Abstract
Angiostatin, a plasminogen fragment containing 3-4 N-terminal kringle domains, is a potent inhibitor of tumor-induced angiogenesis, but its mechanism of action is unclear. Angiostatin is a ligand for integrin alphavbeta(3) but does not induce stress fiber formation upon integrin binding, suggesting that angiostatin is a potential integrin antagonist. Plasmin, the parent molecule of angiostatin and a major extracellular protease, induces platelet aggregation, migration of peripheral blood monocytes, and release of arachidonate and leukotriene from several cell types. In the current study, we found that plasmin specifically bound to alphavbeta(3) through the kringle domains and induced migration of endothelial cells. In contrast, angiostatin did not induce cell migration. Notably, angiostatin, anti-alphavbeta(3) antibodies, RGD-peptide, and a serine protease inhibitor effectively blocked plasmin-induced cell migration. These results suggest that plasmin-induced migration of endothelial cells requires alphavbeta(3) and the catalytic activity of plasmin and that this process is a potential target for the inhibitory activity of angiostatin.
Highlights
Angiostatin, a plasminogen fragment containing 3– 4 N-terminal kringle domains, is a potent inhibitor of tumor-induced angiogenesis, but its mechanism of action is unclear
Plasmin Is a Ligand for Integrin ␣v3—Because ␣v3 on endothelial cells binds to angiostatin but not to plasminogen [17], it is probable that proteolysis of plasminogen to angiostatin exposes the integrin binding sites in the kringle domains
The present results establish that plasmin, like angiostatin, binds to integrin ␣v3 through the kringle domains as well. These results suggest that the integrin binding sites in the kringle domains are exposed by proteolytic activation of plasminogen to plasmin
Summary
We found that plasmin bound to ␣v3 through the kringle domains and induced migration of endothelial cells. Angiostatin, anti-␣v3 antibodies, RGDpeptide, and a serine protease inhibitor effectively blocked plasmin-induced cell migration. These results suggest that plasmin-induced migration of endothelial cells requires ␣v3 and the catalytic activity of plasmin and that this process is a potential target for the inhibitory activity of angiostatin. We hypothesized that angiostatin potentially perturbs the critical ␣v3-mediated signaling pathway in endothelial cells Consistent with this idea, we have shown that angiostatin does not induce stress fiber formation on ␣v3 binding [17]. Angiostatin, anti-␣v3 agents, and a serine protease inhibitor effectively blocked plasmin-induced cell migration. We propose that plasmin signaling is a potential target for angiostatin
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