05, France
Monitoring Editor: John York
Angiotensin II (AngII) type 1 receptors (AT1) regulate cell growth through the extracellular signal-regulated kinase (ERK1/2) and phosphatidylinositol 3-kinase (PI3K) pathways. ERK1/2 and Akt/PKB, 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 using 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 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.
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)
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