PAPP-A and the IGF system
PAPP-A and the IGF system
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DOI：
10.1016/j.ando.2016.04.015
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发表时间：
2016-06-01
影响因子：
3.1
通讯作者：
Oxvig, Claus
中科院分区：
文献类型：
--
作者：
Monget, Philippe;Oxvig, Claus
妊娠相关血浆蛋白-A（PAPP-A）作为一种胎盘蛋白，在妊娠妇女的血液循环中大量存在，在多种组织中广泛表达。PAPP-A是一种金属蛋白酶，能够特异性切割三种胰岛素样生长因子结合蛋白（IGFBP）：IGFBP-2，-4和-5。PAPP-A与细胞表面存在的糖胺聚糖紧密结合，从而在组织内作为生长促进酶发挥作用，在IGF受体附近释放生物活性IGF。Pro-MBP和斯钙素-2（STC 2）通过与蛋白酶形成共价复合物而似乎是PAPP-A活性的主要抑制剂。根据体内实验，IGFBP-4被认为是调节IGF生物利用度的主要PAPP-A底物。PAPP-A的调节包括其基因的转录控制，与其他IGFBP的竞争反应，可能从IGFBP-4中螯合IGF，从而拮抗PAPP-A介导的IGF活化，以及PAPP-A的蛋白水解抑制。最后，PAPP-A可以作为治疗靶点，间接抑制组织中的IGF信号传导，其中这是由增加的PAPP-A活性驱动的。通过利用PAPP-A和IGFBP-4之间复杂的相互作用，可以高度特异性和选择性地抑制PAPP-A。(C)2016 Elsevier Masson SAS。All rights reserved.
Firstly discovered as a placental protein present abundantly in the circulation of pregnant women, pregnancy-associated plasma protein-A (PAPP-A) is widely expressed in multiple tissues. PAPP-A is a metalloproteinase that is able to specifically cleave three insulin-like growth factor binding proteins (IGFBPs): IGFBP-2, -4 and -5. PAPP-A binds tightly to glycosaminoglycans present on the surface of cells, thus functioning within tissues as a growth-promoting enzyme, releasing bioactive IGF in close proximity to the IGF receptor. Pro-MBP and stanniocalcin-2 (STC2) appear to be the main inhibitors of PAPP-A activity, by forming a covalent complex with the protease. According to in vivo experiments, IGFBP-4 is believed to be the main PAPP-A substrate to regulate IGF bioavailability. The regulation of PAPP-A includes transcriptional control of its gene, competing reactions with other IGFBPs potentially sequestering IGF from IGFBP-4 and hence antagonizing PAPP-A-mediated IGF activation, and proteolytic inhibition of PAPP-A. Finally, PAPP-A may serve as a therapeutic target to indirectly inhibit IGF signalling in tissues where this is driven by increased PAPP-A activity. By taking advantage of the intricate interaction between PAPP-A and IGFBP-4, highly specific and selective inhibition of PAPP-A is possible. (C) 2016 Elsevier Masson SAS. All rights reserved.