The Pregnancy-Associated Plasma Protein-A (PAPP-A) Story

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. Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; ApoE, apolipoprotein E; CD, catalytic domain; CPCs, cardiac progenitor cells; DDR, discoidin domain collagen receptor; EMT, epithelial-mesenchymal transition; EWS, Ewing sarcoma; GAG, glycosaminoglycan; GH, growth hormone; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; IGF-IR, IGF-I receptor; IL, interleukin; IPF, idiopathic pulmonary fibrosis; KO, knockout; LNR, Lin12-notch repeat; miRNA, microRNA; PAPP-A, pregnancy-associated plasma protein-A; PPBC, postpartum-associated breast cancer; proMBP, precursor major basic protein; PTH, parathyroid hormone; RCC, renal cell carcinoma; SAT, subcutaneous adipose tissue; SCR, short consensus repeat; STC, stanniocalcin; TGF-β, transforming growth factor; TNF-α, tumor necrosis factor; VAT, visceral adipose tissue; WT, wild-type.