Plasmin is a major extracellular protease that elicits intracellular signals to mediate platelet aggregation, chemotaxis of peripheral blood monocytes, and release of arachidonate and leukotriene from several cell types in a G protein-dependent manner. Angiostatin, a fragment of plasmin(ogen), is a ligand and an antagonist for integrin α9β1. Here we report that plasmin specifically interacts with α 9β1 and that plasmin induces migration of cells expressing recombinant α9β1 (α9-Chinese hamster ovary (CHO) cells). Migration was dependent on an interaction of the kringle domains of plasmin with α 9β1 as well as the catalytic activity of plasmin. Angiostatin, representing the kringle domains of plasmin, alone did not induce the migration of α9-CHO cells, but simultaneous activation of the G protein-coupled protease-activated receptor (PAR)-1 with an agonist peptide induced the migration on angiostatin, whereas PAR-2 or PAR-4 agonist peptides were without effect. Furthermore, a small chemical inhibitor of PAR-1 (RWJ 58259) and a palmitoylated PAR-1-blocking peptide inhibited plasmin-induced migration of α9-CHO cells. These results suggest that plasmin induces migration by kringle-mediated binding to α9β 1 and simultaneous proteolytic activation of PAR-1.
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