Urokinase‐type plasminogen activator and its receptor synergize to promote pathogenic proteolysis

Urokinase‐type plasminogen activator (uPA) is a potent catalyst of extracellular proteolysis, which also binds to a high‐affinity plasma membrane receptor (uPAR). Binding of uPA may influence pericellular proteolysis and/or activate intracellular signal transduction. Transgenic mice overexpressing either uPA or uPAR in basal epidermis and hair follicles had no detectable cutaneous alterations. In contrast, bi‐transgenic mice overexpressing both uPA and uPAR, obtained by crossing the two transgenic lines, developed extensive alopecia induced by involution of hair follicles, epidermal thickening and sub‐epidermal blisters. The phenotype was due to uPA catalytic activity since combined overexpression of uPAR and uPAR‐binding but catalytically inactive uPA in the same tissue was not detrimental in another bi‐transgenic line. It was accompanied by increased plasmin‐generating capacity, up‐regulation and activation of matrix metalloproteinases type‐2 and ‐9, and cleavage of uPAR. Thus, combined overexpression of uPA and uPAR acts in synergy to promote pathogenic extracellular proteolysis.