This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, H. Articles by Soff, G. A. Search for Related Content PubMed PubMed Citation Articles by Wang, H. Articles by Soff, G. A.

Cell Surface-Dependent Generation of Angiostatin4.5

Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Hematology/Oncology, Chicago, Illinois

Angiostatin4.5 (AS4.5) is a naturally occurring human angiostatin isoform, consisting of plasminogen kringles 1–4 plus 85% of kringle 5 (amino acids Lys78 to Arg529). Prior studies indicate that plasminogen is converted to AS4.5 in a two-step reaction. First, plasminogen is activated to plasmin. Then plasmin undergoes autoproteolysis within the inner loop of kringle 5, which can be induced by a free sulfhydryl donor or an alkaline pH. We now demonstrate that plasminogen can be converted to AS4.5 in a cell membrane-dependent reaction. Actin was shown previously to be a surface receptor for plasmin(ogen). We now show that ß-actin is present on the extracellular membranes of cancer cells (PC-3, HT1080, and MDA-MB231), and ß-actin can mediate plasmin binding to the cell surface and autoproteolysis to AS4.5. In the presence of ß-actin, no small molecule-free sulfhydryl donor is needed for generation of AS4.5. Antibodies to actin reduced membrane-dependent generation of AS4.5 by 70%. In a cell-free system, addition of actin to in vitro-generated plasmin resulted in stoichiometric conversion to AS4.5. Annexin II and -enolase have been reported to be plasminogen receptors, but we did not demonstrate a role for these proteins in conversion of plasminogen to AS4.5. Our data indicate that membrane-associated ß-actin, documented previously as a plasminogen receptor, is a key cell membrane receptor capable of mediating conversion of plasmin to AS4.5. This conversion may serve an important role in regulating tumor angiogenesis, invasion, and metastasis, and surface ß-actin may also serve as a prognostic marker to predict tumor behavior.

This article has been cited by other articles:

				M. Candela, S. Bergmann, M. Vici, B. Vitali, S. Turroni, B. J. Eikmanns, S. Hammerschmidt, and P. Brigidi Binding of Human Plasminogen to Bifidobacterium J. Bacteriol., August 15, 2007; 189(16): 5929 - 5936. [Abstract] [Full Text] [PDF]

				L. A. Miles, N. M. Andronicos, N. Baik, and R. J. Parmer Cell-Surface Actin Binds Plasminogen and Modulates Neurotransmitter Release from Catecholaminergic Cells J. Neurosci., December 13, 2006; 26(50): 13017 - 13024. [Abstract] [Full Text] [PDF]

				H. Wang, J. A. Doll, K. Jiang, D. L. Cundiff, J. S. Czarnecki, M. Wilson, K. M. Ridge, and G. A. Soff Differential Binding of Plasminogen, Plasmin, and Angiostatin4.5 to Cell Surface {beta}-Actin: Implications for Cancer-Mediated Angiogenesis. Cancer Res., July 15, 2006; 66(14): 7211 - 7215. [Abstract] [Full Text] [PDF]

				G. A. Soff, H. Wang, D. L. Cundiff, K. Jiang, B. Martone, A. W. Rademaker, J. A. Doll, and T. M. Kuzel In vivo Generation of Angiostatin Isoforms by Administration of a Plasminogen Activator and a Free Sulfhydryl Donor: A Phase I Study of an Angiostatic Cocktail of Tissue Plasminogen Activator and Mesna Clin. Cancer Res., September 1, 2005; 11(17): 6218 - 6225. [Abstract] [Full Text] [PDF]

				M. Kwon, C.-S. Yoon, W. Jeong, S. G. Rhee, and D. M. Waisman Annexin A2-S100A10 Heterotetramer, a Novel Substrate of Thioredoxin J. Biol. Chem., June 24, 2005; 280(25): 23584 - 23592. [Abstract] [Full Text] [PDF]

				I. P. Michael, G. Sotiropoulou, G. Pampalakis, A. Magklara, M. Ghosh, G. Wasney, and E. P. Diamandis Biochemical and Enzymatic Characterization of Human Kallikrein 5 (hK5), a Novel Serine Protease Potentially Involved in Cancer Progression J. Biol. Chem., April 15, 2005; 280(15): 14628 - 14635. [Abstract] [Full Text] [PDF]