Heparin is essential for the storage of specific granule proteases in mast cells

Nature. 1999 Aug 19;400(6746):769-72. doi: 10.1038/23481.


All mammals produce heparin, a negatively charged glycosaminoglycan that is a major constituent of the secretory granules of mast cells which are found in the peritoneal cavity and most connective tissues. Although heparin is one of the most studied molecules in the body, its physiological function has yet to be determined. Here we describe transgenic mice, generated by disrupting the N-deacetylase/N-sulphotransferase-2 gene, that cannot express fully sulphated heparin. The mast cells in the skeletal muscle that normally contain heparin lacked metachromatic granules and failed to store appreciable amounts of mouse mast-cell protease (mMCP)-4, mMCP-5 and carboxypeptidase A (mMC-CPA), even though they contained substantial amounts of mMCP-7. We developed mast cells from the bone marrow of the transgenic mice. Although these cultured cells contained high levels of various protease transcripts and had substantial amounts of mMCP-6 protein in their granules, they also failed to express mMCP-5 and mMC-CPA. Our data show that heparin controls, through a post-translational mechanism, the levels of specific cassettes of positively charged proteases inside mast cells.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Amidohydrolases / genetics
  • Amidohydrolases / metabolism
  • Animals
  • Bone Marrow Cells / enzymology
  • Carboxypeptidases / metabolism
  • Carboxypeptidases A
  • Cell Differentiation
  • Cells, Cultured
  • Chymases
  • Coculture Techniques
  • Cytoplasmic Granules / enzymology
  • Cytoplasmic Granules / physiology*
  • Enzyme Precursors / metabolism
  • Heparin / physiology*
  • Intestinal Mucosa / cytology
  • Jejunum / cytology
  • Mast Cells / cytology
  • Mast Cells / enzymology
  • Mast Cells / immunology
  • Mast Cells / physiology*
  • Mice
  • Mice, Transgenic
  • Serine Endopeptidases / metabolism*
  • Sulfates / metabolism
  • Sulfotransferases / genetics
  • Sulfotransferases / metabolism
  • Trichinella spiralis
  • Trichinellosis / immunology
  • Tryptases


  • Enzyme Precursors
  • Sulfates
  • Tpsb2 protein, mouse
  • Heparin
  • Ndst2 protein, mouse
  • Sulfotransferases
  • Carboxypeptidases
  • Carboxypeptidases A
  • Serine Endopeptidases
  • mast cell protease 4
  • Chymases
  • Tpsab1 protein, mouse
  • Tryptases
  • Amidohydrolases