Plasminogen binds the heparin-binding domain of insulin-like growth factor-binding protein-3

Am J Physiol. 1998 Aug;275(2):E321-31. doi: 10.1152/ajpendo.1998.275.2.E321.

Abstract

Limited proteolysis lowers affinity of insulin-like growth factor (IGF)-binding protein (IGFBP)-3 for bound IGFs, resulting in greater IGF bioavailability. Plasmin is one of many proteases that cleave IGFBP-3, and the plasmin system may regulate IGFBP-3 proteolysis and IGF bioavailability in cultured cells in vitro. A role for the plasmin system in IGFBP-3 proteolysis in vivo is suggested by data presented here showing that IGFBP-3 binds plasminogen (Pg; Glu-Pg) with a dissociation constant (Kd) ranging from 1.43 to 3.12 nM. IGF-I and Glu-Pg do not compete for IGFBP-3 binding; instead, the binary IGFBP-3/Glu-Pg complex binds IGF-I with high affinity (Kd = 0. 47 nM) to form a ternary complex. Competitive binding studies suggest that the kringle 1, 4, and 5 domains of Glu-Pg and the heparin-binding domain of IGFBP-3 participate in forming the IGFBP-3/Glu-Pg complex, and other studies show that Glu-Pg in this complex is activated at a normal rate by tissue Pg activator. Importantly, IGFBP-3/Glu-Pg complexes were detected in both human citrate plasma and serum, indicating that these complexes exist in vivo. Binding of IGFBP-3 to Glu-Pg in vivo suggests how Glu-Pg activation can specifically lead to IGFBP-3 proteolysis with subsequent release of IGFs to local target tissues.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding Sites
  • CHO Cells
  • Cricetinae
  • DNA, Complementary
  • Gene Library
  • Heparin / metabolism*
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / chemistry*
  • Insulin-Like Growth Factor Binding Protein 3 / genetics
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism*
  • Insulin-Like Growth Factor I / metabolism
  • Kinetics
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Oligodeoxyribonucleotides
  • Placenta / metabolism
  • Plasminogen / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Transfection

Substances

  • DNA, Complementary
  • Insulin-Like Growth Factor Binding Protein 3
  • Oligodeoxyribonucleotides
  • Recombinant Proteins
  • Insulin-Like Growth Factor I
  • Plasminogen
  • Heparin