Oxvig Claus
Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, 8000, Aarhus C, Denmark,
J Cell Commun Signal. 2015 Jun;9(2):177-87. doi: 10.1007/s12079-015-0259-9. Epub 2015 Jan 25.
Although 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 highly specific metalloproteinase binding tightly to glycosaminoglycans present on the surface of cells. By cleaving a subset of insulin-like growth factor binding proteins (IGFBPs), PAPP-A thus functions within tissues as a growth-promoting enzyme, releasing bioactive IGF in close proximity to the IGF receptor. IGFBP-4 is believed to be the principal PAPP-A substrate, and the focus in this review is on PAPP-A enzymatic activity and its role in the PAPP-A-IGFBP-4-IGF axis, which is subject to regulation at several different levels. These include e.g., transcriptional control, competing reactions potentially sequestering IGF from IGFBP-4 and hence antagonizing PAPP-A-mediated IGF activation, and proteolytic inhibition of PAPP-A. The latter may involve the protein stanniocalcin-2 (STC2), recently found to potently inhibit PAPP-A activity by forming a covalent complex with PAPP-A. PAPP-A or complex-bound variants may escape from pathological tissues into the circulation. It is emphasized that the potential use of PAPP-A as a diagnostic or predictive biomarker in nonpregnant individuals requires precise knowledge of analyte identity and assay specificity in addition to an appropriate material for standardization. Finally, PAPP-A may serve as a therapeutic target to indirectly inhibit IGF signaling 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.
尽管妊娠相关血浆蛋白A（PAPP-A）最初是作为一种在孕妇循环系统中大量存在的胎盘蛋白被发现的，但它在多种组织中广泛表达。PAPP-A是一种高度特异性的金属蛋白酶，能紧密结合细胞表面存在的糖胺聚糖。通过切割胰岛素样生长因子结合蛋白（IGFBPs）的一个亚群，PAPP-A在组织内作为一种促进生长的酶发挥作用，在IGF受体附近释放生物活性IGF。IGFBP-4被认为是PAPP-A的主要底物，本综述的重点是PAPP-A的酶活性及其在PAPP-A-IGFBP-4-IGF轴中的作用，该轴在几个不同水平受到调控。这些调控包括例如转录控制、可能将IGF从IGFBP-4中隔离从而拮抗PAPP-A介导的IGF激活的竞争反应，以及对PAPP-A的蛋白水解抑制。后者可能涉及蛋白磷酸调节蛋白2（STC2），最近发现它通过与PAPP-A形成共价复合物来有效抑制PAPP-A的活性。PAPP-A或与复合物结合的变体可能从病理组织逃逸到循环系统中。需要强调的是，除了合适的标准化材料外，在非孕妇个体中潜在地将PAPP-A用作诊断或预测生物标志物需要对分析物身份和检测特异性有精确的了解。最后，PAPP-A可能作为一个治疗靶点，间接抑制组织中由PAPP-A活性增加驱动的IGF信号传导。通过利用PAPP-A与IGFBP-4之间复杂的相互作用，有可能实现对PAPP-A的高度特异性和选择性抑制。
