Zinc alters the kinetics of IGF-II binding to cell surface receptors and binding proteins.
The growth of most tissues is markedly depressed as a result of zinc deficiency by uncharacterized mechanisms that clearly involve the insulin-like growth factor (IGF) system. Herein, we describe the mechanism by which zinc (Zn2+) maintains IGF-II in an active form by directly regulating IGF-II binding to IGF-binding proteins (IGFBPs) and the type 1 IGF receptor (IGF-1R). The specificity of Zn2+ effects was confirmed by using other cations that can (Cd2+ and Au3+) or cannot (La3+) mimic Zn2+ actions. Human fibroblasts, glioblastoma cells, and murine myoblasts were used to determine the kinetics of IGF-II binding to cell surface IGFBP-3, IGFBP-5, and the IGF-1R, respectively. Zn2+, Cd2+, and Au3+, but not La3+, decreased total binding and the affinity for [125I]IGF-II association with IGFBP-3 and IGFBP-5. These effects were a result of lowered rate of ligand association without affecting rate of dissociation. In contrast, Zn2+ enhanced [125I]IGF-II binding to the IGF-1R by enhancing the rate of ligand association and decreasing the rate of dissociation. Our previous work had shown that Zn2+ acts at physiological levels to alter IGF binding. Together with the current work, these findings imply that Zn2+ acts in vivo to prevent secreted IGF-II from binding to IGFBP-3 and IGFBP- 5, thus maintaining IGF-II in an "active state," i.e., readily available for IGF-1R association.
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D032446:Myoblasts / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D013997:Time Factors; D015032:Zinc / Q000494:pharmacology*
D018972:Insulin-Like Growth Factor Binding Protein 3; D018975:Insulin-Like Growth Factor Binding Protein 5; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D015032:Zinc