Akt down-regulates ERK1/2 nuclear localization and angiotensin II- induced cell proliferation through PEA-15.
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.[1]References
- Akt down-regulates ERK1/2 nuclear localization and angiotensin II-induced cell proliferation through PEA-15. Gervais, M., Dugourd, C., Muller, L., Ardidie, C., Canton, B., Loviconi, L., Corvol, P., Chneiweiss, H., Monnot, C. Mol. Biol. Cell (2006) [Pubmed]
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