Processing and localization of ADAMTS-1 and proteolytic cleavage of versican during cumulus matrix expansion and ovulation

J Biol Chem. 2003 Oct 24;278(43):42330-9. doi: 10.1074/jbc.M300519200. Epub 2003 Aug 7.


ADAMTS-1 (a disintegrin and metalloprotease with thrombospondin motifs-1) is a member of the ADAMTS family of metalloproteases which, together with ADAMTS-4 and ADAMTS-5, has been shown to degrade members of the lectican family of proteoglycans. ADAMTS-1 mRNA is induced in granulosa cells of periovulatory follicles by the luteinizing hormone surge through a progesterone receptor-dependent mechanism. Female progesterone receptor knockout (PRKO) mice are infertile primarily due to ovulatory failure and lack the normal periovulatory induction of ADAMTS-1 mRNA. We therefore investigated the protein localization and function of ADAMTS-1 in ovulating ovaries. Antibodies against two specific peptide regions, the pro-domain and the metalloprotease domain of ADAMTS-1, were generated. Pro-ADAMTS-1 of 110 kDa was identified in mural granulosa cells and appears localized to cytoplasmic secretory vesicles. The mature (85-kDa pro-domain truncated) form accumulated in the extracellular matrix of the cumulus oocyte complex (COC) during the process of matrix expansion. Each form of ADAMTS-1 protein increased >10-fold after the ovulatory luteinizing hormone surge in wild-type but not PRKO mice. Versican is also localized selectively to the ovulating COC matrix and was found to be cleaved yielding a 70-kDa N-terminal fragment immunopositive for the neoepitope DPEAAE generated by ADAMTS-1 and ADAMTS-4 protease activity. This extracellular processing of versican was reduced in ADAMTS-1-deficient PRKO mouse ovaries. These observations suggest that one function of ADAMTS-1 in ovulation is to cleave versican in the expanded COC matrix and that the anovulatory phenotype of PRKO mice is at least partially due to loss of this function.

MeSH terms

  • ADAM Proteins
  • ADAMTS1 Protein
  • Animals
  • Antibodies, Monoclonal
  • Chondroitin Sulfate Proteoglycans / metabolism*
  • Disintegrins / biosynthesis*
  • Disintegrins / immunology
  • Disintegrins / metabolism*
  • Enzyme Precursors / biosynthesis
  • Enzyme Precursors / metabolism
  • Extracellular Matrix / enzymology
  • Extracellular Matrix / metabolism*
  • Female
  • Granulosa Cells / cytology
  • Granulosa Cells / enzymology
  • Granulosa Cells / ultrastructure*
  • Immunohistochemistry
  • Isoenzymes / analysis
  • Isoenzymes / metabolism
  • Lectins, C-Type
  • Metalloendopeptidases / biosynthesis*
  • Metalloendopeptidases / immunology
  • Metalloendopeptidases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oocytes / cytology
  • Ovulation*
  • Peptide Hydrolases / biosynthesis
  • Peptide Hydrolases / metabolism
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / physiology
  • Tissue Distribution
  • Versicans


  • Antibodies, Monoclonal
  • Chondroitin Sulfate Proteoglycans
  • Disintegrins
  • Enzyme Precursors
  • Isoenzymes
  • Lectins, C-Type
  • Receptors, Progesterone
  • Vcan protein, mouse
  • Versicans
  • Peptide Hydrolases
  • ADAM Proteins
  • ADAMTS1 Protein
  • Adamts1 protein, mouse
  • Metalloendopeptidases