The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A
Open accessAbstract
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.
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A high concentration of PAPPA is found in the serum of pregnant women.
“A high concentration of this protein is found in the serum of pregnant women (Silahtaroglu et al. 1993; Conover et al. 1999; Lawrence et al. 1999).”
From Limb-Girdle Muscular Dystrophy Type 2H Associated with Mutation in TRIM32, a Putative E3-Ubiquitin–Ligase Gene (2002) · cites this paper as Lawrence et al. 1999
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- Authors
- Lawrence, J. B., Oxvig, C., Overgaard, M. T., Sottrup-Jensen, L., Gleich, G. J., Hays, L. G., Yates, J. R., & Conover, C. A.
- Affiliations
- Mayo Clinic (US)
- Endocrine Research Unit, Mayo Clinic and Mayo Foundation, Rochester, MN 55905; Department of Molecular and Structural Biology, University of Aarhus, 8000 Aarhus C, Denmark; Department of Immunology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN 55905; and Department of Molecular Biotechnology, University of Washington, Seattle, WA 98195
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1999-03-16
- Volume
- 96
- Issue
- 6
- Pages
- 3149-3153
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC15910
- OpenAlex
- W2042693437
- Cited by
- 706
- References
- 39
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 19 · 2023: 20 · 2022: 21 · 2021: 17 · 2020: 24 · 2019: 18 · 2018: 23 · 2017: 24 · 2016: 24 · 2015: 34 · 2014: 25 · 2013: 31 · 2012: 35
- FWCI
- 18.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (9214821)
- Mayo Foundation for Medical Education and Research
- National Institutes of Health (5r01gm052095-03)
- National Institute of General Medical Sciences (GM52095)
- National Institute of Allergy and Infectious Diseases (AI 09728, R01AI009728)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-07352, T32DK007352)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- PAPP-A, IGFBP-4, human fibroblasts, osteoblasts, IGF bioavailability, protein secretion, conditioned medium, maternal serum
- MeSH terms
- Amino Acid Sequence, Female, Fibroblasts, Humans, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Male, Metalloendopeptidases, Molecular Sequence Data, Pregnancy, Pregnancy-Associated Plasma Protein-A, Mass Spectrometry, Sequence Analysis, Insulin-Like Growth Factor Binding Protein 4
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