Essential role of Vav family guanine nucleotide exchange factors in EphA receptor-mediated angiogenesis.
Angiogenesis, the process by which new blood vessels are formed from preexisting vasculature, is critical for vascular remodeling during development and contributes to the pathogenesis of diseases such as cancer. Prior studies from our laboratory demonstrate that the EphA2 receptor tyrosine kinase is a key regulator of angiogenesis in vivo. The EphA receptor-mediated angiogenic response is dependent on activation of Rho family GTPase Rac1 and is regulated by phosphatidylinositol 3-kinase. Here we report the identification of Vav2 and Vav3 as guanine nucleotide exchange factors (GEFs) that link the EphA2 receptor to Rho family GTPase activation and angiogenesis. Ephrin-A1 stimulation recruits the binding of Vav proteins to the activated EphA2 receptor. The induced association of EphA receptor and Vav proteins modulates the activity of Vav GEFs, leading to activation of Rac1 GTPase. Overexpression of either Vav2 or Vav3 in primary microvascular endothelial cells promotes Rac1 activation, cell migration, and assembly in response to ephrin-A1 stimulation. Conversely, loss of Vav2 and Vav3 GEFs inhibits Rac1 activation and ephrin-A1-induced angiogenic responses both in vitro and in vivo. In addition, embryonic fibroblasts derived from Vav2-/- Vav3-/- mice fail to spread on an ephrin-A1-coated surface and exhibit a significant decrease in the formation of ephrin-A1-induced lamellipodia and filopodia. These findings suggest that Vav GEFs serve as a molecular link between EphA2 receptors and the actin cytoskeleton and provide an important mechanism for EphA2-mediated angiogenesis.
Hunter
Sonja G
SG
Vanderbilt University School of Medicine, A-4323 MCN, 1161 21st Avenue South, Nashville, TN 37232-2363, USA.
Zhuang
Guanglei
G
Brantley-Sieders
Dana
D
Swat
Wojciech
W
Cowan
Christopher W
CW
Chen
Jin
J
D000818:Animals; D002465:Cell Movement / Q000235:genetics; D003599:Cytoskeleton / Q000201:enzymology / Q000648:ultrastructure; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D004789:Enzyme Activation; D036382:Ephrin-A1 / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D018919:Neovascularization, Physiologic / Q000235:genetics; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary / Q000235:genetics; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D036104:Receptor, EphA2 / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D036382:Ephrin-A1; D020662:Guanine Nucleotide Exchange Factors; D051567:Proto-Oncogene Proteins c-vav; C490565:Vav2 protein, mouse; C496622:Vav3 protein, mouse; D036104:Receptor, EphA2; D020830:rac1 GTP-Binding Protein