title: Akt down-regulates ERK1/2 nuclear localization and angiotensin II-induced cell proliferation through PEA-15.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U36, Collège de France, 75231 Paris, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Gervais
authors.forename: Céline
authors.initials: C
authors.lastname: Dugourd
authors.forename: Laurent
authors.initials: L
authors.lastname: Muller
authors.forename: Corinne
authors.initials: C
authors.lastname: Ardidie
authors.forename: Brigitte
authors.initials: B
authors.lastname: Canton
authors.forename: Laetitia
authors.initials: L
authors.lastname: Loviconi
authors.forename: Pierre
authors.initials: P
authors.lastname: Corvol
authors.forename: Hervé
authors.initials: H
authors.lastname: Chneiweiss
authors.forename: Catherine
authors.initials: C
authors.lastname: Monnot
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D016466:CHO Cells; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D006207:Half-Life; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D016760:Proto-Oncogene Proteins c-fos; D050807:ets-Domain Protein Elk-1; D000804:Angiotensin II; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3