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Structural and Biological Characterization of Bovine Insulin-Like Growth Factor Binding Protein-3^*

Endocrine Research Unit (C.A.C.), Mayo Clinic, Rochester, Minnesota 55905; Division of Immunology (M.R.), Beckman Research Institute of the City of Hope Duarte, California 91010
Department of Pediatrics (F.L., D.R.P.), Baylor College of Medicine, Diabetes Research Center Houston, Texas 77054

Address requests for reprints to: Dr. Cheryl Conover, Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota 55905.

Abstract

Insulin-like growth factor binding protein-3 (IGFBP-3) purified from bovine serum shares 19 of 25 aminoterminal amino acid residues with IGFBP-3 purified from human, rat, and porcine sources. A newly characterized bovine fibroblast model was used to investigate the biological effects of purified bovine IGFBP-3 (bIGFBP-3). Coincubation of insulinlike growth factor I (IGF-I) with increasing concentrations of bIGFBP-3 produced a dose-dependent inhibition of IGF-I-stimulated [³H]aminoisobutyric acid (AIB) uptake in cultured bovine fibroblasts. Inhibition was complete at equimolar concentrations of IGF-I andbIGFBP-3. Inhibition of IGF-I-stimulated [³H]AIB uptake paralleled the ability of bIGFBP-3 to prevent [125I]IGFI cell surface binding. In contrast, preincubation with blGFBP- 3 resulted in a dose-dependent enhancement of IGF-I-stimulated [³H]AIB uptake; a 32-86% increase in IGF-I bioactivity was seen after a 24 h preexposure to 10 nM bIGFBP-3, and a 2- to 6-fold potentiation was seen after a 72 h preincubation. Preincubation with bIGFBP-3 increased both the sensitivity and maximal responsiveness of the cells to IGF-I. The potentiating effects of bIGFBP-3 were associated with increased [¹²⁵I]IGF-I binding to cultured bovine fibroblasts. Affinity cross-linking experiments indicated that the increase in IGF-I binding was due to increased membrane-associated bIGFBP-3 rather than to a bIGFBP-3-induced increase in type I IGF receptors. blGFBP- 3 had no effect on insulin stimulation of [³H]AIB uptake under either experimental condition. These data suggest that soluble bIGFBP-3 inhibits IGF-I action by sequestering and preventing IGF-I receptor binding, whereas surface-associated bIGFBP-3 enhances the growth-promoting effects of IGF-I in bovine fibroblasts. We propose that IGFBP-3 serves a dual function in modulating IGF action in vivo. (Endocrinology 127: 2795–2803, 1990)

Footnotes

^* This work was supported in part by the Mayo Foundation (to C.A.C.) and by NIH Grant DK-38777 (to D.R.P.) and March of Dimes Basic Research Grant 1-1186 (to D.R.P.).

Received June 30, 1990.

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