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Insulin-Like Growth Factor (IGF)-Binding Protein-3 Blocks IGF-I-Induced Receptor Down-Regulation and Cell Desensitization in Cultured Bovine Fibroblasts^*

Endocrine Research Unit, Mayo Clinic Rochester, Minnesota 55905 the Department of Pediatrics, Baylor College of Medicine, Diabetes Research Center Houston, Texas 77054

Address all correspondence and requests for reprints to: Cheryl A. Conover, Ph.D., Mayo Clinic, Endocrine Research Unit, 5–164 West Joseph, Rochester, Minnesota 55905.

Abstract

Insulin-like growth factor-I (IGF-I) initiates its diverse biological effects by binding to type I IGF receptors on cells. In addition, IGF-I associates with distinct proteins that can modulate its actions. One of these IGF-binding proteins, IGFBP-3, is the major circulating form in adults and is produced by many cells in culture. We investigated the effect of purified bovine IGFBP-3 on IGF-I binding and IGF-I stimulation of amino acid uptake and DNA synthesis in cultured bovine fibroblasts, a cell culture system highly suitable for these types of studies. Incubation of cells with IGF-I resulted in time- and dose-dependent decreases in [¹²⁵I]IGF-I binding and IGF-I stimulated [³H]aminoisobutyric acid uptake and [³H]thymidine incorporation. Preincubation with 4 nM IGF-I resulted in a 50–60% decrease in IGF-I receptor binding, accompanied by marked decreases in IGF-I-stimulated [³H]aminoisobutyric acid uptake (50–60%) and [³H]thymidine incorporation (80–90%). Preincubation with the IGF-I analog [QAYL]IGF-I (4 nM) or with 100 nM insulin, growth factors that bind and activate type I IGF receptor signalling but have little or no affinity for IGFBP-3, had effects comparable to IGF-I, decreasing both IGF-I binding and action 50–95%. The addition of IGFBP-3 during the preincubation period with IGF-I blocked the decrease in receptor availability and prevented the cells from becoming desensitized. IGFBP-3 did not prevent the [QAYL]IGF-I- or insulin-induced receptor loss and cellular resistance to IGF-I. These data indicate that IGFBP-3 can prevent IGF-I-induced receptor down-regulation, a process that renders cells refractory to further stimulation by IGF-I. Thus, cell-derived IGFBP-3 may function in a buffering capacity to restrict IGF-I and target cell interaction, thereby modulating the biological response to changes in local IGF-I levels.

Footnotes

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

Received March 7, 1991.

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