Mondino A, Resnati M, Blasi F
Dipartimento di Patologia e Medicina Molecolare, Università Vita-Salute San Raffaele, Milan, Italy.
Thromb Haemost. 1999 Sep;82 Suppl 1:19-22.
The binding of the urokinase plasminogen activator (uPA) to its receptor (uPAR) regulates cell adhesion, surface proteolysis, chemotaxis and cell extravasation in a number of experimental systems. Recent evidences have suggested that uPAR can by itself mediate chemotaxis of human monocytes and cause profound changes in cytoskeletal organization indicating that this receptor has the properties of a cell-surface regulated chemokine. Indeed, it is likely that upon binding to uPA, uPAR undergoes a conformational change that uncovers a new epitope located in the linker region between domain 1 and 2 of the receptor and is endowed with a potent chemotactic activity. This conformational change can be mimicked in vitro by enzymatic processing of a recombinant receptor. We have shown that chymotrypsin cleaves uPAR between domain 1 and 2 in an area that can be also cleaved by uPA at high efficiency and generate a receptor that can mediate monocytes migration independently of uPA binding. This mechanism is pertussis-toxin sensitive and involves activation of tyrosine kinases and cytoskeletal reorganization events in vitro. These studies indicate that in addition to its receptor function, upon binding to uPA, uPAR becomes a pleiotropic ligand for other still to be identified surface molecules.
在许多实验系统中，尿激酶型纤溶酶原激活剂（uPA）与其受体（uPAR）的结合可调节细胞黏附、表面蛋白水解、趋化性和细胞外渗。最近的证据表明，uPAR自身可介导人类单核细胞的趋化性，并导致细胞骨架组织发生深刻变化，这表明该受体具有细胞表面调节趋化因子的特性。实际上，与uPA结合后，uPAR可能会发生构象变化，从而暴露出位于受体结构域1和2之间连接区的新表位，并具有强大的趋化活性。这种构象变化在体外可通过重组受体的酶促加工来模拟。我们已经表明，胰凝乳蛋白酶在结构域1和2之间的一个区域切割uPAR，该区域也可被uPA高效切割，并产生一种可独立于uPA结合介导单核细胞迁移的受体。这种机制对百日咳毒素敏感，且在体外涉及酪氨酸激酶的激活和细胞骨架重组事件。这些研究表明，除了其受体功能外，与uPA结合后，uPAR还成为其他有待鉴定的表面分子的多效性配体。
