Identification of endothelial cell-specific signal transaction pathways leading to angiogenic cellular responses

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We investigated the signal transduction pathways leading to cellular responses of endothelial cells for establishment of endothelial cell-specific antiangiogenic therapy. C-Fes is a protein tyrosine kinase, which is exclusively expressed in endothelial cells as well as hematopoietic cells. We identified that angiopoietin 2 (Ang2) induced migration and tube formation by nurine brain capillary endothelial cells, denoted IBE cells. Ang2-induced migration was dependent on phosphoinositide 3-kinase (PI3-kinase) and activation of PI3-kinase required c-Fes activity. In cells treated with stromal cell-derived factor-1 (SDF-1) and sonic hedgehog (Shh) also induced tube formation of endothelial cells in PI3-kinase- and c-Fes-dependent manner. These results indicate that c-Fes and is important for ligand-dependent activation of PI3-kinase and subsequent cellular responses of endothelial cells. Tube formation was regulated by c-Fyn, a member of Src family protein tyrosine kinase, in FGF-2- and Ang2-treated cells, suggesting that c-Fyn plays pivotal role in tube formation of endothelial cells. To examine the details of downstream signaling pathways of c-Fes and c-Fyn would thus be great importance to find new targets for antiangiogenic therapies, which are specific for endothelial cells.