Tie-2 is a receptor tyrosine kinase that is expressed primarily on endothelial cells (ECs) and plays a critical role in vascular development. The Tie-2 gene encodes a protein of 1122 amino acids. The extracellular region has three distinct structural motifs including two immunoglobulin (Ig)-like loops separated by three EGF-like repeats, and three repeats with fibronectin type III homology located after the second Ig loop. The intracellular portion of Tie-2 contains two tyrosine kinase domains that, when phosphorylated, interact with a number of binding partners including Grb2, Grb7, Grb14, Shp2, the p85 subunit of phosphatidylinositol 3-kinase (PI3K), and Dok-R. Deletion of the last 16 amino acids of the intracellular C-terminus results in increased levels of autophosphorylation, suggesting that it may play an autoinhibitory role.