Active plasma kallikrein localizes to mast cells and regulates epithelial cell apoptosis, adipocyte differentiation, and stromal remodeling during mammary gland involution.
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.
Lilla
Jennifer N
JN
Department of Anatomy, University of California, San Francisco, California 94143-0452.
Joshi
Ravi V
RV
Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143-2280.
Craik
Charles S
CS
Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143-2280.
Werb
Zena
Z
Department of Anatomy, University of California, San Francisco, California 94143-0452. Electronic address: zena.werb@ucsf.edu.
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D004847:Epithelial Cells; D005260:Female; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D020842:Plasma Kallikrein / Q000378:metabolism*; D011247:Pregnancy / Q000502:physiology*; D011288:Prekallikrein / Q000096:biosynthesis; D012741:Sexual Maturation / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000097:blood
D011288:Prekallikrein; D020842:Plasma Kallikrein; D014568:Urokinase-Type Plasminogen Activator