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PMID: 10077652 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 6 ·1999-03-16 ·Pages 3149-53

Lawrence JB, Oxvig C, Overgaard MT, Sottrup-Jensen L, Gleich GJ, Hays LG, Yates JR, Conover CA

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.

MeSH Terms
Amino Acid Sequence Female Fibroblasts/metabolism Humans Insulin-Like Growth Factor Binding Protein 4/metabolism Insulin-Like Growth Factor I/metabolism Insulin-Like Growth Factor II/metabolism Male Mass Spectrometry Metalloendopeptidases/chemistry,genetics,isolation & purification,metabolism Molecular Sequence Data Pregnancy Pregnancy-Associated Plasma Protein-A/chemistry,genetics Sequence Analysis
Chemicals
Insulin-Like Growth Factor Binding Protein 4 Insulin-Like Growth Factor I Insulin-Like Growth Factor II Metalloendopeptidases Pregnancy-Associated Plasma Protein-A
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Lawrence J B
Endocrine Research Unit, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
Oxvig C
Overgaard M T
Sottrup-Jensen L
Gleich G J
Hays L G
Yates J R
Conover C A
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.6.3149
Published
1999-03-16
Pages
3149-53
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC15910
Subset
IM
Grants
NIAID NIH HHS · R01 AI009728 · United States
NIGMS NIH HHS · GM52095 · United States
NIDDK NIH HHS · DK07352 · United States
NIDDK NIH HHS · T32 DK007352 · United States
NIAID NIH HHS · AI09728 · United States
External Links
PubMed source DOI: 10.1073/pnas.96.6.3149 PMC Full Text View journal details
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