Akt Down-regulation of p38 Signaling Provides a Novel Mechanism of Vascular Endothelial Growth Factor-mediated Cytoprotection in Endothelial Cells

Abstract

Vascular endothelial growth factor (VEGF) utilizes a phosphoinositide 3-kinase (PI 3-kinase)/Akt signaling pathway to protect endothelial cells from apoptotic death. Here we show that PI 3-kinase/Akt signaling promotes endothelial cell survival by inhibiting p38 mitogen-activated protein kinase (MAPK)-dependent apoptosis. Blockade of the PI 3-kinase or Akt pathways in conjunction with serum withdrawal stimulates p38-dependent apoptosis. Blockade of PI 3-kinase/Akt also led to enhanced VEGF activation of p38 and apoptosis. In this context, the pro-apoptotic effect of VEGF is attenuated by the p38 MAPK inhibitor SB203580. VEGF stimulation of endothelial cells or infection with an adenovirus expressing constitutively active Akt causes MEKK3 phosphorylation, which is associated with decreased MEKK3 kinase activity and down-regulation of MKK3/6 and p38 MAPK activation. Conversely, activation-deficient Akt decreases VEGF-stimulated MEKK3 phosphorylation and increases MKK/p38 activation. Activation of MKK3/6 is not dependent on Rac activation since dominant negative Rac does not decrease p38 activation triggered by inhibition of PI 3-kinase. Thus, cross-talk between the Akt and p38 MAPK pathways may regulate the level of cytoprotection versus apoptosis and is a new mechanism to explain the cytoprotective actions of Akt.

Protein kinase a modulates Cdc25B activity during meiotic resumption of mouse oocytes

“…The differences in GVBD-inducing ability of the two phosphatases, Cdc25A and Cdc25B, suggest that they have different substrates and nonredundant functions (Solc et al, 2008 (Yaffe et al, 2001;Obenauer et al, 2003). This program has been quite successful and some predictions have been experimentally verified (Gratton et al, 2001;Zhou et al, 2001;Gottlieb et al, 2002;Kim et al, 2002Kim et al, , 2005She et al, 2004;Park et al, 2006;Lemeer et al, 2008). In this study, several strong PKA phosphorylation consensus sites were predicted in Cdc25B including Ser-321 which corresponds to Cdc25-S287 in Xenopus oocytes and human Cdc25B-S323.…”

Cellular response to oxidative stress: Signaling for suicide and survival*

“…Such an approach has yielded evidence for both pro-apoptotic (Bulavin et al, 1999;Shimizu et al, 1999;Zhuang et al, 2000;Gratton et al, 2001) as well as anti-apoptotic (Nemoto et al, 1998;Ivanov and Ronai, 2000) functions of these kinases. In addition, although many studies have correlated p38 activation with oxidative stress-induced apoptosis, in some of these circumstances, inhibiting the kinase through use of pharmacologic inhibitors does not alter the apoptosis (Wang et al, , 2000a.…”

Vascular endothelial growth factor in eye disease

“…This kinase is an important modulator of the pro-apoptotic process in various cell types, including endothelial cells. Blockade of VEGF-induced PI3K or Akt signaling enhances the activation of p38 MAPK, leading to increased apoptosis (Gratton et al, 2001). Treatment of RECs with high glucose medium or exogenous peroxynitrite has been shown to trigger a similar phenomenon of accelerated apoptosis even in the presence of exogenous VEGF (El-Remessy et al, 2005;Gu et al, 2003).…”