Active plasma kallikrein localizes to mast cells and regulates epithelial cell apoptosis, adipocyte differentiation, and stromal remodeling during mammary gland involution

J Biol Chem. 2009 May 15;284(20):13792-13803. doi: 10.1074/jbc.M900508200. Epub 2009 Mar 18.


The plasminogen cascade of serine proteases directs both development and tumorigenesis in the mammary gland. Plasminogen can be activated to plasmin by urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), and plasma kallikrein (PKal). The dominant plasminogen activator for mammary involution is PKal, a serine protease that participates in the contact activation system of blood coagulation. We observed that the prekallikrein gene (Klkb1) is expressed highly in the mammary gland during stromal remodeling periods including puberty and postlactational involution. We used a variant of ecotin (ecotin-PKal), a macromolecular inhibitor of serine proteases engineered to be highly specific for active PKal, to demonstrate that inhibition of PKal with ecotin-PKal delays alveolar apoptosis, adipocyte replenishment, and stromal remodeling in the involuting mammary gland, producing a phenotype resembling that resulting from plasminogen deficiency. Using biotinylated ecotin-PKal, we localized active PKal to connective tissue-type mast cells in the mammary gland. Taken together, these results implicate PKal as an effector of the plasminogen cascade during mammary development.

Publication types

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

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / metabolism*
  • Animals
  • Apoptosis / physiology*
  • Cell Differentiation / physiology*
  • Epithelial Cells
  • Female
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / growth & development
  • Mammary Glands, Animal / metabolism*
  • Mast Cells / cytology
  • Mast Cells / metabolism*
  • Mice
  • Plasma Kallikrein / metabolism*
  • Pregnancy / physiology*
  • Prekallikrein / biosynthesis
  • Sexual Maturation / physiology
  • Stromal Cells / cytology
  • Stromal Cells / metabolism
  • Urokinase-Type Plasminogen Activator / blood


  • Prekallikrein
  • Plasma Kallikrein
  • Urokinase-Type Plasminogen Activator