ABSTRACT
Angiogenic growth factors serve as ligands that bind to and thereby activate their corresponding receptors, and this in turn leads to the activation of downstream signal transduction pathways. Interestingly, and most relevant for the potential ‘‘other’’ effects of angiogenic growth factors that will be discussed later, some of the signal transduction pathways are unique to a receptor while others have common downstream effects and functions. For example, most RTKs expressed on endothelial cells, including VEGFR-2 (Flk-1), HGFR, and both of the Tie receptors, are capable of activating at least one common pathway, the phosphatidylinositol (PI) 3-kinase/Akt pathway (17,23,26,27). Following growth factor binding and receptor activation, PI 3-kinase is recruited to the plasma membrane where it is activated in part through phosphorylation by RTKs. This serves to localize PI 3-kinase in close proximity to its substrates, the plasma membrane-bound phosphoinositides, particularly PI (4,5) bis-phosphate. Pi 3-kinase transfers a phosphate group to the d-3 position of the inositol ring of these lipid substrates. This leads to the recruitment of a number of other proteins to the cell surface, including the serine/threonine kinases pdk1 and Akt, or protein kinase B. Signaling through other intermediate effector proteins, PI 3-kinase also plays a role in cell proliferation and chemotaxis (16,28,29), both of which are important for VEGF-mediated angiogenesis.
