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 (La ³⁺) 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. Zn ²⁺, 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.