title: PAPP-A and the IGF system.
abstract: Firstly 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 metalloproteinase that is able to specifically cleave three insulin-like growth factor binding proteins (IGFBPs): IGFBP-2, -4 and -5. PAPP-A binds tightly to glycosaminoglycans present on the surface of cells, thus functioning within tissues as a growth-promoting enzyme, releasing bioactive IGF in close proximity to the IGF receptor. Pro-MBP and stanniocalcin-2 (STC2) appear to be the main inhibitors of PAPP-A activity, by forming a covalent complex with the protease. According to in vivo experiments, IGFBP-4 is believed to be the main PAPP-A substrate to regulate IGF bioavailability. The regulation of PAPP-A includes transcriptional control of its gene, competing reactions with other IGFBPs potentially sequestering IGF from IGFBP-4 and hence antagonizing PAPP-A-mediated IGF activation, and proteolytic inhibition of PAPP-A. Finally, PAPP-A may serve as a therapeutic target to indirectly inhibit IGF signalling 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.
authors.affiliation: Institut national de la recherche agronomique, physiologie de la reproduction et des comportements, 37380 Nouzilly, France. Electronic address: pmonget@tours.inra.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Monget
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus C, Denmark. Electronic address: co@mbg.au.dk.
authors.forename: Claus
authors.initials: C
authors.lastname: Oxvig
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D011247:Pregnancy; D011266:Pregnancy-Associated Plasma Protein-A / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013002:Somatomedins / Q000502:physiology*
chemical_list: D013002:Somatomedins; D011266:Pregnancy-Associated Plasma Protein-A
keywords: IGF, IGFBP, Protéine-A plasmatique (PAPP-A), Pappalysine, PAPP-A, Pro-MBP, Stanniocalcine; Insulin-like growth factor (IGF); Insulin-like growth factor binding protein (IGFBP); Pappalysin; Pregnancy-associated plasma protein-A (PAPP-A); Proform of eosinophil major basic protein (pro-MBP); Stanniocalcin (STC)