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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

Institut National de la Santé et de la Recherche Médicale, U.142, Hôpital Saint Antoine, 75571 Paris Cedex 12, France

Address all correspondence and requests for reprints to: Michel Binoux, M.D., INSERM U142, Hôpital Saint-Antoine, 184 rue du Faubourg Saint Antoine, 75571 Paris Cedex 12, France.

	Abstract

Top Abstract

 
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 at IGF-I in dissociating IGFR-1-bound ligand. After preincubation 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.

Received July 10, 1997.

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