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Title page for ETD etd-03312008-163540


Type of Document Dissertation
Author DeBusk, Laura M
Author's Email Address laura.debusk@vanderbilt.edu
URN etd-03312008-163540
Title AKT/IKKα/VAV1 signaling in endothelial cell survival and angiogenesis
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Dennis Hallahan Committee Chair
Ann Richmond Committee Member
Charles Lin Committee Member
Jin Chen Committee Member
Scott Baldwin Committee Member
Keywords
  • angiogenesis
  • Neovascularization -- Regulation
  • Vascular endothelial growth factors -- Pathophysiology
  • Cellular control mechanisms
Date of Defense 2008-03-25
Availability unrestricted
Abstract
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.
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