Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells
Open Access
- 1 August 2004
- journal article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 287 (2), C494-C499
- https://doi.org/10.1152/ajpcell.00439.2003
Abstract
Angiotensin II activates a variety of signaling pathways in vascular smooth muscle cells (VSMCs), including the MAPKs and Akt, both of which are required for hypertrophy. However, little is known about the relationship between these kinases or about the upstream activators of Akt. In this study, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive kinase p38 MAPK and its substrate MAPKAPK-2 mediate Akt activation in VSMCs. In unstimulated VSMCs, Akt and p38 MAPK are constitutively associated and remain so after angiotensin II stimulation. Inhibition of p38 MAPK activity with SB-203580 dose-dependently inhibits Akt phosphorylation on Ser473, but not Thr308. Angiotensin II-induced phosphorylation of MAPKAPK-2 is also attenuated by SB-203580, as well as by inhibitors of ROS. In addition, angiotensin II stimulates the association of MAPKAPK-2 with the Akt-p38 MAPK complex, and an in vitro kinase assay shows that MAPKAPK-2 immunoprecipitates of VSMC lysates phosphorylate recombinant Akt in an angiotensin II-inducible manner. Finally, intracellular delivery of a MAPKAPK-2 peptide inhibitor blocks Akt phosphorylation on Ser473. These results suggest that the p38 MAPK-MAPKAPK-2 pathway mediates Akt activation by angiotensin II in these cells by recruiting active MAPKAPK-2 to a signaling complex that includes both Akt and p38 MAPK. Through this mechanism, p38 MAPK confers ROS sensitivity to Akt and facilitates downstream signaling. These results provide evidence for a novel signaling complex that may help to spatially organize hypertrophy-related, ROS-sensitive signaling in VSMCs.Keywords
This publication has 28 references indexed in Scilit:
- Pyk2- and Src-Dependent Tyrosine Phosphorylation of PDK1 Regulates Focal AdhesionsMolecular and Cellular Biology, 2003
- Distinct Cellular Functions of MK2Molecular and Cellular Biology, 2002
- Phosphoinositide-Regulated Kinases and Phosphoinositide PhosphatasesChemical Reviews, 2001
- Dual Regulation of Platelet Protein Kinase BPublished by Elsevier ,2000
- Intracellular Signaling of Angiotensin II-induced p70 S6 Kinase Phosphorylation at Ser411 in Vascular Smooth Muscle CellsJournal of Biological Chemistry, 1999
- Phosphorylation by MAPKAP Kinase 2 Activates Mg2+-ATPase Activity of Myosin IIBiochemical and Biophysical Research Communications, 1996
- Identification of an Essential Signaling Cascade for Mitogen-activated Protein Kinase Activation by Angiotensin II in Cultured Rat Vascular Smooth Muscle CellsJournal of Biological Chemistry, 1996
- Pro-inflammatory Cytokines and Environmental Stress Cause p38 Mitogen-activated Protein Kinase Activation by Dual Phosphorylation on Tyrosine and ThreonineJournal of Biological Chemistry, 1995
- A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteinsCell, 1994
- Identification of MAPKAP kinase 2 as a major enzyme responsible for the phosphorylation of the small mammalian heat shock proteinsFEBS Letters, 1992