Apoptotic effect of cleaved high molecular weight kininogen is regulated by extracellular matrix proteins
Apoptotic effect of cleaved high molecular weight kininogen is regulated by extracellular matrix proteins
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DOI：
10.1002/jcb.10536
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发表时间：
2003-06-01
影响因子：
4
通讯作者：
Colman, RW
中科院分区：
文献类型：
--
作者：
Guo, YL;Wang, SJ;Colman, RW
我们先前报道了裂解的高分子量激肽原（HKa）及其结构域5（D5）抑制血管生成和体内新血管形成所需的关键步骤（Colman等[2000]：Blood 95：543-550）。我们还表明，D5能够诱导内皮细胞凋亡，这可能代表HKa和D5的抗血管生成活性的关键部分（Guo等人[2001]：Arterioscler Thromb Vasc Biol 21：1427-1433）。在这项研究中，我们证明，HKa和D5诱导的细胞凋亡是密切相关的，其抗粘附作用。一个重要的新发现是，HKa和D5的凋亡活性受到它们与不同细胞外基质（ECM）蛋白的相互作用的高度调节。HKa对细胞与玻璃体粘连蛋白（Vn）和明胶（Gel）的粘附有90%的抑制作用，但对细胞与纤维粘连蛋白（Fn）的粘附无明显影响。D5在细胞粘附上显示出类似的模式，但不如HKa有效。HKa诱导Vn和Gel上生长的内皮细胞凋亡，但不诱导Fn上生长的细胞凋亡，这与其抗粘附能力密切相关。进一步的结果显示，HKa的抗粘附作用和凋亡作用与其抑制粘着斑激酶（FAK）和桩蛋白（paxillin）磷酸化的能力相关，这两种重要的信号分子是细胞粘附和细胞活力所需的。我们的结论是，HKA和D5的抗粘附活性是负责他们的凋亡作用，并且Vn可能是介导HKA和D5的作用的ECM组分。
We previously reported that cleaved high molecular weight kininogen (HKa) and its domain 5 (D5) inhibit critical steps required for angiogenesis and in vivo neovascularization (Colman et al. [2000]: Blood 95:543-550). We have further shown that D5 is able to induce apoptosis of endothelial cells, which may represent a critical part of the antiangiogenic activity of HKa and D5 (Guo et al. [2001]: Arterioscler Thromb Vasc Biol 21:1427-1433). In this study, we demonstrate that HKa- and D5-induced apoptosis is closely correlated with their anti-adhesive effect. An important new finding is that the apoptotic activity of HKa and D5 is highly regulated by their interactions with different extracellular matrix (ECM) proteins. HKa inhibited cell adhesion to vitronectin (Vn, 90%) and gelatin (Gel) (40%), but it had no apparent effect on cell adhesion to fibronectin (Fn). D5 showed a similar pattern on cell adhesion but was less potent than HKa. HKa induced apoptosis of endothelial cells grown on Vn and Gel but not cells grown on Fn which closely parallels with its anti-adhesive potency. Further results revealed that the anti-adhesive effect and the apoptotic effect of HKa are associated with its ability to inhibit phosphorylation of focal adhesion kinase (FAK) and paxillin, two important signal molecules required for cell adhesion and cell viability. We conclude that the anti-adhesive activity of HKa and D5 is responsible for their apoptotic effect and that Vn is likely an ECM component that mediates the effect of HKa and D5.