PMID- 10077652
OWN - NLM
STAT- MEDLINE
DCOM- 19990520
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 6
DP  - 1999 Mar 16
TI  - The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease
      secreted by human fibroblasts is pregnancy-associated plasma protein-A.
PG  - 3149-53
AB  - 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.
FAU - Lawrence, J B
AU  - Lawrence JB
AD  - Endocrine Research Unit, Mayo Clinic and Mayo Foundation, Rochester, MN 55905,
      USA.
FAU - Oxvig, C
AU  - Oxvig C
FAU - Overgaard, M T
AU  - Overgaard MT
FAU - Sottrup-Jensen, L
AU  - Sottrup-Jensen L
FAU - Gleich, G J
AU  - Gleich GJ
FAU - Hays, L G
AU  - Hays LG
FAU - Yates, J R 3rd
AU  - Yates JR 3rd
FAU - Conover, C A
AU  - Conover CA
LA  - eng
GR  - R01 AI009728/AI/NIAID NIH HHS/United States
GR  - GM52095/GM/NIGMS NIH HHS/United States
GR  - DK07352/DK/NIDDK NIH HHS/United States
GR  - T32 DK007352/DK/NIDDK NIH HHS/United States
GR  - AI09728/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Insulin-Like Growth Factor Binding Protein 4)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - 67763-97-7 (Insulin-Like Growth Factor II)
RN  - EC 3.4.24.- (Metalloendopeptidases)
RN  - EC 3.4.24.- (Pregnancy-Associated Plasma Protein-A)
SB  - IM
MH  - Amino Acid Sequence
MH  - Female
MH  - Fibroblasts/*metabolism
MH  - Humans
MH  - Insulin-Like Growth Factor Binding Protein 4/*metabolism
MH  - Insulin-Like Growth Factor I/metabolism
MH  - Insulin-Like Growth Factor II/metabolism
MH  - Male
MH  - Mass Spectrometry
MH  - Metalloendopeptidases/chemistry/*genetics/*isolation & purification/metabolism
MH  - Molecular Sequence Data
MH  - Pregnancy
MH  - Pregnancy-Associated Plasma Protein-A/chemistry/*genetics
MH  - Sequence Analysis
PMC - PMC15910
EDAT- 1999/03/17 03:04
MHDA- 2001/03/28 10:01
CRDT- 1999/03/17 03:04
PHST- 1999/03/17 03:04 [pubmed]
PHST- 2001/03/28 10:01 [medline]
PHST- 1999/03/17 03:04 [entrez]
AID - 10.1073/pnas.96.6.3149 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3149-53. doi: 10.1073/pnas.96.6.3149.