PAPP-A

Initially identified as a placental protein highly abundant in the circulation of pregnant women, pregnancy-associated plasma protein-A (PAPP-A) is now recognized as a widely expressed metalloproteinase with a crucial role in insulin-like growth factor (IGF) regulation. PAPP-A specifically cleaves IGF binding proteins (IGFBPs) -2, -4, and -5, thereby modulating IGF bioavailability at the cellular level. Anchored to glycosaminoglycans on cell surfaces, PAPP-A functions as a growth-promoting enzyme, facilitating localized IGF activation. Its activity is tightly regulated by inhibitors such as pro-MBP and stanniocalcin-2 (STC2), which form covalent complexes with PAPP-A to suppress its proteolytic function. Among its substrates, IGFBP-4 is considered the principal mediator of IGF bioavailability. PAPP-A regulation involves multiple layers, including gene transcription, competitive IGF sequestration by other IGFBPs, and direct proteolytic inhibition. Given its role in IGF signaling, PAPP-A presents a promising therapeutic target for conditions driven by dysregulated IGF activity, with highly specific inhibition strategies offering potential for precision medicine applications.