ADAMTS1 mediates the release of antiangiogenic polypeptides from TSP1 and 2

Nathan V. Lee, Makoto Sato, Douglas S. Annis, Joseph A. Loo, Lily Wu, Deane F. Mosher, M. Luisa Iruela-Arispe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

158 Scopus citations

Abstract

Matrix metalloproteases regulate both physiological and pathological events by processing matrix proteins and growth factors. ADAMTS1 in particular is required for normal ovulation and renal function and has been shown to modulate angiogenesis. Here we report that TSP1 and 2 are substrates of ADAMTS1. Using a combination of mass spectrometry and Edman degradation, we mapped the cleavage sites and characterized the biological relevance of these processing events. ADAMTS1 cleavage mediates the release of polypeptides from the trimeric structure of both TSP1 and 2 generating a pool of antiangiogenic fragments from matrix-bound thrombospondin. Using neo-epitope antibodies we confirmed that processing occurs during wound healing of wild-type mice. However, TSP1 proteolysis is decreased or absent in ADAMTS1 null mice; this is associated with delayed wound closure and increased angiogenic response. Finally, TSP1-/- endothelial cells revealed that the antiangiogenic response mediated by ADAMTS1 is greatly dependent on TSP1. These findings have unraveled a mechanistic explanation for the angiostatic functions attributed to ADAMTS1 and demonstrated in vivo processing of TSP1 under situations of tissue repair.

Original languageEnglish (US)
Pages (from-to)5270-5283
Number of pages14
JournalEMBO Journal
Volume25
Issue number22
DOIs
StatePublished - Nov 15 2006

Keywords

  • Angiogenesis
  • Extracellular matrix
  • Matrix metalloproteases
  • Thrombospondin
  • Wound healing

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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