Urokinase‐type plasminogen activator and its receptor synergize to promote pathogenic proteolysis
Urokinase‐type plasminogen activator and its receptor synergize to promote pathogenic proteolysis
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DOI：
10.1093/emboj/19.17.4817
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发表时间：
2000-09
期刊：
影响因子：
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通讯作者：
Hongming Zhou;A. Nichols;P. Meda;J. Vassalli
中科院分区：
文献类型：
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作者：
Hongming Zhou;A. Nichols;P. Meda;J. Vassalli
尿激酶型纤溶酶原激活物（uPA）是细胞外蛋白水解的有效催化剂，也与高亲和力质膜受体（uPAR）结合。uPA的结合可能影响细胞周围蛋白水解和/或激活细胞内信号转导。在基底表皮和毛囊中过度表达uPA或uPAR的转基因小鼠没有检测到皮肤变化。相比之下，通过交叉两个转基因系获得的过表达uPA和uPAR的双转基因小鼠，发生了由毛囊退化、表皮增厚和表皮下水疱诱导的广泛脱发。该表型是由于uPA催化活性，因为在同一组织中uPAR和uPAR结合但无催化活性的uPA的组合过表达在另一个双转基因系中是无害的。伴随纤溶酶生成能力增加、2型和9型基质金属蛋白酶上调和激活以及uPAR裂解。因此，uPA和uPAR的组合过表达协同作用以促进致病性细胞外蛋白水解。
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.