Cell Surface-Dependent Generation of Angiostatin4.5

Hao Wang, Ryan Schultz, Jerome Hong, Deborah L. Cundiff, Keyi Jiang, Gerald A. Soff*

*Corresponding author for this work

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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 β-actin is present on the extracellular membranes of cancer cells (PC-3, HT1080, and MDA-MB231), and β-actin can mediate plasmin binding to the cell surface and autoproteolysis to AS4.5. In the presence of β-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 α-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 β-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 β-actin may also serve as a prognostic marker to predict tumor behavior.

Original languageEnglish (US)
Pages (from-to)162-168
Number of pages7
JournalCancer Research
Volume64
Issue number1
DOIs
StatePublished - Jan 1 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Cell Surface-Dependent Generation of Angiostatin4.5'. Together they form a unique fingerprint.

  • Cite this

    Wang, H., Schultz, R., Hong, J., Cundiff, D. L., Jiang, K., & Soff, G. A. (2004). Cell Surface-Dependent Generation of Angiostatin4.5. Cancer Research, 64(1), 162-168. https://doi.org/10.1158/0008-5472.CAN-03-1862