Negative regulation of Akt activity by p38alpha MAP kinase in cardiomyocytes involves membrane localization of PP2A through interaction with caveolin-1

Cell Signal. 2007 Jan;19(1):62-74. doi: 10.1016/j.cellsig.2006.05.032. Epub 2006 Jul 14.


Cardiomyocyte-derived cell lines deficient in p38alpha are more resistant to apoptosis owing to lower expression of the pro-apoptotic proteins Bax and Fas and upregulation of the ERK survival pathway. Here, we show that increased Akt activity also contributes to the enhanced survival of p38alpha-deficient cardiomyocytes. We found that the serine/threonine phosphatase PP2A can be targeted to caveolae through interaction with caveolin-1 in a p38alpha-dependent manner. In agreement with this, PP2A activity associated with caveolin-1 was higher in wild type than in p38alpha-deficient cells. Akt was also present in caveolae and incubation of wild-type cells with the PP2A inhibitor okadaic acid increases the levels of Akt activity. Thus, p38alpha-induced re-localization of PP2A to caveolae can lead to dephosphorylation and inhibition of Akt, which in turn would contribute to the decreased survival observed in wild type cells. However, cell detachment impairs the formation of the PP2A/caveolin-1 complex and, as a consequence, phospho-Akt levels and survival are no longer regulated by p38alpha in detached wild type cardiomyocytes. Our results suggest that p38alpha can negatively modulate Akt activity, independently of PI3K, by regulating the interaction between caveolin-1 and PP2A through a mechanism dependent on cell attachment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Caveolae / physiology
  • Caveolin 1 / metabolism*
  • Cell Adhesion
  • Cell Membrane / metabolism*
  • Cell Survival
  • Cells, Cultured
  • Enzyme Activation
  • Mice
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 14 / physiology*
  • Myocytes, Cardiac / metabolism*
  • Oncogene Protein v-akt / antagonists & inhibitors
  • Oncogene Protein v-akt / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoprotein Phosphatases / metabolism*
  • Protein Kinase Inhibitors
  • Protein Phosphatase 2
  • Signal Transduction


  • Caveolin 1
  • Phosphoinositide-3 Kinase Inhibitors
  • Ppp2r1b protein, mouse
  • Protein Kinase Inhibitors
  • Oncogene Protein v-akt
  • Mitogen-Activated Protein Kinase 14
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2