Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the circulation of pregnant women. In the mid-to-late 1990s, PAPP-A was discovered to be a metzincin metalloproteinase, expressed by many nonplacental cells, that regulates local insulin-like growth factor (IGF) activity through cleavage of high-affinity IGF binding proteins (IGFBPs), in particular IGFBP-4. With PAPP-A as a cell surface-associated enzyme, the reduced affinity of the cleavage fragments results in increased IGF available to bind and activate IGF receptors in the pericellular environment. This proteolytic regulation of IGF activity is important, since the IGFs promote proliferation, differentiation, migration, and survival in various normal and cancer cells. Thus, there has been a steady growth in investigation of PAPP-A structure and function outside of pregnancy. This review provides historical perspective on the discovery of PAPP-A and its structure and cellular function, highlights key studies of the first 50 years in PAPP-A research, and introduces new findings from recent years.

中文翻译：

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妊娠相关血浆蛋白 A (PAPP-A) 的故事。

妊娠相关血浆蛋白 A (PAPP-A) 在 20 世纪 70 年代初首次被鉴定为功能未知的胎盘蛋白，在孕妇的循环中以高浓度存在。20世纪90年代中后期，PAPP-A被发现是一种metzincin金属蛋白酶，由许多非胎盘细胞表达，通过切割高亲和力IGF结合蛋白（IGFBP）来调节局部胰岛素样生长因子（IGF）活性，特别是IGFBP-4。当 PAPP-A 作为细胞表面相关酶时，切割片段亲和力的降低导致可用于结合和激活细胞周环境中 IGF 受体的 IGF 增加。IGF 活性的这种蛋白水解调节很重要，因为 IGF 促进各种正常细胞和癌细胞的增殖、分化、迁移和存活。因此，对妊娠期以外的 PAPP-A 结构和功能的研究一直在稳步增长。本综述提供了 PAPP-A 的发现及其结构和细胞功能的历史视角，重点介绍了 PAPP-A 研究前 50 年的关键研究，并介绍了近年来的新发现。