Akt down-regulation of p38 signaling provides a novel mechanism of vascular endothelial growth factor-mediated cytoprotection in endothelial cells
Akt down-regulation of p38 signaling provides a novel mechanism of vascular endothelial growth factor-mediated cytoprotection in endothelial cells
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DOI：
10.1074/jbc.m009698200
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发表时间：
2001-08-10
影响因子：
4.8
通讯作者：
Sessa, WC
中科院分区：
文献类型：
--
作者：
Gratton, JP;Morales-Ruiz, M;Sessa, WC
血管内皮生长因子（VEGF）通过磷脂酰肌醇3-激酶（PI 3-kinase）/Akt信号通路保护内皮细胞免于凋亡性死亡。在这里，我们发现PI 3-激酶/Akt信号通过抑制p38丝裂原活化蛋白激酶（MAPK）依赖性凋亡促进内皮细胞存活。PI 3-激酶或Akt通路的阻断结合血清戒断刺激p38依赖性细胞凋亡。PI 3-激酶/Akt的阻断也导致p38的VEGF活化和细胞凋亡的增强。在这种情况下，VEGF的促凋亡作用被p38 MAPK抑制剂SE 203580减弱。VEGF刺激内皮细胞或用表达组成型活性Akt的腺病毒感染引起MEKK 3磷酸化，这与MEKK 3激酶活性降低以及MKK 3/6和p38 MAPK活化的下调有关。相反，活化缺陷型Akt降低VEGF刺激的MEKK 3磷酸化并增加MKK/p38活化。MKK 3/6的活化不依赖于Rac活化，因为显性负性Rac不降低由PI 3-激酶抑制触发的p38活化。因此，Akt和p38 MAPK通路之间的串扰可能调节细胞保护相对于凋亡的水平，并且是解释Akt的细胞保护作用的新机制。
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 SE203580. 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.