Bone morphogenetic protein 1 processes prolactin to a 17-kDa antiangiogenic factor
Bone morphogenetic protein 1 processes prolactin to a 17-kDa antiangiogenic factor
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DOI：
10.1073/pnas.0704179104
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发表时间：
2007-06-12
影响因子：
11.1
通讯作者：
Greenspan, Daniel S.
中科院分区：
文献类型：
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作者：
Ge, Gaoxiang;Fernandez, Cecilia A.;Greenspan, Daniel S.
除了在垂体和胎盘中的经典表达模式以及在生长和生殖中的功能之外，包括催乳素（PRL）、生长激素（GH）和胎盘催乳素在内的激素小家族的成员由内皮细胞表达并具有血管生成作用。相反，这些激素的16至17 kDa蛋白水解片段具有抗血管生成作用。在这里，我们表明，PRL和GH的绑定和处理的骨形态发生蛋白1（BMP 1）亚组的细胞外金属蛋白酶的成员，以前显示在形成细胞外基质和激活某些TGF β超家族成员中发挥关键作用。以前已经提出BMP 1在血管生成中发挥作用，因为高通量筛选已经发现其mRNA是与静息内皮相比在肿瘤相关内皮中诱导至最高水平的mRNA之一。PRL和GH裂解显示发生在每个激素在一个单一的网站典型的网站以前的特点是在已知的底物的BMP 1样蛋白酶，和近似17 kDa的PRL N-末端片段，因此产生的证明具有有效的抗血管生成活性。显示小鼠胚胎成纤维细胞产生PRL和GH，并将它们加工成接近17-kDa的形式，而GH和PRL加工活性在小鼠胚胎成纤维细胞中丢失，对于编码BMP 1样蛋白酶的两个基因为双重无效。
In addition to classical expression patterns in pituitary and placenta and functions in growth and reproduction, members of the small family of hormones that includes prolactin (PRL), growth hormone (GH), and placental lactogen are expressed by endothelia and have angiogenic effects. In contrast, 16- to 17-kDa proteolytic fragments of these hormones have antiangiogenic effects. Here we show that PRL and GH are bound and processed by members of the bone morphogenetic protein 1 (BMP1) subgroup of extracellular metalloproteinases, previously shown to play key roles in forming extracellular matrix and in activating certain TGF ss superfamily members. BMP1 has previously been suggested to play roles in angiogenesis, as high throughput screens have found its mRNA to be one of those induced to highest levels in tumor-associated endothelia compared with resting endothelia. PRL and GH cleavage is shown to occur in each hormone at a single site typical of sites previously characterized in known substrates of BMP1-like proteinases, and the approximate to 17-kDa PRL N-terminal fragment so produced is demonstrated to have potent antiangiogenic activity. Mouse embryo fibroblasts are shown to produce both PRL and GH and to process them to approximate to 17-kDa forms, whereas GH and PRL processing activity is lost in mouse embryo fibroblasts doubly null for two genes encoding BMP1-like proteinases.