RECEPTOR-MEDIATED INTERNALIZATION AND DEGRADATION OF UROKINASE IS CAUSED BY ITS SPECIFIC INHIBITOR PAI-1
RECEPTOR-MEDIATED INTERNALIZATION AND DEGRADATION OF UROKINASE IS CAUSED BY ITS SPECIFIC INHIBITOR PAI-1
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DOI：
10.1002/j.1460-2075.1990.tb08213.x
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发表时间：
1990-04-01
期刊：
影响因子：
11.4
通讯作者：
BLASI, F
中科院分区：
文献类型：
--
作者：
CUBELLIS, MV;WUN, TC;BLASI, F
尿激酶型纤溶酶原激活剂受体(UPA)不是将其配体内化，而是将其活性集中在细胞表面，允许受调控的细胞表面纤溶酶依赖的蛋白分解。事实上，受体结合了原酶原-uPA，并使其非常有效地转化为活性双链形式。受体结合的活性uPA还可以与其特异性的1型抑制物(PAI-1)相互作用，从而能够抑制细胞表面纤溶酶的形成。在这篇文章中，我们证明了与uPA受体结合的uPA-PAI-1复合体被内化和降解。U937细胞与标记的uPA-PAI-1(和其他配体)在4℃孵育，然后升温至37℃，然后观察配体的命运3小时。UPA-PAI-1复合体被内化到细胞内(即不能通过酸处理解离)，然后降解(即以非TCA可沉淀的形式出现在上清液中)。其他配体(游离uPA、ATF和DFP处理的uPA)既不内化也不降解。UPA-PAI-1复合体的降解是在内化之前进行的，并被溶酶体蛋白降解的抑制剂氯喹抑制。这些数据表明uPA存在一个细胞周期。合成后，原-uPA被分泌出来，与受体结合并激活为两条链uPA。在表面，uPA可以激活表面结合的纤溶酶原产生表面结合的纤溶酶。在PAI-1存在的情况下，uPA活性被抑制，纤溶酶的产生中断，而uPA-PAI-1复合体内化和降解。
The receptor for urokinase plasminogen activator (uPA) has been previously shown not to internalize its ligand, but rather to focalize its activity at the cell surface, allowing a regulated cell surface plasmin dependent proteolysis. The receptor in fact binds the proenzyme pro-uPA and allows its very efficient conversion to the active two chains form. Receptor bound active uPA can also interact with its specific type 1 inhibitor (PAI-1) which is therefore able to inhibit the cell surface plasmin formation. In this paper we show that the uPA-PAI-1 complex bound to the uPA receptor is internalized and degraded. U937 cells were incubated at 4.degree.C with labeled uPA-PAI-1 (and other ligands), the temperature then raised to 37.degree.C and the fate of the ligand followed for 3 h thereafter. The uPA-PAI-1 complex was internalized into the cells (i.e. could not be dissociated by acid treatment) and thereafter degraded (i.e. appeared in the supernatant in a non TCA-precipitable form). Other ligands (free uPA, ATF and DFP-treated uPA) were not internalized nor degraded. The degradation of the uPA-PAI-1 complex is preceded by internalization and is inhibited by chloroquine, an inhibitor of lysosomal protein degradation. These data suggest the existence of a cellular cycle of uPA. After synthesis pro-uPA is secreted, bound to the receptor and activated to two chain uPA. On the surface, uPA can activate surface bound plasminogen to produce surface bound plasmin. In the presence of PAI-1 uPA activity is inhibited and plasmin production interrupted, while the uPA-PAI-1 complex is internalized and degraded.