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Differential Binding of Plasminogen, Plasmin, and Angiostatin4.5 to Cell Surface ß-Actin: Implications for Cancer-Mediated Angiogenesis

¹ Division of Hematology/Oncology and ² Division of Pulmonary and Critical Care Medicine, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois and ³ Division of Hematology/Oncology, State University of New York Downstate Medical Center, Brooklyn, New York

Requests for reprints: Gerald A. Soff, Division of Hematology/Oncology, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Box 20, Suite 850, Brooklyn, NY 11203. Phone: 718-270-2785; E-mail: gsoff{at}downstate.edu.

Angiostatin4.5 (AS4.5) is the product of plasmin autoproteolysis and consists of kringles 1 to 4 and 85% of kringle 5. In culture, cancer cell surface globular ß-actin mediates plasmin autoproteolysis to AS4.5. We now show that plasminogen binds to prostate cancer cells and that the binding colocalizes with surface ß-actin, but AS4.5 does not bind to the cell surface. Plasminogen and plasmin bind to immobilized ß-actin similarly, with a K_d of 140 nmol/L. The binding is inhibited by -aminocaproic acid (ACA), indicating the requirement for a lysine-kringle domain interaction. Using a series of peptides derived from ß-actin in competitive binding studies, we show that the domain necessary for plasminogen binding is within amino acids 55 to 69 (GDEAQSKRGILTLKY). Substitution of Lys⁶¹ or Lys⁶⁸ with arginine results in the loss of the ability of the peptide to block plasminogen binding, indicating that Lys⁶¹ and Lys⁶⁸ are essential for plasminogen binding. Other actin peptides, including peptides with lysine, did not inhibit the plasminogen-actin interaction. AS4.5 did not bind actin at concentrations up to 40 µmol/L. Plasminogen, plasmin, and AS4.5 all contain kringles 1 to 4; however, kringle 5 is truncated in AS4.5. Isolated kringle 5 binds to actin, suggesting intact kringle 5 is necessary for plasminogen and plasmin to bind to cell surface ß-actin, and the truncated kringle 5 in AS4.5 results in its release from ß-actin. These data may explain the mechanism by which AS4.5 is formed locally on cancer cell surfaces and yet acts on distant sites. (Cancer Res 2006; 66(14): 7211-5)

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