AKT/IKKα/VAV1 signaling in endothelial cell survival and angiogenesis
DeBusk, Laura M
We have identified a novel signaling pathway, AKT/IKKα/VAV1, which induces endothelial cell survival and motility. Ang1/Tie2 and VEGF/VEGFR signaling activates Akt and induces cell survival. Akt and IKKƒÑ both induce endothelial EMT and endothelial cell motility. This can be blocked with co-expression of IƒÛB-ƒÑ, suggesting that endothelial EMT is mediated through the NF-ƒÛB canonical pathway. Vav1 and ƒÔ-catenin are both upregulated by IKKƒÑ. Vav1 is required for induction of endothelial EMT, and induces endothelial motility and tumor angiogenesis. ƒÔ-catenin also induces endothelial cell motility and tumor angiogenesis, through regulation of RhoA and Cdc42 activity. The proposed model advances the study of angiogenesis. We demonstrate a novel mechanism for endothelial cell survival and endothelial cell motility. More importantly, we show that the Akt/IKKƒÑ/Vav1 signaling pathway can induce endothelial EMT and that this process plays a role in tumor angiogenesis.