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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

Academic Article
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Overview

authors

  • Lawrence, J. B.
  • Oxvig, C.
  • Overgaard, M. T.
  • Sottrup-Jensen, L.
  • Gleich, G. J.
  • Hays, L. G.
  • Yates III, John
  • Conover, C. A.

publication date

  • March 1999

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

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.

subject areas

  • Amino Acid Sequence
  • Female
  • Fibroblasts
  • Humans
  • Insulin-Like Growth Factor Binding Protein 4
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • Male
  • Mass Spectrometry
  • Metalloendopeptidases
  • Molecular Sequence Data
  • Pregnancy
  • Pregnancy-Associated Plasma Protein-A
  • Sequence Analysis
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Identity

PubMed Central ID

  • PMC15910

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.96.6.3149

PubMed ID

  • 10077652
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Additional Document Info

start page

  • 3149

end page

  • 3153

volume

  • 96

issue

  • 6

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