Insulin-like Growth Factor-binding Protein-5 Activates Plasminogen by Interaction with Tissue Plasminogen Activator, Independently of Its Ability to Bind to Plasminogen Activator Inhibitor-1, Insulin-like Growth Factor-I, or Heparin*
Insulin-like Growth Factor-binding Protein-5 Activates Plasminogen by Interaction with Tissue Plasminogen Activator, Independently of Its Ability to Bind to Plasminogen Activator Inhibitor-1, Insulin-like Growth Factor-I, or Heparin*
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胰岛素样生长因子结合蛋白 5 通过与组织纤溶酶原激活剂相互作用来激活纤溶酶原，而与纤溶酶原激活剂抑制剂 1、胰岛素样生长因子 I 或肝素的结合能力无关*
DOI：
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发表时间：
2006
影响因子：
4.8
通讯作者：
D. Flint
中科院分区：
文献类型：
--
作者：
Alice M Sorrell;J. Shand;E. Tonner;M. Gamberoni;P. Accorsi;J. Beattie;G. Allan;D. Flint
在乳腺中表达IGFBP-5的转基因小鼠表现出细胞死亡和纤溶酶生成增加。由于已有报道IGFBP-5与纤溶酶原激活物抑制剂-1 （PAI-1）结合，我们确定了这种相互作用在HC11细胞中的作用。PAI-1阻止纤溶酶原产生纤溶酶，抑制局灶粘连的裂解、caspase 3的表达和细胞死亡。IGFBP-5反过来可以阻止PAI-1的作用。IGFBP-5突变体对IGF-I （N-term）的亲和力降低或肝素结合缺陷（HEP -和C-term E和F）也有效。这是令人惊讶的，因为据报道IGFBP-5通过其肝素结合域与PAI-1相互作用。生物传感器分析证实，尽管野生型IGFBP-5和N-term都与PAI-1结合，但C-term E与PAI-1的相互作用大大降低。这表明IGFBP-5不会通过直接的分子相互作用拮抗PAI-1的作用。在无细胞系统中，使用组织纤溶酶原激活剂（tPA）和尿激酶纤溶酶原激活剂（uPA）激活纤溶酶原，PAI-1抑制两种激活剂诱导的纤溶酶生成，而IGFBP-5阻止PAI-1对tPA的影响，而对uPA不起作用。此外，我们注意到IGFBP-5激活纤溶酶原的程度比单独抑制PAI-1的程度更大，这表明IGFBP-5可以直接激活tPA。事实上，IGFBP-5和C-term E和F都能增强tPA的活性，但不能增强uPA的活性。这些数据表明，IGFBP-5可以增强tPA的活性，从而导致局灶性粘连的分裂引起细胞死亡。因此，IGFBP-5可以通过隔离igf - 1和增强纤溶酶的生成来诱导细胞死亡。
Transgenic mice expressing IGFBP-5 in the mammary gland exhibit increased cell death and plasmin generation. Because IGFBP-5 has been reported to bind to plasminogen activator inhibitor-1 (PAI-1), we determined the effects of this interaction in HC11 cells. PAI-1 prevented plasmin generation from plasminogen and inhibited cleavage of focal adhesions, expression of caspase 3, and cell death. IGFBP-5 could in turn prevent the effects of PAI-1. IGFBP-5 mutants with reduced affinity for IGF-I (N-term) or deficient in heparin binding (HEP– and C-term E and F) were also effective. This was surprising because IGFBP-5 reportedly interacts with PAI-1 via its heparin-binding domain. Biosensor analysis confirmed that, although wild-type IGFBP-5 and N-term both bound to PAI-1, the C-term E had greatly decreased interaction with PAI-1. This suggests that IGFBP-5 does not antagonize the actions of PAI-1 by a direct molecular interaction. In a cell-free system, using tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) to activate plasminogen, PAI-1 inhibited plasmin generation induced by both activators, whereas IGFBP-5 prevented the effects of PAI-1 on tPA but not uPA. Furthermore, we noted that IGFBP-5 activated plasminogen to a greater extent than could be explained solely by inhibition of PAI-1, suggesting that IGFBP-5 could directly activate tPA. Indeed, IGFBP-5 and the C-term E and F were all able to enhance the activity of tPA but not uPA. These data demonstrate that IGFBP-5 can enhance the activity of tPA and that this can result in cell death induced by cleavage of focal adhesions. Thus IGFBP-5 can induce cell death by both sequestering IGF-I and enhancing plasmin generation.
DOI：
10.1073/pnas.81.12.3756
发表时间：
1984-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
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作者：
DANIELSON, KG;OBORN, CJ;MEDINA, D
通讯作者：
MEDINA, D
可溶性纤维蛋白制剂抑制纤溶酶与α2-巨球蛋白的反应。
DOI：
10.1042/bj2750053
发表时间：
1991
期刊：
The Biochemical journal
影响因子：
--
作者：
Anonick,PK;Gonias,SL
通讯作者：
Gonias,SL