Objective: The cleaved form of high molecular weight kininogen (HKa) is a potent inhibitor of angiogenesis and tumor growth in vivo; the functional domain has been identified as domain 5 (D5, named as kininostatin). We now identify the subcellular targeting site for D5 on endothelial cells (ECs), and investigate D5 inhibition of integrin functions.
Methods And Results: Endothelial membrane rafts were isolated using sucrose density gradient centrifugation. D5, bound to ECs, was predominantly associated with membrane rafts, in which uPAR, a HKa receptor, was also localized. In contrast, other HKa receptors, cytokeratin-1 and gC1q receptor, were not detected in membrane rafts. Colocalization of D5 with caveolin-1 was demonstrated on ECs by confocal microscopy. Disruption of membrane rafts by cholesterol removal decreased D5 binding to ECs. On stimulation with vascular endothelial growth factor, alpha(v)beta3 integrin formed a complex with uPAR and caveolin-1, which was accompanied by an increase in ligand binding affinity of alpha(v)beta3 integrin. These events were inhibited by D5. Consistently, D5 suppressed specific alpha(v)beta3 integrin-mediated EC adhesion and spreading as well as small guanosine triphosphatase Rac1 activation.
Conclusions: D5 binds to ECs via membrane rafts and downregulates alpha(v)beta3 integrin bidirectional signaling and the downstream Rac1 activation pathway.
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