A physiological role for pregnancy associated plasma protein E
NM Page & PJ Lowry
The pregnancy associated plasma proteins (PAPP) -A, -B, -C and -D were first isolated from pregnancy serum in 1974. Since, these proteins have been re-characterised; PAPP-B and PAPP-C are now known as pregnancy-specific beta-1 glycoproteins and PAPP-D as placental lactogen. PAPP-A was subsequently found to be a member of the metzincins family of metalloproteases. Recently we have identified a full-length cDNA encoding the preproprotein of pregnancy associated plasma protein-E (PAPP-E), a putative metalloprotease of 1790-residues 1. This protein has 46% identity and 65% similarity to PAPP-A. Unlike, PAPP-A an alternatively spliced mRNA was found to encode a shorter 826-residue precursor protein corresponding to the N-terminus. Both PAPP-E variants are expressed abundantly in the placenta and mammary gland along with PAPP-A. Computer analysis of PAPP-A and the longer PAPP-E variant suggest they are both targeted to the nucleus, as each possesses bipartite nuclear localisation signals, while the shorter variant is secreted extracellularly. The proposed main substrates for PAPP-A and PAPP-E are IGFBP-4 and IGFBP-5 respectively. IGFBP-5 found to circulate in the blood also possesses bipartite nuclear localisation signals and is imported into the nucleus. We have also demonstrated that a variety of normal and breast carcinoma cell lines and placental trophoblast cells express PAPP-A and PAPP-E. We propose that these metalloproteases may play an important and previously unrecognised role in the regulation of the IGFs and IGFBP-4 and 5 not only in breast cancer but also the regulation of growth during pregnancy. Our discovery of expressed sequence tags representing the PAPP-E proteins in the rat, mouse and cow demonstrates that these proteins likewise may have a fundamental role in a range of other species.
1 Page et al. Placenta (2001) (in press).