Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities

The insulin-like growth factor (IGF) binding proteins (IGFBPs) are a family of six homologous proteins with high binding affinity for IGF-I and IGF-II . Information from NMR and mutagenesis studies is advancing knowledge of th e key residues involved in these interactions. IGF binding may be modulated by IGFBP modifications, such as phosphorylation and proteolysis, and by ce ll or matrix association of the IGFBPs. All six IGFBPs have been shown to i nhibit IGF action, but stimulatory effects have also been established for I GFBP-1, -3, and -5. These generally involve a decrease in IGFBP affinity an d may require cell association of the IGFBP, but precise mechanisms are unk nown. The same three IGFBPs have well established effects that are independ ent of type I IGF receptor signaling. IGFBP-1 exerts these effects by signa ling through alpha(5)beta(1)-integrin, whereas IGFBP-3 and -5 may have spec ific cell-surface receptors with serine kinase activity. The regulation of cell sensitivity to inhibitory IGFBP signaling may play a role in the growt h control of malignant cells.