Zinc Partitions Insulin-Like Growth Factors (IGFs) from Soluble IGF Binding Protein (IGFBP)-5 to the Cell Surface Receptors of BC₃H-1 Muscle Cells

Zinc (Zn²⁺) is a multifunctional micronutrient. The list of functions for this micronutrient expanded with the recent discovery that Zn ²⁺ retains insulin-like growth factors binding proteins (IGFBPs) on the surface of cultured cells, lowers the affinity of cell-associated IGFBPs, and increases the affinity of the cell surface insulin-like growth factor (IGF)-type 1 receptor (IGF-1R). However, currently there is no information concerning the effect of Zn²⁺ on soluble IGFBPS. In the current study, the soluble IGFBP-5 secreted by BC₃H-1 cells is shown to bind approximately 50% more [¹²⁵I]-IGF-II than [¹²⁵I]-IGF-I at pH 7.4. Zn²⁺ is shown to depress the binding of both IGF-I and IGF-II to soluble secreted IGFBP-5; [¹²⁵I]-IGF-I binding is affected more so than [¹²⁵I]-IGF-II binding. Zn²⁺ acts by lowering the affinity (K_a) of IGFBP-5 for the IGFs. Scatchard plots are non-linear indicating the presence of high and low affinity binding sites; Zn²⁺ affects only binding to the high affinity site. In contrast, Zn²⁺ increases the affinity by which either [¹²⁵I]-IGF-I or [¹²⁵I]-R³-IGF-I binds to the IGF-1R, but depresses [¹²⁵I]-IGF-II binding to the IGF-type 2 receptor (IGF-2R) on BC ₃H-1 cells. By depressing the association of the IGFs with soluble IGFBPs, Zn²⁺ is shown to repartition either [¹²⁵I]-IGF-I or [¹²⁵I]-IGF-II from soluble IGFBP-5 onto cell surface IGF receptors. Zn²⁺ was active at physiological doses depressing IGF binding to IGFBP-5 and the IGF-2R at 15-20 μM. Hence, a novel mechanism is further characterized by which the trace micronutrient Zn²⁺ could regulate IGF activity.