Regulation and physiological role of insulin-like growth factor binding proteins

The insulin-like growth factors (IGFs) are potent anabolic agents, structurally related to insulin, that can influence growth processes in virtually every system of the body. Unlike insulin, these peptides associate with distinct binding proteins present in serum and other biological fluids as well as in medium conditioned by cultured cells. The IGFs are pleiotropic in activity and near ubiquitous in distribution, making the IGF binding proteins (IGFBPs) integral components of IGF physiology that define and coordinate IGF and insulin action at the level of the target cell. Thus, to fully understand and, ultimately, manipulate IGF-directed growth, it is critical to take into account the IGFBPs. Six distinct IGFBPs have been cloned and characterized, and they are postulated to serve specific, but as yet poorly defined, functional roles. Expression of these multiple IGFBP species is under developmental, hormonal, and nutritional control. In addition, IGFBPs can undergo a variety of posttranslational modifications that can have profound effects on IGFBP structure/function, and, hence, IGF action. The significance of IGFBP glycosylation, phosphorylation, proteolysis, and cell-membrane and extracellular matrix association as components of IGF physiology has only begun to be appreciated. In each case identified so far the modified IGFBP acts dramatically different from native or recombinant IGFBP in solution. In this presentation, I will briefly review the IGF/IGFBP system and use data from in vitro models to illustrate the potential power of posttranslational regulation of IGFBP in cellular response to IGFs.