Jepsen Malene R, Kløverpris Søren, Mikkelsen Jakob H, Pedersen Josefine H, Füchtbauer Ernst-Martin, Laursen Lisbeth S, Oxvig Claus
From the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark.
From the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark
J Biol Chem. 2015 Feb 6;290(6):3430-9. doi: 10.1074/jbc.M114.611665. Epub 2014 Dec 22.
Mammalian stanniocalcin-2 (STC2) is a secreted polypeptide widely expressed in developing and adult tissues. However, although transgenic expression in mice is known to cause severe dwarfism, and targeted deletion of STC2 causes increased postnatal growth, its precise biological role is still unknown. We found that STC2 potently inhibits the proteolytic activity of the growth-promoting metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). Proteolytic inhibition requires covalent binding of STC2 to PAPP-A and is mediated by a disulfide bond, which involves Cys-120 of STC2. Binding of STC2 prevents PAPP-A cleavage of insulin-like growth factor-binding protein (IGFBP)-4 and hence release within tissues of bioactive IGF, required for normal growth. Concordantly, we show that STC2 efficiently inhibits PAPP-A-mediated IGF receptor signaling in vitro and that transgenic mice expressing a mutated variant of STC2, STC2(C120A), which is unable to inhibit PAPP-A, grow like wild-type mice. Our work identifies STC2 as a novel proteinase inhibitor and a previously unrecognized extracellular component of the IGF system.
哺乳动物的鲽源钙调蛋白-2（STC2）是一种分泌型多肽，在发育中的组织和成年组织中广泛表达。然而，尽管已知在小鼠中进行转基因表达会导致严重侏儒症，而靶向缺失STC2会使出生后生长加快，但其确切的生物学作用仍然未知。我们发现，STC2能有效抑制促进生长的金属蛋白酶——妊娠相关血浆蛋白-A（PAPP-A）的蛋白水解活性。蛋白水解抑制作用需要STC2与PAPP-A共价结合，并由一个二硫键介导，该二硫键涉及STC2的半胱氨酸-120。STC2的结合可防止PAPP-A对胰岛素样生长因子结合蛋白（IGFBP）-4的切割，从而阻止生物活性IGF在组织内释放，而生物活性IGF是正常生长所必需的。与此一致的是，我们表明STC2在体外能有效抑制PAPP-A介导的IGF受体信号传导，并且表达无法抑制PAPP-A的STC2突变体STC2（C120A）的转基因小鼠生长情况与野生型小鼠相似。我们的研究工作将STC2鉴定为一种新型蛋白酶抑制剂以及IGF系统中一个此前未被认识的细胞外成分。
