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.
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