Insulin-like growth factor (IGF) binding protein-3 interacts with the type 1 IGF receptor, reducing the affinity of the receptor for its ligand: an alternative mechanism in the regulation of IGF action.
With a view to determining the mechanisms by which insulin-like growth factor binding protein-3 (IGFBP-3) and its proteolytic fragments modulate IGF action, we used a fibroblast cell line to investigate the possibility of an interaction with the type 1 IGF receptor (IGFR-1). In competitive binding experiments, IGFBP-3 was as potent as unlabelled IGF-I in displacing its truncated analogue, 125I-des(1-3)IGF-I, which has weak affinity for IGFBPs, from its binding to the cell surface. None of the proteolytic fragments of IGFBP-3 tested affected this binding. IGFBP-3 had no effect on insulin binding to its receptor. At 10 nM, IGFBP-1 was ineffective where IGFBP-3 provoked 90% displacement of 125I-des(1-3)IGF-I, but it was equally potent in displacing 125I-IGF-I. At the same concentration, binding of 125I-des(1-3)IGF-I to free IGFBP-3 in the supernatant was only 2%. After pre-incubation of the cells with 125I-des(1-3)IGF-I, low concentrations of IGFBP-3 were as potent as IGF-I in dissociating IGFR-1-bound ligand. After pre-incubation of cells with IGFBP-3, washing and then incubation with 125I-des(1-3)IGF-I, inhibition by low IGFBP-3 concentrations was suppressed, but some degree of inhibition by high concentrations persisted. At these high concentrations, addition of IGF-I restored binding owing to uptake of cell-associated IGFBP-3. The present results provide the first evidence that IGFBP-3 may inhibit IGF binding to IGFR-1, and hence limit IGF action via a cellular mechanism that is different from the extracellular mechanism of sequestration.
Mohseni-Zadeh
S
S
Institut National de la Santé et de la Recherche Médicale, U.142, Hôpital Saint Antoine, Paris, France.
Binoux
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M
D000818:Animals; D001667:Binding, Competitive; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D008024:Ligands; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D017451:Receptors, Somatomedin / Q000378:metabolism*
D018972:Insulin-Like Growth Factor Binding Protein 3; D008024:Ligands; D010446:Peptide Fragments; D017451:Receptors, Somatomedin; C058957:insulin-like growth factor 1, des-(1-3)-; D007334:Insulin-Like Growth Factor I