Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15
- 1 September 2006
- journal article
- Published by American Society for Cell Biology (ASCB) in Molecular Biology of the Cell
- Vol. 17 (9), 3940-3951
- https://doi.org/10.1091/mbc.e06-06-0501
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.Keywords
This publication has 40 references indexed in Scilit:
- Akt negatively regulates translation of the ternary complex factor Elk-1Oncogene, 2003
- Protein Kinase B/Akt Binds and Phosphorylates PED/PEA-15, Stabilizing Its Antiapoptotic ActionMolecular and Cellular Biology, 2003
- Akt Is a Major Downstream Target of PI3-Kinase Involved in Angiotensin II–Induced ProliferationHypertension, 2003
- Negative Regulation of ERK and Elk by Protein Kinase B Modulates c-fos TranscriptionPublished by Elsevier BV ,2003
- Regulation of Raf by Akt Controls Growth and Differentiation in Vascular Smooth Muscle CellsJournal of Biological Chemistry, 2001
- Akt1/PKB upregulation leads to vascular smooth muscle cell hypertrophy and polyploidizationJCI Insight, 2000
- Negative regulation of the serine/threonine kinase B-Raf by AktJournal of Biological Chemistry, 2000
- The Death Effector Domain of PEA-15 Is Involved in Its Regulation of Integrin ActivationJournal of Biological Chemistry, 1998
- The Major Astrocytic Phosphoprotein PEA-15 Is Encoded by Two mRNAs Conserved on Their Full Length in Mouse and HumanJournal of Biological Chemistry, 1996
- A recombinant rat vascular AT1 receptor confers growth properties to angiotensin II in Chinese Hamster Ovary cellsBiochemical and Biophysical Research Communications, 1992