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The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. 1999

J B Lawrence, and C Oxvig, and M T Overgaard, and L Sottrup-Jensen, and G J Gleich, and L G Hays, and J R Yates, and C A Conover
Endocrine Research Unit, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.

Proteolytic cleavage of the six known insulin-like growth factor binding proteins (IGFBPs) is a powerful means of rapid structure and function modification of these important growth-regulatory proteins. Intact IGFBP-4 is a potent inhibitor of IGF action in vitro, and cleavage of IGFBP-4 has been shown to abolish its ability to inhibit IGF stimulatory effects in a variety of systems, suggesting that IGFBP-4 proteolysis acts as a positive regulator of IGF bioavailability. Here we report the isolation of an IGF-dependent IGFBP-4-specific protease from human fibroblast-conditioned media and its identification by mass spectrometry microsequencing as pregnancy-associated plasma protein-A (PAPP-A), a protein of unknown function found in high concentrations in the maternal circulation during pregnancy. Antibodies raised against PAPP-A both inhibited and immunodepleted IGFBP-4 protease activity in human fibroblast-conditioned media. Moreover, PAPP-A purified from pregnancy sera had IGF-dependent IGFBP-4 protease activity. PAPP-A mRNA was expressed by the human fibroblasts and osteoblasts, and PAPP-A protein was secreted into the culture medium. In conclusion, we have identified an IGF-dependent IGFBP protease and at the same time assigned a function to PAPP-A. This represents an unanticipated union of two areas of research that were not linked in any way before this report.

UI MeSH Term Description Entries
D007334 Insulin-Like Growth Factor I A well-characterized basic peptide believed to be secreted by the liver and to circulate in the blood. It has growth-regulating, insulin-like, and mitogenic activities. This growth factor has a major, but not absolute, dependence on GROWTH HORMONE. It is believed to be mainly active in adults in contrast to INSULIN-LIKE GROWTH FACTOR II, which is a major fetal growth factor. IGF-I,Somatomedin C,IGF-1,IGF-I-SmC,Insulin Like Growth Factor I,Insulin-Like Somatomedin Peptide I,Insulin Like Somatomedin Peptide I
D007335 Insulin-Like Growth Factor II A well-characterized neutral peptide believed to be secreted by the LIVER and to circulate in the BLOOD. It has growth-regulating, insulin-like and mitogenic activities. The growth factor has a major, but not absolute, dependence on SOMATOTROPIN. It is believed to be a major fetal growth factor in contrast to INSULIN-LIKE GROWTH FACTOR I, which is a major growth factor in adults. IGF-II,Multiplication-Stimulating Activity,Somatomedin MSA,IGF-2,Insulin Like Growth Factor II,Insulin-Like Somatomedin Peptide II,Multiplication-Stimulating Factor,Somatomedin A,Factor, Multiplication-Stimulating,Insulin Like Somatomedin Peptide II,Multiplication Stimulating Activity,Multiplication Stimulating Factor
D008297 Male Males
D008666 Metalloendopeptidases ENDOPEPTIDASES which use a metal such as ZINC in the catalytic mechanism. Metallo-Endoproteinases,Metalloendopeptidase
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D011247 Pregnancy The status during which female mammals carry their developing young (EMBRYOS or FETUSES) in utero before birth, beginning from FERTILIZATION to BIRTH. Gestation,Pregnancies
D011266 Pregnancy-Associated Plasma Protein-A A product of the PLACENTA, and DECIDUA, secreted into the maternal circulation during PREGNANCY. It has been identified as an IGF binding protein (IGFBP)-4 protease that proteolyzes IGFBP-4 and thus increases IGF bioavailability. It is found also in human FIBROBLASTS, ovarian FOLLICULAR FLUID, and GRANULOSA CELLS. The enzyme is a heterotetramer of about 500-kDa. PAPP-A,IGFBP-4 Metalloproteinase,IGFBP-4 Protease,IGFBP-4-Specific Proteinase,Insulin-Like Growth Factor-Dependent IGF Binding Protein-4 Protease,Insulin-Like-Growth Factor Binding Protein-4 Protease,PAPP-alpha,Pregnancy Associated alpha Plasma Protein,Pregnancy-Associated alpha-Plasma Protein,IGFBP 4 Metalloproteinase,IGFBP 4 Protease,Insulin Like Growth Factor Binding Protein 4 Protease,Insulin Like Growth Factor Dependent IGF Binding Protein 4 Protease,Metalloproteinase, IGFBP-4,PAPP alpha,Pregnancy Associated Plasma Protein A,Protease, IGFBP-4
D005260 Female Females
D005347 Fibroblasts Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. Fibroblast
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man

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