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Angiostatin inhibits endothelial and melanoma cellular invasion by blocking matrix-enhanced plasminogen activation

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  • M S Stack, Denmark
  • S Gately, Denmark
  • L M Bafetti, Denmark
  • J J Enghild
  • G A Soff, Denmark
  • Interdisciplinary Nanoscience Center
  • Department of Molecular Biology
Angiostatin, a kringle-containing fragment of plasminogen, is a potent inhibitor of angiogenesis. The mechanism(s) responsible for the anti-angiogenic properties of angiostatin are unknown. We now report that human angiostatin blocks plasmin(ogen)-enhanced in vitro invasion of tissue plasminogen activator (t-PA)-producing endothelial and melanoma cells. Kinetic analyses demonstrated that angiostatin functions as a non-competitive inhibitor of extracellular-matrix (ECM)-enhanced, t-PA-catalysed plasminogen activation, with a Ki of 0.9+/-0.03 microM. This mechanism suggests that t-PA has a binding site for the inhibitor angiostatin, as well as for its substrate plasminogen that, when occupied, prevents ternary complex formation between t-PA, plasminogen and matrix protein. Direct binding experiments confirmed that angiostatin bound to t-PA with an apparent Kd [Kd(app)] of 6.7+/-0.7 nM, but did not bind with high affinity to ECM proteins. Together, these data suggest that angiostatin in the cellular micro-environment can inhibit matrix-enhanced plasminogen activation, resulting in reduced invasive activity, and suggest a biochemical mechanism whereby angiostatin-mediated regulation of plasmin formation could influence cellular migration and invasion.
Original languageEnglish
JournalBiochemical Journal
Volume340 ( Pt 1)
Pages (from-to)77-84
Number of pages7
Publication statusPublished - 1999

    Research areas

  • Angiostatins, Animals, Antibodies, Antiplasmin, Cattle, Cell Movement, Cells, Cultured, Endothelium, Vascular, Enzyme Activation, Extracellular Matrix, Extracellular Matrix Proteins, Female, Humans, Kinetics, Melanoma, Mice, Neovascularization, Pathologic, Peptide Fragments, Plasmin, Plasminogen, Protein Binding, Tissue Plasminogen Activator, Tumor Cells, Cultured

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