Mechanisms underlying antiangiogenic activity of HKa.

Vitronectin (VN) is pictured bound to both the integrin (αvβ3) and the urokinase receptor (uPAR) by domains 2 and 3 (D2, D3). In this tentative hypothesis, HKa is pictured as binding by D5 to domains 2/3 of uPAR. By doing so, HKa displaces VN from the same domains of uPAR, thus acting as an antiadhesive ligand. In addition, prekallikrein (PK), which circulates in complex with HK or HKa bound to D6, is recruited to the endothelial surface. PK is converted to kallikrein (K) by an endothelial cell cysteine protease (CP). K then cleaves pro-uPA to uPA. Plasminogen (PG) bound to 1 of its receptors, such as annexin 2, is converted by uPA to plasmin (PN). Thus, HKa can augment cell-bound plasmin-dependent proteolysis to facilitate endothelial cell migration. Finally, pro-uPA is known to stimulate endothelial cell signal transduction, probably by the association of uPAR with integrins such as αvβ3. It remains to be shown that the action of HKa to inhibit cell proliferation is by a similar mechanism.