Pregnancy-associated plasma protein-A2 (PAPP-A2), a novel insulin-like growth factor-binding protein-5 proteinase

A novel metalloproteinase with similarity to]pregnancy-associated plasma pr otein-A (PAPP-A), which we denoted PAPP-A2, has been identified. Through ex pression in mammalian cells we showed that recombinant PAPP-A2 polypeptide of 1558 residues resulted from processing of a 1791-residue prepro-protein, Unlike PAPP-A, PAPP-A2 migrated as a monomer (of 220 kDa) in non-reducing SDS-polyacrylamide gel electrophoresis. The prepro-parts of PAPP-A2 and PAP P-A are not homologous, but mature PAPP-A2 shares 45% of its residues with PAPP-A, Because PAPP-A specifically cleaves insulin-like growth factor-bind ing protein (IGFBP)-4, one of six known modulators of IGF-I and -II, we loo ked for a possible PAPP-A2 substrate among the members of this family. We s howed that PAPP-A2 specifically cleaved IGFBP-5 at one site, between Ser-14 3 and Lys-144, In contrast to the cleavage of IGFBF-4 by PAPP-A that strict ly requires the presence of IGF, the cleavage of IGFBP-5 by PAPP-A2 was IGF -independent. Recent data firmly establish PAPP-A and IGFBPP-4 as an import ant functional pair in several systems. Because of its close relationship w ith PAPP-A, both structurally and functionally, PAPP-A2 is a likely candida te IGFBP-5 proteinase in many tissues and conditioned media where IGFBP-5 p roteolysis has been reported.