ADAMTS1: A matrix metalloprotease with angioinhibitory properties

M. Luisa Iruela-Arispe*, Darren Carpizo, Alfonso Luque

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

Neovascularization is a hallmark of cancer progression. Suppression of the angiogenic response in tumors has been associated with inhibition and even regression of total tumor mass. Therefore, the derivation of synthetic or natural products that could interfere with proangiogenic signaling pathways can greatly impact cancer therapy. Using the antiangiogenic motifs in thrombospondin-1, we have recently cloned METH1/ADAMTS1, a secreted metalloproteinase with three thrombospondin-1, and shown that the protein inhibits endothelial cell proliferation in vitro and blocks the neovascular response induced by growth factors in vivo. The mechanism of action responsible for these events has not been elucidated. In this report, we present evidence to support two effects of METH1/ADAMTS1 that impact proangiogenic signaling events. ADAMTS1 binds to VEGF and dampens VEGFR2 phosphorylation. The ability of ADAMTS1 to bind VEGF and functionally inactivate VEGFR2 is reversible as dissociation of the complex results in active growth factor. A second activity of ADAMTS1 requires the catalytic domain as a single point mutation in the metalloproteinase domain renders the protein inactive in tumor xenograft assays. The emerging theme is that both domains are likely required for the antiangiogenic/antitumor activities of ADAMTS1.

Original languageEnglish (US)
Pages (from-to)183-190
Number of pages8
JournalAnnals of the New York Academy of Sciences
Volume995
DOIs
StatePublished - 2003

Keywords

  • Angiogenesis
  • Extracellular matrix
  • Tumor suppression

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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