4.8 Article

aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2-mediated SphK1-S1PR1-Akt signaling axis

出版社

NATL ACAD SCIENCES
DOI: 10.1073/pnas.2106623118

关键词

biased signaling; cytoprotection; GPCR; endothelial dysfunction

资金

  1. NIH/National Institute of General Medical Sciences (NIGMS) [R01 GM116597, R35 GM127121]
  2. NIH/NIGMS [K12 GM068524, R25 GM083275]
  3. NIH/National Heart, Lung, Blood Institute [T32 HL007444]
  4. NIH/National Institute of Child Health and Human Development Grant [P50 HD12303]
  5. University of California President's Postdoctoral Fellowship award

向作者/读者索取更多资源

Endothelial dysfunction is associated with vascular disease, and aPC/PAR1 signaling promotes Rac1 activation and barrier protection via beta-arr2. The cytoprotective responses of aPC/PAR1 involve various signaling pathways, including the beta-arr2-mediated SphK1-S1PR1-Akt signaling axis.
Endothelial dysfunction is associated with vascular disease and results in disruption of endothelial barrier function and increased sensitivity to apoptosis. Currently, there are limited treatments for improving endothelial dysfunction. Activated protein C (aPC), a promising therapeutic, signals via protease-activated receptor-1 (PAR1) and mediates several cytoprotective responses, including endothelial barrier stabilization and anti-apoptotic responses. We showed that aPC-activated PAR1 signals preferentially via beta-arrestin-2 (beta-arr2) and dishevelled-2 (Dvl2) scaffolds rather than G proteins to promote Rac1 activation and barrier protection. However, the signaling pathways utilized by aPC/PAR1 to mediate anti-apoptotic activities are not known. aPC/PAR1 cytoprotective responses also require coreceptors; however, it is not clear how coreceptors impact different aPC/PAR1 signaling pathways to drive distinct cytoprotective responses. Here, we define a beta-arr2-mediated sphingosine kinase-1 (SphK1)-sphingosine-1-phosphate receptor-1 (S1PR1)-Akt signaling axis that confers aPC/PAR1-mediated protection against cell death. Using human cultured endothelial cells, we found that endogenous PAR1 and S1PR1 coexist in caveolin-1 (Cav1)-rich microdomains and that S1PR1 coassociation with Cav1 is increased by aPC activation of PAR1. Our study further shows that aPC stimulates beta-arr2-dependent SphK1 activation independent of Dvl2 and is required for transactivation of S1PR1-Akt signaling and protection against cell death. While aPC/PAR1-induced, extracellular signal-regulated kinase 1/2 (ERK1/2) activation is also dependent on beta-arr2, neither SphK1 nor S1PR1 are integrated into the ERK1/2 pathway. Finally, aPC activation of PAR1-beta-arr2-mediated protection against apoptosis is dependent on Cav1, the principal structural protein of endothelial caveolae. These studies reveal that different aPC/PAR1 cytoprotective responses are mediated by discrete, beta-arr2-driven signaling pathways in caveolae.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.8
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据