MOHAN, S*; BAYLINK, D.J.: IGF Binding Proteins (IGFBPs) Are Multifunctional And Act Via IGF-Dependent and IGF-Independent Mechanisms

Traditionally, binding proteins are known to regulate the activity of ligands by prolonging their half-life and IGFBPs are no exception to this. In addition to the function of IGFBPs as simple carrier proteins, IGFBPs in serum function to regulate the endocrine actions of IGFs by regulating the amount of bioavailable IGF, while locally produced IGFBPs act as autocrine/paracrine regulators of IGF action. Furthermore, recent in vitro and in vivo findings that IGFBPs function independently of the IGFs as growth modulators are particularly exciting. Regarding the role of IGFBPs as ligand-independent growth modulators, our recent data that IGFBP-5 stimulates bone formation parameters in osteoblasts lacking functional IGFs provide evidence that IGFBP-5 itself is a growth factor that can act independently of IGFs to regulate bone formation. In terms of the mechanism by which certain IGFBPs mediate their effects in a ligand-independent manner, the binding of IGFBP to its putative receptor on the cell membrane may stimulate the signaling pathway independent of an IGF receptor to mediate the effects of IGFBPs in certain target cell types. IGFBPs could also exert IGF-independent effects by transcriptional activation of genes by IGFBPs transported into the nucleus via their nuclear localization signal. In conclusion, IGFBPs are unusually pleotrophic molecules with functions ranging from the traditional role of prolonging the half-life of the IGFs to functioning as growth factors independent of the IGFs. In this regard, it was unusually surprising to find that the human genome contains only about 35,000 genes. One mechanism to account for complexity with a relatively small number of genes is strikingly illustrated by the multifunctional IGFBP class of proteins.