Fibrinolytic Activation Promoted by the Cyclopentapeptide Malformin: Involvement of Cytoskeletal Reorganization

Malformin A(1), a cyclopentapeptide of fungal origin, enhances cellular fibrinolytic activity depending on the existence of a cofactor in blood plasma. However, the nature of this cofactor remains unknown. Here, we report that vitronectin acts as a plasma cofactor of malformin A(1). We purified the cofactor from bovine plasma by activity-based fractionation, and confirmed that vitronectin in conjunction with plasminogen supports the activity of malformin A(1) to promote the fibrinolytic activity of U937 cells. Malformin A(1) action was abolished by Arg-Gly-Asp peptide (a competitor of vitronectin integrin binding), wortmannin (an inhibitor of signaling kinases), and cytochalasin B (an inhibitor of actin polymerization). Changes in actin organization and a decrease in filopodia were observed in cells treated with malformin A(1) and plasma. A focal localization of plasminogen on the cell surface was augmented by malformin A(1), whereas the amount of cell-surface-bound plasminogen was minimally altered by the treatment. Our results suggest the involvement of cytoskeletal reorganization via vitronectin signaling in the cellular fibrinolytic activity-enhancing action of malformin A(1).