Plasmin degradation of insulin-like growth factor-binding protein-5 (IGFBP-5): regulation by IGFBP-5-(201-218).
Using the major bone insulin-like growth factor-binding protein (IGFBP) IGFBP-5, we took a mechanistic approach in evaluating the role of the heparin-binding domain of IGFBP-5 in regulating plasmin (Pm) proteolysis of IGFBP-5. Using synthetic IGFBP-5 peptide fragments, we determined that the heparin-binding domain, IGFBP-5-(208-218), inhibits Pm proteolysis of intact IGFBP-5. The mechanism of action of IGFBP-5-(201-218) was by inhibiting Pm binding to substrate IGFBP-5. IGFBP-5-(201-218) action was independent of site of proteolysis, fluid, or solid phase interaction. In addition, IGFBP-5-(201-218) was found to inhibit plasminogen (Pg) activation to Pm IGFBP-5-(201-218) did not directly inhibit the activity of Pm, urokinase Pg activator (PA), or tissue-type PA but acted as a competitive inhibitor of Pg activation by PA, which is in contrast to the stimulating effect of heparin on Pg activation. These data indicate that the heparin-binding domain contains the serine protease (Pg-to-Pm) binding site region of IGFBP-5, and that this region, which is presumed to represent a Pm-induced proteolytic product of IGFBP-5, is capable of regulating Pm action.
Campbell
P G
PG
Orthopaedic Research Laboratory, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212, USA.
Andress
D L
DL
D001665:Binding Sites; D005341:Fibrinolysin / Q000187:drug effects / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007700:Kinetics; D010446:Peptide Fragments / Q000494:pharmacology*; D010449:Peptide Mapping; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D012685:Sepharose / Q000031:analogs & derivatives; D013379:Substrate Specificity
D018975:Insulin-Like Growth Factor Binding Protein 5; D010446:Peptide Fragments; D011994:Recombinant Proteins; C037405:heparin-sepharose; C109256:insulin-like growth factor binding protein 5 (201-218); D007334:Insulin-Like Growth Factor I; D006493:Heparin; D012685:Sepharose; D005341:Fibrinolysin