Urokinase-type plasminogen activator and its receptor synergize to promotepathogenic proteolysis

Urokinase-type plasminogen activator (uPA) is a potent catalyst of extracel lular proteolysis, which also binds to a high-affinity plasma membrane rece ptor (uPAR). Binding of uPA may influence pericellular proteolysis and/or a ctivate intracellular signal transduction. Transgenic mice overexpressing e ither uPA or uPAR in basal epidermis and hair follicles had no detectable c utaneous alterations. In contrast, bi-transgenic mice overexpressing both u PA and uPAR, obtained by crossing the two transgenic lines, developed exten sive alopecia induced by involution of hair follicles, epidermal thickening and sub-epidermal blisters. The phenotype was due to uPA catalytic activit y since combined overexpression of uPAR and uPAR-binding but catalytically inactive uPA in the same tissue was not detrimental in another bi-transgeni c line. It was accompanied by increased plasmin-generating capacity, up-reg ulation and activation of matrix metalloproteinases type-2 and -9, and clea vage of uPAR, Thus, combined overexpression of uPA and uPAR acts in synergy to promote pathogenic extracellular proteolysis.