Cited by 706Growth Hormone and Insulin-like Growth FactorsPregnancy and preeclampsia studiesProtease and Inhibitor Mechanisms

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

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Lawrence, James B., Oxvig, Claus, Overgaard, Michael T., Sottrup-Jensen, Lars, Gleich, Gerald J., Hays, Lara G., Yates, John R., Conover, Cheryl A.·1999·Proceedings of the National Academy of Sciences

Abstract

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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Research works printed but not linked: 5

  1. [7]Lawrence, J. B., Bale, L. K., Haddad, T. C., Clarkson, J. T. & Conover, C. A. Growth Horm. IGF Res., in press. [DOI] [PubMed]
  2. [23]Qin Q-P, Christiansen M, Oxvig C, Pettersson K, Sottrup-Jensen L, Koch C, Norgaard-Pedersen B. Clin Chem. 1997;43:2323–2332. [PubMed] [Google Scholar]
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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
Published
1999-03-16
Volume
96
Issue
6
Pages
3149-3153
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
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
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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