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| The EMBO Journal
(2000) 19, 4817–4826, doi:10.1093/emboj/19.17.4817 |
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| Urokinase-type plasminogen activator and its receptor synergize to promote pathogenic proteolysis |
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| Hong-Ming Zhou1, Anthony Nichols1, 2, Paolo Meda1 and Jean-Dominique Vassalli1 |
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1 Department of Morphology, Faculty of Medicine, University of Geneva, CMU, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland 2 Present address: Department of Cellular Biochemistry, Serono Parmaceutical Research Institute S.A., 14 Chemin des Aulx, CH-1228 Plan-les-Ouates, Switzerland To whom correspondence should be addressed Jean-Dominique Vassalli, Jean-Dominique.Vassalli@medecine.unige.ch Received 25 April 2000; Revised 17 July 2000; Accepted 19 July 2000. |
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| Abstract |
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| 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. |
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| Keywords: alopecia, epidermal thickening, hair follicle involution, skin blistering, uPA |
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