Evidence that Receptor Aggregation may Play a Role in Transmembrane Signaling through the Insulin-Like Growth Factor-I Receptor

Abstract

alpha IR-3 is a mouse monoclonal antibody that binds to an epitope on the human insulin-like growth factor I (IGF-I) receptor and inhibits [125I]IGF-I binding to this receptor on human skin fibroblasts (HSF) and Hep G2 human hepatoblastoma cells. Unlike the natural ligand (IGF-I), neither intact alpha IR-3 nor its monovalent Fab fragment stimulate aminoisobutyric acid (AIB) uptake in HSF, and both competitively antagonize IGF-I's ability to produce this effect. However, when HSF are incubated with alpha IR-3 or its Fab' fragment, subsequent exposure to anti-mouse immunoglobulin G (IgG) produces a potent stimulation of AIB uptake. Anti-Mouse IgG by itself does not effect AIB uptake. alpha IR-3 also antagonizes IGF-I's ability to stimulate glycogen synthesis in Hep G2 cells. As with AIB uptake in HSF, the combination of alpha IR-3 followed by anti-mouse IgG stimulates glycogen synthesis in Hep G2 cells to the same extent as that produced by IGF-I. The triggering of these two biological effects depends on the concentration of both alpha IR-3 and anti-mouse IgG. These results are consistent with the possibility that local aggregation or cross-linking of IGF-I receptors plays an important role in transmembrane signaling by this receptor.